Current Issues in Molecular Biology

26 pages, 1268 KB

Open AccessReview

Epigenetic Mechanisms in Fabry Disease: A Thematic Analysis Linking Differential Methylation Profiles and Genetic Modifiers to Disease Phenotype

by Jatinder Singh, Paramala Santosh and Uma Ramaswami

Curr. Issues Mol. Biol. 2025, 47(10), 855; https://doi.org/10.3390/cimb47100855 (registering DOI) - 16 Oct 2025

Abstract

Background/Objectives: Fabry disease is an X-linked lysosomal storage disorder. It is characterised by impaired metabolism of glycosphingolipids whose accumulation causes irreversible organ damage and life-threatening complications. Genotype–phenotype correlations have a limited scope in Fabry disease as the disorder presents with wide-ranging [...] Read more.

Background/Objectives: Fabry disease is an X-linked lysosomal storage disorder. It is characterised by impaired metabolism of glycosphingolipids whose accumulation causes irreversible organ damage and life-threatening complications. Genotype–phenotype correlations have a limited scope in Fabry disease as the disorder presents with wide-ranging clinical variability. In other X-linked disorders, epigenetic profiling has identified methylation patterns and disease modifiers that may explain clinical heterogeneity. In this narrative review and thematic analysis, the role of DNA methylation and epigenetics on the clinical phenotype in Fabry disease was investigated. Methods: Embase, PubMed, and PsycINFO were searched to identify literature on DNA methylation and epigenetics in Fabry disease. Based on the eligibility criteria, 20 articles were identified, and a thematic analysis was performed on the extracted data to identify themes. Results: Three themes emerged: (I) genetic modifiers, (II) methylation profiling, and (III) insights into X chromosome inactivation (XCI). The evidence synthesis revealed that telomere length, especially in early disease stages, bidirectional promoter (BDP) methylation by sphingolipids, epigenetic reader proteins, mitochondrial DNA haplogroups, and DNA methylation of the promoter region of the calcitonin receptor gene are potential genetic modifiers in Fabry disease. Methylation patterns also reveal episignatures in Fabry disease evolution and genes implicated in the maintenance of basement membranes. Studies on XCI further emphasise disease heterogeneity and draw attention to methodological issues in the assessment of XCI. Conclusions: This thematic review shows that DNA methylation and genetic modifiers are key factors modifying clinical variability in Fabry disease. More broadly, it underscores a crucial role for epigenetic processes in driving disease onset, progression, and severity in X-linked disorders. Full article

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

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16 pages, 587 KB

Open AccessReview

Pathophysiological Links Between Stroke and Prediabetes: A Systematic Review

by Yerushka Naicker and Andile Khathi

Curr. Issues Mol. Biol. 2025, 47(10), 854; https://doi.org/10.3390/cimb47100854 (registering DOI) - 16 Oct 2025

Abstract

Prediabetes is an intermediate stage between normoglycaemia and type 2 diabetes mellitus (T2DM), affecting over 425 million people globally and contributing to vascular damage and increased stroke risk. Despite the severity of both conditions, their association remains underexplored. This review examines the literature [...] Read more.

Prediabetes is an intermediate stage between normoglycaemia and type 2 diabetes mellitus (T2DM), affecting over 425 million people globally and contributing to vascular damage and increased stroke risk. Despite the severity of both conditions, their association remains underexplored. This review examines the literature on stroke-related biomarkers in normoglycaemia, prediabetes and T2DM to identify potential links between prediabetes and stroke. This systematic review followed PRISMA-2020 guidelines. PubMed, Google Scholar, Scopus, Web of Science and Science Direct were searched for studies (2003–2023) on stroke biomarkers in prediabetes. Eligible studies were original human research in English, with defined diagnostic criteria (ADA or WHO) for glycaemic status and reported biomarker associations or stroke risk. Studies with major comorbidities were excluded. Data were extracted and bias was assessed using the Newcastle–Ottawa Scale. Meta-analysis was not performed due to limited studies per biomarker. Eight studies (n = 3003) were included. NSE was examined in three studies, all reporting significant elevations in hyperglycaemic individuals. Interleukin-6 (IL-6) was assessed in two studies; one showed a significant increase in diabetes, while the other found a non-significant upward trend. D-dimer and GFAP were each reported in separate single studies, both showing significant elevations in hyperglycaemic individuals with stroke or neurocognitive impairment. S100B was investigated in two studies, with divergent findings: one showed a positive association with glycaemic status, while the other reported lower levels in hyperglycaemia. Findings indicate biomarker alterations in T2DM, suggesting that early changes may occur in prediabetes. Our review suggests that individuals with prediabetes may show alterations in inflammatory (IL-6), coagulation (D-dimer), and neurovascular (S100B, GFAP, NSE) markers, though some findings are inconsistent, reflecting early pathophysiological changes that may increase stroke risk. Further well-designed studies are needed to clarify these associations and establish biomarker-based tools for earlier stroke risk detection and prevention in individuals with prediabetes. Full article

(This article belongs to the Special Issue Cerebrovascular Diseases: From Pathogenesis to Treatment)

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31 pages, 1423 KB

Open AccessReview

The Pathogenesis of Chronic Kidney Disease (CKD) and the Preventive and Therapeutic Effects of Natural Products

by Yuxin Dong and Yanqing Tong

Curr. Issues Mol. Biol. 2025, 47(10), 853; https://doi.org/10.3390/cimb47100853 (registering DOI) - 16 Oct 2025

Abstract

Chronickidney disease (CKD) poses a major global public health challenge, driven by a complex pathogenesis involving multiple interconnected processes—including metabolic disturbances, chronic inflammation, oxidative stress, endoplasmic reticulum stress, and ferroptosis—which collectively contribute to progressive and often irreversible loss of renal function. Although current [...] Read more.

Chronickidney disease (CKD) poses a major global public health challenge, driven by a complex pathogenesis involving multiple interconnected processes—including metabolic disturbances, chronic inflammation, oxidative stress, endoplasmic reticulum stress, and ferroptosis—which collectively contribute to progressive and often irreversible loss of renal function. Although current standard therapies can ameliorate CKD progression, a substantial number of patients still advance to end-stage renal disease, highlighting the urgent need for innovative treatment strategies. Natural products have shown great promise in the prevention and management of CKD, largely attributable to their multi-target and multi-pathway synergistic effects. This review systematically outlines the core pathogenic mechanisms underlying CKD and elucidates the molecular mechanisms through which bioactive natural compounds exert renoprotective effects. Despite robust preclinical evidence, the clinical translation of these compounds remains hindered by limitations such as poor bioavailability and a lack of large-scale clinical trials. Moving forward, research should prioritize clinical translation of these compounds, aiming to provide novel therapeutic perspectives for CKD management. Full article

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

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13 pages, 1826 KB

Open AccessArticle

IL-6 Inhibition Partially Ameliorates Maternal Immune Activation-Induced Autism-Like Behavioral Abnormalities in Mice

by Xiaoyun Zhang, Weili Luo, Kaiyue He, Yuping Li, Yan Chen, Zhipeng Xu and Zi-Kai Zhou

Curr. Issues Mol. Biol. 2025, 47(10), 852; https://doi.org/10.3390/cimb47100852 (registering DOI) - 16 Oct 2025

Abstract

Prenatal maternal immune activation (MIA) has been implicated in autism spectrum disorder (ASD) pathogenesis, with interleukin-6 (IL-6) identified as a key inflammatory mediator. We investigated the therapeutic potential of IL-6 inhibition in an MIA mouse model induced by Toxoplasma gondii soluble tachyzoite antigen [...] Read more.

Prenatal maternal immune activation (MIA) has been implicated in autism spectrum disorder (ASD) pathogenesis, with interleukin-6 (IL-6) identified as a key inflammatory mediator. We investigated the therapeutic potential of IL-6 inhibition in an MIA mouse model induced by Toxoplasma gondii soluble tachyzoite antigen (STAg). Adult MIA offspring received systemic administration of the IL-6-neutralizing antibody (MP5-20F3) or isotype control, followed by behavioral assessments one week later. Open field and elevated plus maze tests revealed heightened anxiety-like behaviors in the STAg offspring, which were largely reversed by IL-6 inhibition. Reciprocal social interaction tests showed diminished sociability in the STAg offspring, which was partially restored by IL-6 inhibition. However, core ASD-like features, including impaired social preference and recognition in the three-chamber test, as well as increased repetitive behaviors, remained resistant to IL-6 inhibition. These findings demonstrate that STAg-induced MIA elicits anxiety-like and ASD-like phenotypes in adult offspring, with IL-6 playing an important role in anxiety-like behaviors and social interaction deficits. Systemic IL-6 inhibition partially ameliorates behavioral abnormalities. This study suggests that IL-6-targeted therapies may address a subset of ASD-related symptoms, and comprehensive strategies are needed for broader efficacy. Full article

(This article belongs to the Section Molecular Medicine)

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58 pages, 3486 KB

Open AccessReview

Pro-Angiogenic Bioactive Molecules in Vascular Morphogenesis: Integrating Endothelial Cell Dynamics

by Claudiu N. Lungu, Gabriela Gurau and Mihaela C. Mehedinti

Curr. Issues Mol. Biol. 2025, 47(10), 851; https://doi.org/10.3390/cimb47100851 - 15 Oct 2025

Abstract

During embryonic development, angiogenesis and arteriogenesis are responsible for vast growth and remodeling. These processes have distinct mechanisms, like budding, cord hollowing, cell hollowing, cell wrapping, and intussusception. This review discusses the diversity of morphogenetic mechanisms contributing to vessel assembly and angiogenic sprouting [...] Read more.

During embryonic development, angiogenesis and arteriogenesis are responsible for vast growth and remodeling. These processes have distinct mechanisms, like budding, cord hollowing, cell hollowing, cell wrapping, and intussusception. This review discusses the diversity of morphogenetic mechanisms contributing to vessel assembly and angiogenic sprouting in blood vessels and how molecular pathways regulate some complex cell behaviors concerning the VEGFR pathway. Also, a particular part is dedicated to the HIF 1α gene. The key components of the VEGFR pathway are VEGF receptors VEGFR1, VEGFR2, and VEGFR3. VEGFR2 plays a central role in vascular morphogenesis. VEGF is the primary ligand involved in angiogenesis and arteriogenesis. Various types of VEGF are being studied in terms of their therapeutic use. The ultimate goal of the vascular morphogenesis study is to enable the development of organized vascular tissue that presumably might be used to replace the diseased one. Cellular chirality—the intrinsic “handedness” of cells in movement, structure, and organization—plays a crucial role in angiogenesis, the process by which new blood vessels develop from old ones. This chiral activity is essential for the directed and patterned organization of endothelial cells during vascular formation and remodeling. In angiogenesis, cellular chirality directs endothelial cells to adopt specific orientations and migratory patterns, which are crucial for the formation of functionally organized blood vessels that provide tissues with the necessary nutrients and oxygen. Cellular chirality in this environment is affected by multiple mechanisms, including VEGF/VEGFR signaling, mechanical pressures, interactions with the extracellular matrix (ECM), and cytoskeletal movements. Lately, researchers have focused on the molecular control of blood vessel morphogenesis, the study of signaling circuitry implied in vascular morphogenesis, the emerging mechanism of vascular stabilization, and helical vasculogenesis driven by cell chirality. Full article

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

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12 pages, 629 KB

Open AccessReview

Significant Association Between Glucokinase Regulatory Protein Variants and Genetic and Metabolic Diseases

by Ke Xu, Peng Chen, Yujing Su, Yanghui Chen, Xiuli Song, Bo Yu and Hong Wang

Curr. Issues Mol. Biol. 2025, 47(10), 850; https://doi.org/10.3390/cimb47100850 - 15 Oct 2025

Abstract

As next-generation sequencing develops, there are significant associations between glucokinase regulatory protein (GCKR) variants and many diseases, especially metabolic diseases. However, there is a lack of solid descriptions and summaries of how GCKR variants lead to diseases and a lack of successful translations [...] Read more.

As next-generation sequencing develops, there are significant associations between glucokinase regulatory protein (GCKR) variants and many diseases, especially metabolic diseases. However, there is a lack of solid descriptions and summaries of how GCKR variants lead to diseases and a lack of successful translations of drugs targeting this molecular variant. We searched literature datasets, mainly including PubMed and Web of Science, with “GCKR” or “GKRP”, “Variants”, “Hypertriglyceridemia”, “NAFLD”, and “Metabolic diseases” as the search terms. Our review firstly introduces the biological function of the GCKR gene and its encoding protein GKRP and then describes the GCKR variants in different diseases, such as hypertriglyceridemia and NAFLD, revealing that GCKR/GKPR is strongly associated with metabolic diseases. GKPR might be a potential target for T2D and other metabolic diseases. One drug for interfering with the GCK-GKRP complex has been developed and has shown its effectiveness in preclinical studies, with some possible side effects. More and more different-structured drugs should be developed to improve side effects, and more clinical trials should be carried out to determine the best intervention window and timing points to improve prognosis. Taken together, these insights show that GCKR/GKRP is significantly associated with many metabolic diseases via its complex metabolism system and is a potential target in many metabolic diseases. Full article

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

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15 pages, 1786 KB

Open AccessArticle

Identification and Association of CYP2R1, CYP27B1, and GC Gene Polymorphisms with Vitamin D Deficiency in Apparently Healthy Population and in Silico Analysis of the Binding Pocket of Vitamin D3

by Saima Manzoor, Asifa Majeed, Palvasha Waheed and Amir Rashid

Curr. Issues Mol. Biol. 2025, 47(10), 849; https://doi.org/10.3390/cimb47100849 - 15 Oct 2025

Abstract

Vitamin D deficiency is highly prevalent in Pakistan, but there is limited data on its genetic aspects. This case–control pilot study aimed to determine the association of rs782153744, rs200183599, rs118204011, and rs28934604 with vitamin D deficiency along rs7041 which has been studied in [...] Read more.

Vitamin D deficiency is highly prevalent in Pakistan, but there is limited data on its genetic aspects. This case–control pilot study aimed to determine the association of rs782153744, rs200183599, rs118204011, and rs28934604 with vitamin D deficiency along rs7041 which has been studied in our population. The DNA of a total of 600 subjects (300 cases and 300 controls) was extracted and genotyped by tetra ARMS PCR, followed by Sanger DNA sequencing of exon 4 of the CYP2R1 and CYP27B1 genes and exon 8 of the GC gene. SNP Stat was employed to analyze the data, while logistic regression was used to calculate the p-values and odds ratios (ORs). The R package version R studio (2025.05.1) Build 513 was used to statistically analyze rs782153744. In silico modeling of wild and mutant CYP2R1 and GC proteins was performed in Swiss-Model, Swiss-Dock, Discovery Studio, and PyMol using 3c6g and IJ78 as templates to perform binding pocket analysis of vitamin D3. The rs782153744 showed a protective association in the additive (OR: 0.15, 95% CI: 0.08–0.27, p-value < 0.001), recessive (OR: 0.19, 95% CI: 0.10–0.33, p-value < 0.001), and dominant (OR: 0.19, CI = 0.10–0.33, p-value < 0.001) models, while GC rs7041 (T > A, T > G) displayed a p-value < 0.0001 across all genetic models. Sanger sequencing yielded insignificant results, and the SNPs rs200183599, rs118204011, and rs28934604 had no significant association with vitamin D deficiency. The molecular pocket analysis of wild and mutant CYP2R1 proteins carrying rs782153744 polymorphisms revealed no changes. GC proteins carrying the rs7041 polymorphism revealed a shift in their 3D and 2D configuration, as well as a change in the amino acid residue of the binding pocket of VD3. The risk-associated rs7041 and protective rs782153744 variants back genetic screening for vitamin D deficiency risk stratification, allowing targeted supplementation in predisposed subjects and assisting in formulating a genotype-specific therapeutic approach. Full article

(This article belongs to the Collection Bioinformatics Approaches to Biomedicine)

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25 pages, 6158 KB

Open AccessArticle

Hydrogen Sulfide and Nitric Oxide Improve Renal Function and α-Adrenergic Responsiveness in Rats with Left Ventricular Hypertrophy

by Tabinda Fatima, Latifah Al Shammari, Mohamed Ibrahim Lazhari, Waad Alrohily, Tan Yong Chia, Nimer Alsabeelah, Eid Fahad Alanazi, Khalid Abdulrahman Almutairi, Sultan Mujahid Alhabradi, Naif Saleh Alharbi and Ashfaq Ahmad

Curr. Issues Mol. Biol. 2025, 47(10), 848; https://doi.org/10.3390/cimb47100848 - 15 Oct 2025

Abstract

In left ventricular hypertrophy (LVH), the combined external administration of hydrogen sulfide (H₂S) and nitric oxide (NO) has been shown to reverse LVH by activating the endothelial nitric oxide synthase pathway (eNOS/NO), independent of the cystathionine γ-lyase (CSE/H₂S) pathway. [...] Read more.

In left ventricular hypertrophy (LVH), the combined external administration of hydrogen sulfide (H₂S) and nitric oxide (NO) has been shown to reverse LVH by activating the endothelial nitric oxide synthase pathway (eNOS/NO), independent of the cystathionine γ-lyase (CSE/H₂S) pathway. Individually, both H₂S and NO have also been reported to significantly improve RCBP, restore renal excretory performance, and enhance α-adrenergic receptor responsiveness in rats. The induction of LVH was performed over a period of two weeks using drinking water with caffeine and isoprenaline. Five weeks later, the rats were fed with L-arginine (1.25 g/L) as a nitrogen oxide donor. Vascular reactions to methoxamine, phenylephrine, and noradrenaline were assessed in presences and absence of 5-methylurapidil (5-MeU), BMY7378, and chloroethylclonidine (CeC) and α1-adrenoceptor antagonists. In both the Control WKY and LVH-WKY groups, combined H₂S+NO therapy significantly (p < 0.05) upregulated the renal mRNA of CSE and eNOS when compared with untreated LVH rats. The treatment also markedly increased RCBP in LVH-H₂S+NO rats relative to LVH controls. Furthermore, H₂S+NO administration enhanced the activity of α_1A, α_1B, and α_1D adrenergic receptors in mediating renal vasoconstriction. Even under receptor blockade with high doses (HDs) of 5-MeU, CeC, and BMY 7378, renal vasoconstriction responses to adrenergic agonists like NA, PE, and ME in the LVH-H₂S+NO group remained comparable to those observed in the counterpart Control-H₂S+NO group. The findings of current study suggest that simultaneous exogenous administration of H₂S and NO donors improve renal cortical blood flow, support renal function, and augment α_1A, α_1B, and α_1D adrenergic receptor responsiveness to adrenergic agonists like NA, PE, and ME in LVH rats. This effect appears to rely primarily on the eNOS/NO pathway, with partial contribution from the CSE/H₂S pathway. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pharmacological Underlying Cardiorenal Diseases)

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15 pages, 751 KB

Open AccessReview

Gut Microbiota Changes in Metabolic Dysfunction-Associated Steatohepatitis and Inflammatory Bowel Disease: Common Pathogenic Features

by Giuseppe Guido Maria Scarlata, Domenico Morano, Abdulrahman Ismaiel, Rocco Spagnuolo, Francesco Luzza, Dan Lucian Dumitrascu and Ludovico Abenavoli

Curr. Issues Mol. Biol. 2025, 47(10), 847; https://doi.org/10.3390/cimb47100847 - 15 Oct 2025

Abstract

Gut microbiota changes have emerged as central players in the pathogenesis of both metabolic dysfunction-associated steatohepatitis (MASH) and inflammatory bowel disease (IBD). Although these diseases affect distinct primary organs, they share converging mechanisms driven by dysbiosis, including loss of beneficial short-chain fatty acid-producing taxa [...] Read more.

Gut microbiota changes have emerged as central players in the pathogenesis of both metabolic dysfunction-associated steatohepatitis (MASH) and inflammatory bowel disease (IBD). Although these diseases affect distinct primary organs, they share converging mechanisms driven by dysbiosis, including loss of beneficial short-chain fatty acid-producing taxa such as Faecalibacterium prausnitzii and Roseburia, enrichment of pro-inflammatory Enterobacteriaceae, and disruption of bile acid and tryptophan metabolism. These shifts compromise epithelial barrier integrity, promote the translocation of microbial products such as lipopolysaccharide, and trigger toll-like receptor 4-mediated activation of inflammatory cascades dominated by tumor necrosis factor-alpha, interleukin-6, and transforming growth factor-beta. In MASH, this dysbiotic environment fuels hepatic inflammation, insulin resistance, and fibrogenesis, while in IBD it sustains chronic mucosal immune activation. Shared features include impaired butyrate availability, altered bile acid pools affecting farnesoid X receptor and Takeda G protein-coupled Receptor 5 signaling, and defective aryl hydrocarbon receptor activation, all of which link microbial dysfunction to host metabolic and immune dysregulation. Understanding these overlapping pathways provides a deeper understanding of the role of the gut-liver and gut-immune axes as unifying frameworks in disease progression. This narrative review synthesizes current evidence on gut microbiota in MASH and IBD, underscoring the need for longitudinal, multi-omics studies and microbiome-targeted strategies to guide personalized therapeutic approaches. Full article

(This article belongs to the Special Issue Intestinal Inflammation: From Molecular Mechanisms to Therapeutic Strategies)

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14 pages, 2237 KB

Open AccessArticle

Empagliflozin Attenuates Liver Inflammation and Fibrosis in NAFLD: Evidence from Mendelian Randomization and Mouse Experiments

by Chao Fu, Lijiao Deng, Xiaochan Zhu, Bin Wang, Bin Hu, Huan Xue, Qingxuan Zeng and Yi Zhang

Curr. Issues Mol. Biol. 2025, 47(10), 846; https://doi.org/10.3390/cimb47100846 - 15 Oct 2025

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disorder and a major global health challenge, yet effective pharmacological therapies are lacking. Empagliflozin, a sodium–glucose cotransporter-2 (SGLT2) inhibitor, has shown systemic metabolic and anti-inflammatory benefits, but its liver-specific molecular mechanisms remain incompletely [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disorder and a major global health challenge, yet effective pharmacological therapies are lacking. Empagliflozin, a sodium–glucose cotransporter-2 (SGLT2) inhibitor, has shown systemic metabolic and anti-inflammatory benefits, but its liver-specific molecular mechanisms remain incompletely understood. In this study, we evaluated the therapeutic effects of empagliflozin in a diet-induced mouse model of NAFLD, supported by Mendelian randomization analysis. Histological examination, serum biochemistry, and hepatic triglyceride quantification demonstrated that empagliflozin markedly attenuated hepatic steatosis and improved liver injury indices. At the molecular level, empagliflozin suppressed NF-κB-mediated inflammatory signaling and significantly downregulated fibrotic markers including α-SMA and COL1A1, while modulating TIMP-1 and MMP-9 expression. Collectively, these findings reveal that empagliflozin ameliorates NAFLD by inhibiting inflammatory and fibrotic molecular pathways, highlighting its potential as a mechanism-based therapeutic option for NAFLD. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying Fatty Liver Disease: From Pathogenesis to Treatment, 2nd Edition)

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16 pages, 4440 KB

Open AccessArticle

Action of Carnosic Acid Against Melanoma: A Strategy for Selective Radiosensitization with Protection of Non-Tumoral Cells

by Amparo Olivares, Isabel de la Fuente, Daniel Gyingiri Achel, Ana María Mercado, José Antonio Garcia-Gamuz, María del Rosario Tudela and Miguel Alcaraz

Curr. Issues Mol. Biol. 2025, 47(10), 845; https://doi.org/10.3390/cimb47100845 - 14 Oct 2025

Abstract

Carnosic acid (CA) is a phenolic diterpene with high antioxidant activity that supports its radioprotective capacity. This study aims to determine whether the radiosensitizing effect of CA established in B16F10 melanoma cells also occurs in other melanin-producing cells. Cell survival analysis, apoptosis, intracellular [...] Read more.

Carnosic acid (CA) is a phenolic diterpene with high antioxidant activity that supports its radioprotective capacity. This study aims to determine whether the radiosensitizing effect of CA established in B16F10 melanoma cells also occurs in other melanin-producing cells. Cell survival analysis, apoptosis, intracellular glutathione levels, and cell cycle progression were evaluated by comparing radiosensitive cells (PNT2) with radioresistant melanin-producing cells (MELAN A, SK-MEL-1, and B16F10). In PNT2 cells, CA exhibited radioprotective capacity, with 100% cell survival after exposure to 20 Gy of X-rays (p < 0.001), decreasing apoptosis (p < 0.001) and increasing the GSH/GSSG ratio (p < 0.01), without significant modification in cell cycle progression. However, CA administration to irradiated cells failed to exert radioprotection in MELAN A and SK-MEL-1 cells, and even doubled cell death in B16F10 cells (p < 0.001). Specifically, CA did not alter apoptosis or prevent the decrease in GSH/GSSG ratio in MELAN A and SK-MEL-1 cells, while it intensified radiation-induced cell cycle disruptions in all melanin-producing cells. All of these led to a loss of radioprotective capacity in the melanin-producing cells (MELAN A and SK-MEL-1) and even induced a radiosensitizing effect in B16F10 cells. Understanding the mechanisms of action of substances such as CA could promote new applications that protect healthy cells and exclusively damage neoplastic cells when both are present within the same irradiated volume in cancer patients requiring radiotherapy. Full article

(This article belongs to the Special Issue Molecular Insights into Radiation Oncology)

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19 pages, 914 KB

Open AccessReview

Epigenetic Factors in Pathogenesis of Retinoblastoma: DNA Methylation and Histone Acetylation

by Georgios Kiosis, Kanellos Skourtsidis, Despoina Ioannou, Vasilis-Spyridon Tseriotis, Konstantinos Stergiou, Fani Akritidou, Theodora Papamitsou, Maria Kourti and Sofia Karachrysafi

Curr. Issues Mol. Biol. 2025, 47(10), 844; https://doi.org/10.3390/cimb47100844 - 14 Oct 2025

Abstract

(Background) Retinoblastoma is the most common intraocular malignancy in childhood, primarily caused by mutations in the RB1 gene. However, increasing evidence highlights the significant role of epigenetic mechanisms, particularly DNA methylation and histone acetylation, in tumor initiation and progression. This review aims to [...] Read more.

(Background) Retinoblastoma is the most common intraocular malignancy in childhood, primarily caused by mutations in the RB1 gene. However, increasing evidence highlights the significant role of epigenetic mechanisms, particularly DNA methylation and histone acetylation, in tumor initiation and progression. This review aims to summarize and critically assess recent findings on how DNA methylation and histone acetylation contribute to the pathogenesis of retinoblastoma, and to explore their potential role as diagnostic biomarkers and therapeutic targets. (Methods) We searched the databases PubMed, Scopus, and ScienceDirect following PRISMA guidelines. Eligible studies were English-language, open-access articles published within the last ten years, including cohort studies, research articles, and case reports. After rigorous screening, 18 studies were included in the final analysis. (Results) Aberrant DNA methylation was found to inactivate tumor suppressor genes (RB1, RASSF1A, p16INK4A, MGMT) and promote oncogenesis through hypermethylation of regulatory elements. Similarly, histone acetylation’s dysregulation contributed to chromatin remodeling and overexpression of oncogenic factors such as SYK, GALNT8, and lincRNA-ROR. Elevated histone deacetylase (HDAC) activity was also linked to tumor cell proliferation, metastasis, and treatment resistance. Epigenetic inhibitors targeting these pathways demonstrated promising therapeutic potential. (Conclusions) DNA methylation and histone acetylation play a crucial role in the epigenetic regulation of genes implicated in retinoblastoma. Their dysregulation promotes tumorigenesis, and targeting these mechanisms represents a promising avenue for novel diagnostic and therapeutic strategies in pediatric oncology. Full article

(This article belongs to the Section Molecular Medicine)

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28 pages, 12490 KB

Open AccessArticle

Joint Transcriptomic Analysis of the Effect of Iron Concentration on Piglet Liver and Functional Validation of Iron Regulatory Genes

by Haiming Qian, Ping Wang, Tengchuan Li, Chunyong Zhang, Jintao Li, Qingliang Wang, Haiyang Ren, Fanyu Jin, Jie Huang, Jun Yao, Hongbin Pan, Rongfu Guo and Qingcong An

Curr. Issues Mol. Biol. 2025, 47(10), 843; https://doi.org/10.3390/cimb47100843 - 14 Oct 2025

Abstract

Iron plays a key role in oxygen transport, hematopoiesis, and hypoxia adaptation. This study aimed to explore the dynamic response mechanism of the iron regulatory network and key genes in Duroc piglets. Eighteen weaned piglets were randomly divided into three dietary intervention groups: [...] Read more.

Iron plays a key role in oxygen transport, hematopoiesis, and hypoxia adaptation. This study aimed to explore the dynamic response mechanism of the iron regulatory network and key genes in Duroc piglets. Eighteen weaned piglets were randomly divided into three dietary intervention groups: low iron (0 mg/kg), conventional (100 mg/kg), and high iron (200 mg/kg). Transcriptomics technology was used to screen key liver iron regulatory genes under the influence of different dietary iron concentrations, and the expression of related genes was verified using primary pig liver cells. Fasting serum iron metabolism parameters were detected and iron content in organs was quantified. The results show, enrichment analysis highlighted immune–metabolic signaling, including NF-κB, PI3K-Akt, and TGF-β, and a total of 14 candidate genes (such as FGF21, SAA2/3, FNDC1, ETNPPL, TFR1) were identified. The study observed that these genes showed obvious dosage differentiation and nonlinear patterns. However, findings reflect mRNA-level changes and GO/KEGG over-representation, protein-level validation is planned in follow-up studies. Through the integration of in vitro and in vivo data, this study discovered new liver genes that may be related to pig iron homeostasis function, providing a theoretical basis for analyzing the regulatory mechanism of piglet iron response. Full article

(This article belongs to the Collection Feature Papers in Current Issues in Molecular Biology)

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29 pages, 1974 KB

Open AccessReview

Immunomodulatory Effects of Ganoderma lucidum Bioactive Compounds on Gut–Brain and Gut–Liver Axis Disorders

by Liting Zhao, Zijun Geng, Ying Wang, Jiawei Wen and Da Liu

Curr. Issues Mol. Biol. 2025, 47(10), 842; https://doi.org/10.3390/cimb47100842 - 14 Oct 2025

Abstract

Ganoderma lucidum (Lingzhi), a traditional medicinal mushroom, is renowned for its immunomodulatory, anti-inflammatory, and antioxidant properties, primarily attributed to its bioactive components such as polysaccharides and triterpenoids. This review focuses on the mechanisms by which Ganoderma lucidum modulates immune responses, particularly in the [...] Read more.

Ganoderma lucidum (Lingzhi), a traditional medicinal mushroom, is renowned for its immunomodulatory, anti-inflammatory, and antioxidant properties, primarily attributed to its bioactive components such as polysaccharides and triterpenoids. This review focuses on the mechanisms by which Ganoderma lucidum modulates immune responses, particularly in the context of gut–liver–brain axis disorders. Polysaccharides enhance immune function by activating macrophages, natural killer cells, and T cells, thereby promoting phagocytosis and cytokine production. Triterpenoids contribute through anti-inflammatory and antioxidant activities, inhibiting inflammatory mediators and protecting tissues from damage. Ganoderma lucidum also influences immune regulation via key signaling pathways, including NF-κB and MAPK, and supports immune tolerance, potentially reducing the risk of autoimmune diseases. Additionally, it modulates gut microbiota, which further impacts systemic immunity. Importantly, polysaccharides and triterpenoids demonstrate promising clinical application prospects in metabolic diseases, inflammatory conditions, neurodegenerative disorders, and cancer immunotherapy, attributed to their multi-target immunomodulatory activities and prebiotic properties. Despite promising applications in treating metabolic, inflammatory, and neurodegenerative diseases, further research is needed to fully elucidate the molecular mechanisms and potential of Ganoderma lucidum in precision medicine. This comprehensive analysis underscores the value of Ganoderma lucidum as a multifaceted immunomodulatory agent. Full article

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

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33 pages, 2180 KB

Open AccessReview

Mechanistic Insight into Phenolic Compounds in Mitigating Diabetic Complications Induced by Advanced Glycation End Products

by Wajid Zaman and Adnan Amin

Curr. Issues Mol. Biol. 2025, 47(10), 841; https://doi.org/10.3390/cimb47100841 - 14 Oct 2025

Abstract

Diabetes mellitus is a chronic metabolic disorder that facilitates the formation of advanced glycation end products (AGEs), which contribute to oxidative stress, inflammation, and vascular damage, causing complications including nephropathy, neuropathy, and atherosclerosis. AGEs are primarily synthesized through the Maillard reaction, alongside various [...] Read more.

Diabetes mellitus is a chronic metabolic disorder that facilitates the formation of advanced glycation end products (AGEs), which contribute to oxidative stress, inflammation, and vascular damage, causing complications including nephropathy, neuropathy, and atherosclerosis. AGEs are primarily synthesized through the Maillard reaction, alongside various signaling pathways. Activation of the receptor for AGE (RAGE) triggers inflammatory signaling pathway cascades, exacerbating tissue damage. Phenolic compounds found in plant-based foods, such as quercetin and resveratrol, have shown promise in counteracting AGE-related complications through their antioxidant and anti-inflammatory effects that inhibit AGE formation, reduce oxidative stress, and modulate RAGE signaling, while also enhancing insulin sensitivity and improving glucose homeostasis. Indeed, quercetin can help prevent AGE accumulation and reduce diabetic nephropathy, while resveratrol activates the SIRT1 pathway, improving insulin sensitivity. This review examines the mechanisms through which phenolic compounds mitigate AGE-induced diabetic complications, using computational, in vitro, preclinical, and clinical evidence. This review also explores the synergistic effects of these compounds with conventional antidiabetic drugs, addresses bioavailability challenges, and suggests future research directions. Overall, this review offers a comprehensive understanding of the role of phenolic compounds in managing diabetes, underscoring their potential as complementary agents in diabetes therapy and developing more effective natural treatments. Full article

(This article belongs to the Special Issue Natural Products as Potential Sources of Antidiabetic Compounds, 2nd Edition)

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16 pages, 6203 KB

Open AccessArticle

Microcirculation-Promoting Effect of Escin on Cutaneous Tissue via Gsk3β Down-Regulation

by Jaeyoon Kim, Jang Ho Joo, Heena Rim, Sung Hyun Kim, Jae young Shin, Seung-Hyun Jun and Nae-Gyu Kang

Curr. Issues Mol. Biol. 2025, 47(10), 840; https://doi.org/10.3390/cimb47100840 - 14 Oct 2025

Viewed by 92

Abstract

Microcirculation in cutaneous tissue is essential to balance oxygen delivery and maintain the health of the skin. Senescence contributes to microcirculatory dysfunction through mechanisms involving chronic inflammation, structural remodeling of microvessels, and disturbances in hemodynamics. In this study we investigated the promoting effect [...] Read more.

Microcirculation in cutaneous tissue is essential to balance oxygen delivery and maintain the health of the skin. Senescence contributes to microcirculatory dysfunction through mechanisms involving chronic inflammation, structural remodeling of microvessels, and disturbances in hemodynamics. In this study we investigated the promoting effect of escin on blood flow through topical application. To elucidate the molecular mechanisms of escin, kinase phosphorylation changes in human umbilical vein endothelial cells (HUVECs) were examined. Escin stimulates the Wnt/β-Catenin and c-Jun N-terminal kinase (JNK) signaling pathway in cultured HUVECs. To clarify the target of escin in the Wnt/β-Catenin signaling pathway, gene expression in response to escin treatment was evaluated, and escin-mediated signaling activation was accompanied by glycogen synthase kinase-3 beta (Gsk3β), according to inhibitor studies performed with IWR1 (tankyrase inhibitor). In addition, the expression level of the Gsk3β were down-regulated by escin treatment in cultured HUEVCs. Escin also enhanced vascular remodeling, and, when applied topically, led to a sustained increase in cutaneous blood flow. Escin-mediated Wnt signaling activation could enhance blood vessel networks via Gsk3β down-regulation. In conclusion, our data demonstrate that escin promotes angiogenic behavior and enhances adenosine-induced perfusion in humans, thereby supporting its potential role in modulating cutaneous microcirculation. Full article

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

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12 pages, 1285 KB

Open AccessArticle

Endoplasmic Reticulum Stress Drives VEGF Gene Expression in Monocytic Cells

by Fatemah Bahman, Taha Nadeem, Abdulrahman Alayyaf, Ashraf Al Madhoun, Fahd Al-Mulla, Sardar Sindhu and Rasheed Ahmad

Curr. Issues Mol. Biol. 2025, 47(10), 839; https://doi.org/10.3390/cimb47100839 - 13 Oct 2025

Viewed by 195

Abstract

Obesity is characterized by chronic low-grade inflammation and oxidative stress, conditions that disrupt metabolic homeostasis and promote vascular endothelial growth factor (VEGF) expression. While hypoxia and fatty acid-induced oxidative stress are known regulators of VEGF, the contribution of endoplasmic reticulum (ER) stress in [...] Read more.

Obesity is characterized by chronic low-grade inflammation and oxidative stress, conditions that disrupt metabolic homeostasis and promote vascular endothelial growth factor (VEGF) expression. While hypoxia and fatty acid-induced oxidative stress are known regulators of VEGF, the contribution of endoplasmic reticulum (ER) stress in monocytic cells remains unclear. In this study, we investigated the interplay between ER stress and metabolic stress in regulating VEGF expression using THP-1 monocytic cells. Metabolic stress was induced by palmitic acid (PA) and ER stress by thapsigargin (TG). Co-treatment with PA and TG significantly increased VEGF mRNA and protein levels compared to PA alone. This effect was accompanied by enhanced reactive oxygen species (ROS) production and upregulation of ER stress markers, including CHOP, ATF6, and IRE1. Pretreatment with the antioxidant curcumin markedly reduced VEGF expression and ROS levels, indicating a ROS-dependent mechanism. Additionally, PA+TG co-treatment elevated transcripts of antioxidant defense genes such as SOD2 and NRF2, suggesting a compensatory cellular response to oxidative stress. These findings demonstrate that ER stress amplifies VEGF induction in monocytic cells under lipotoxic conditions through ROS-mediated pathways, highlighting a potential mechanism linking metabolic stress, inflammation, and angiogenesis in obesity-related disorders. Full article

(This article belongs to the Collection Molecular Mechanisms in Human Diseases)

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9 pages, 987 KB

Open AccessArticle

Assessment of Cervical IL-6 Levels and Neonatal Inflammatory Response in Preterm Birth Following Preterm Premature Rupture of Membranes

by Gusztav Labossa, Tamas Koszegi, Balint Farkas, Bernadett Nagy, Rita Jakabfi-Csepregi, Nelli Farkas and Kalman Kovacs

Curr. Issues Mol. Biol. 2025, 47(10), 838; https://doi.org/10.3390/cimb47100838 - 12 Oct 2025

Viewed by 173

Abstract

Background: Preterm premature rupture of membranes (PPROM) is a leading cause of preterm delivery, occurring in 40–50% of cases, with a 3–4% overall incidence. During expectant management, chorioamnionitis is typically monitored using serum inflammatory markers (e.g., leukocyte count, CRP), though cervical interleukin-6 (IL-6) [...] Read more.

Background: Preterm premature rupture of membranes (PPROM) is a leading cause of preterm delivery, occurring in 40–50% of cases, with a 3–4% overall incidence. During expectant management, chorioamnionitis is typically monitored using serum inflammatory markers (e.g., leukocyte count, CRP), though cervical interleukin-6 (IL-6) has emerged as a promising local marker. This study investigated the correlation between cervical IL-6 and maternal and neonatal inflammatory parameters. Methods: This prospective non-randomized clinical trial was performed with 51 patients with expectantly managed PPROM. Samples were obtained twice a week using cervical swabs placed into a stabilizer solution. Cervical IL-6 levels were measured by routine automated chemiluminescence immunoassay, with reference to albumin levels. Maternal serum C-reactive protein (CRP) levels and leukocyte counts and neonatal serum CRP and procalcitonin (PCT) levels were also determined. Spearman correlations of the IL-6 level with other markers and clinicopathological parameters were examined. Results: Cervical IL-6 levels correlated more strongly with neonatal CRP and PCT levels on the first day after delivery than with maternal serum markers while showing no significant association with the PPROM-to-delivery interval. Conclusion: Cervical IL-6 level determination may help to inform the timing of labor induction in cases of PPROM, with consideration of the maternal and neonatal conditions. We believe that the monitoring of the cervical IL-6 level could enable good prediction of perinatal inflammation, although more data are needed to support this hypothesis. Full article

(This article belongs to the Section Molecular Medicine)

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11 pages, 629 KB

Open AccessArticle

Salivary BCAA, Glutamate, Glutamine and Urea as Potential Indicators of Nitrogen Metabolism Imbalance in Breast Cancer

by Elena A. Sarf and Lyudmila V. Bel’skaya

Curr. Issues Mol. Biol. 2025, 47(10), 837; https://doi.org/10.3390/cimb47100837 - 11 Oct 2025

Viewed by 272

Abstract

Nitrogen metabolism in the human body is in a strictly balanced state, which is disturbed in pathologies, including breast cancer. The state of nitrogen balance can be judged by the content of urea and the amount of branched-chain amino acids (BCAAs) (Val, Leu, [...] Read more.

Nitrogen metabolism in the human body is in a strictly balanced state, which is disturbed in pathologies, including breast cancer. The state of nitrogen balance can be judged by the content of urea and the amount of branched-chain amino acids (BCAAs) (Val, Leu, and Ile), glutamine (Gln), and glutamate (Glu). The study involved 1438 people, including patients with breast cancer (n = 543), fibroadenomas (n = 597), and healthy controls (n = 298). Saliva samples were collected from all patients before treatment, and urea levels were determined in all 1438 samples. Salivary levels of BCAAs, Gln, and Glu were determined in 116 patients with breast cancer, 24 with fibroadenomas, and 25 healthy volunteers. An increase in the concentration of urea in saliva was shown in breast cancer, most pronounced in luminal molecular biological subtypes: luminal A 10.46 [7.69; 12.62] mmol/L (p < 0.0001), luminal B HER2-negative 9.52 [6.72; 12.52] mmol/L (p = 0.0198), and luminal B HER2-positive 8.26 [5.27; 12.07] mmol/L. The Gln/Glu ratio increased in the saliva of the control group (5.43 [3.30; 10.5]) compared with breast cancer (2.22 [0.84; 5.40], p = 0.0094) and fibroadenomas (1.94 [0.89; 6.05], p = 0.0184). For luminal B HER2-positive and TNBC, the Gln/Glu ratio increased sharply to 8.23 [3.24; 10.9] (p = 0.0327) and 11.2 [4.28; 15.2] (p < 0.0001) compared with healthy controls. Thus, an increased Gln/Glu ratio in saliva may characterize a more aggressive subtype of breast cancer. Full article

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

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23 pages, 8747 KB

Open AccessArticle

Dietary Acrylamide Induces Depression via SIRT3-Mediated Mitochondrial Oxidative Injury: Evidence from Multi-Omics and Mendelian Randomization

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

Curr. Issues Mol. Biol. 2025, 47(10), 836; https://doi.org/10.3390/cimb47100836 - 10 Oct 2025

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Abstract

Acrylamide (ACR), a common dietary pro-oxidant generated in heat-processed foods, disrupts mitochondrial redox homeostasis. While its neurotoxic effects are recognized, the role of ACR in depression remains poorly understood. We hypothesized that dietary ACR exposure promotes depression via SIRT3-dependent mitochondrial oxidative injury. Through [...] Read more.

Acrylamide (ACR), a common dietary pro-oxidant generated in heat-processed foods, disrupts mitochondrial redox homeostasis. While its neurotoxic effects are recognized, the role of ACR in depression remains poorly understood. We hypothesized that dietary ACR exposure promotes depression via SIRT3-dependent mitochondrial oxidative injury. Through an integrative approach combining network toxicology (to prioritize candidate targets), transcriptomics, and Mendelian randomization (MR), we identified SIRT3 as the central mediator. Molecular dynamics simulations demonstrated that ACR’s primary metabolite glycidamide (GA) formed more stable and rigid complexes with key targets (including SIRT3, TP53, CASP3, JUN, PTGS2, and PTK2) than ACR itself, as evidenced by superior structural stability, reduced flexibility, and enhanced hydrogen bonding. Transcriptomic analysis of the human prefrontal cortex (datasets GSE54567 and GSE54568) revealed mitochondrial deacetylase sirtuin 3 (SIRT3) as the most significantly suppressed gene in depression (p < 0.01), suggesting an impairment in Superoxide dismutase 2 (SOD2)-mediated antioxidant defense. MR further established JUN and PTK2 as causal genetic risk factors for depression (JUN: Odds Ratio (OR) = 1.029, 95% CI = 1.002–1.057; PTK2: OR = 1.040, 95% CI = 1.005–1.076; JUN (OR) = 1.048, 95% CI = 1.021–1.076, PTK2: OR = 1.073, 95% CI = 1.039–1.109) of each MR estimates, while other candidates lacked genetic support. Our findings demonstrate that ACR induces depression primarily through SIRT3 suppression, activating JUN/PTK2 pathways, suggesting its potential role in environmental toxicant-induced redox imbalance. Full article

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

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17 pages, 8227 KB

Open AccessArticle

Transcriptome Analysis Reveals Critical Genes Involved in the Response of Stropharia rugosoannulata to High Temperature and Drought Stress

by Shengze Yan, Shengyou Wang, Meirong Zhan, Xianxin Huang, Ting Xie, Ruijuan Wang, Huan Lu, Qingqing Luo and Wei Ye

Curr. Issues Mol. Biol. 2025, 47(10), 835; https://doi.org/10.3390/cimb47100835 - 10 Oct 2025

Viewed by 175

Abstract

In this study, the differences in gene expression of Stropharia rugosoannulata at different treatment times under high temperature and drought stress were analyzed by transcriptomics. Here, a total of 74,571 transcripts and 16,233 unigenes were identified, with an average assembly length of 3002 [...] Read more.

In this study, the differences in gene expression of Stropharia rugosoannulata at different treatment times under high temperature and drought stress were analyzed by transcriptomics. Here, a total of 74,571 transcripts and 16,233 unigenes were identified, with an average assembly length of 3002 bp. A total of 10,248 differentially expressed genes (DEGs) were identified. DEG analysis indicated that the numbers of DEGs under high-temperature stress for 1 d, 2 d, and 3 d were 798, 851, and 1484, respectively. These DEGs were involved in 96 GO functional categories and 69 KEGG metabolic pathways. Meanwhile, the numbers of DEGs under drought stress for 3 d, 6 d, and 9 d were 421, 1072, and 2880, respectively. These DEGs were involved in 108 GO functional categories and 78 KEGG metabolic pathways. Further analysis of the metabolic pathway (ko04011) commonly enriched by DEGs identified 15 candidate genes responding to high-temperature or drought stress. Eight candidate genes were randomly selected for qRT-PCR verification, and the qRT-PCR results were basically consistent with the transcriptome datasets. These findings provide critical candidate genes for understanding the molecular regulation mechanism of S. rugosoannulata in response to high temperature and drought stress and have important reference value for its stress resistance breeding. Full article

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

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31 pages, 2150 KB

Open AccessReview

The Role of MALDI-TOF Mass Spectrometry in Photodynamic Therapy: From Photosensitizer Design to Clinical Applications

by Dorota Bartusik-Aebisher, Kacper Rogóż and David Aebisher

Curr. Issues Mol. Biol. 2025, 47(10), 834; https://doi.org/10.3390/cimb47100834 - 10 Oct 2025

Viewed by 256

Abstract

Photodynamic therapy (PDT) has evolved considerably over the past decades, progressing from first-generation porphyrins to second- and third-generation photosensitizers, including nanocarrier-based systems with improved selectivity and bioavailability. In parallel, matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) has become a gold standard for [...] Read more.

Photodynamic therapy (PDT) has evolved considerably over the past decades, progressing from first-generation porphyrins to second- and third-generation photosensitizers, including nanocarrier-based systems with improved selectivity and bioavailability. In parallel, matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) has become a gold standard for the characterisation of complex biomolecules, enabling precise determination of molecular mass, purity and stability. This narrative review explores the intersection of these two fields, focusing on how MALDI-TOF MS supports the development, characterisation and clinical application of photosensitizers used in PDT. Literature searches were performed across PubMed, Web of Science, Scopus and Base-search, followed by targeted retrieval of studies on MALDI and PDT applications. Findings indicate that MALDI-TOF MS plays a crucial role at multiple stages: confirming the synthesis and chemical integrity of novel photosensitizers, monitoring their metabolic stability in biological systems and characterising photodegradation products after PDT. Moreover, MALDI imaging mass spectrometry (MALDI-IMS) enables spatial mapping of photosensitizer distribution in tissues, while rapid pathogen identification by MALDI-TOF supports antimicrobial PDT applications. Collectively, the evidence highlights that MALDI-MS is not only a tool for molecular characterisation but also a versatile analytical platform with a direct translational impact on PDT. Its integration with other omics and multimodal imaging approaches is expected to enhance the personalization and clinical effectiveness of photodynamic therapy. Full article

(This article belongs to the Section Molecular Medicine)

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12 pages, 8706 KB

Open AccessArticle

Codon Usage Bias Analysis in the Chloroplast Genome of Actinostemma tenerum (Cucurbitaceae)

by Jing-Jing Mu and Ji-Si Zhang

Curr. Issues Mol. Biol. 2025, 47(10), 833; https://doi.org/10.3390/cimb47100833 - 10 Oct 2025

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Abstract

The plant Actinostemma tenerum is endemic to East Asia and has been used as a traditional medicinal herb for over 1400 years. Investigating the chloroplast genome characteristics and codon usage bias (CUB) is essential for advancing research on molecular markers and genetic diversity [...] Read more.

The plant Actinostemma tenerum is endemic to East Asia and has been used as a traditional medicinal herb for over 1400 years. Investigating the chloroplast genome characteristics and codon usage bias (CUB) is essential for advancing research on molecular markers and genetic diversity in A. tenerum. In this study, we sequenced the complete chloroplast genome of A. tenerum, revealing a length of 160,579 bp, with a GC content of 36.5%. The genome comprised 132 coding genes, including 87 protein-coding genes (CDSs), 8 rRNA genes, and 37 tRNA genes. Analysis of the 51 selected CDSs showed average GC1, GC2, and GC3 values of 46.95%, 39.52%, and 28.11%, respectively. The effective number of codons (ENC) ranged from 35.34% to 56.23%, with an average of 45.57%, indicating a weak CUB. Nucleotide composition analysis revealed unequal distribution of A, T, C, and G, with codon preference biased towards A or U. Neutrality plots, ENC-plots, and PR2-bias plots indicated that natural selection predominantly influences on CUB. A total of 18 optimal codons were identified. This study contributes genetic insights into A. tenerum and enhances our understanding of codon usage patterns in plant chloroplast genomes. Full article

(This article belongs to the Section Molecular Plant Sciences)

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17 pages, 5668 KB

Open AccessArticle

Transcriptome Analysis Reveals Differences in Molecular Mechanisms Between Salt-Tolerant and Salt-Sensitive Rice (Oryza sativa L.) Varieties Under Salt Stress

by Yu Han, Chenyang Wu, Xue Ji, Mengran Yang, Hongyu Zhu, Zhongyou Pei, Mingnan Qu, Lijun Qu, Zhibin Li and Shuangyong Yan

Curr. Issues Mol. Biol. 2025, 47(10), 832; https://doi.org/10.3390/cimb47100832 - 10 Oct 2025

Viewed by 242

Abstract

To elucidate the molecular mechanisms underlying salt tolerance in rice (Oryza sativa L.), this study investigated differential transcriptional responses during the tillering stage. Salt-tolerant (N14) and salt-sensitive (N6) varieties were subjected to 0.3% and 0.6% NaCl treatments for 72 h, and their [...] Read more.

To elucidate the molecular mechanisms underlying salt tolerance in rice (Oryza sativa L.), this study investigated differential transcriptional responses during the tillering stage. Salt-tolerant (N14) and salt-sensitive (N6) varieties were subjected to 0.3% and 0.6% NaCl treatments for 72 h, and their transcriptomes were analyzed via RNA-Seq. The results revealed distinct response strategies: 372 differentially expressed genes (DEGs) were identified in N14 and 393 in N6, with only 17 genes responding similarly. Gene Ontology (GO) analysis showed the tolerant N14 activated protein phosphorylation and lipid transport, primarily in the membrane and extracellular regions (e.g., ATP binding), whereas the sensitive N6 activated photosynthesis and protein folding, localized to chloroplasts and peroxisomes. KEGG analysis highlighted the activation of “Plant-pathogen interaction” in N14 versus “Metabolic pathways” in N6. Differential transcription factor activation was also observed, with N14 mobilizing 52 TFs (mainly WRKY and MYB) and N6 mobilizing 36 TFs (mainly MYB and b-ZIP). This study demonstrates that N14 and N6 utilize significantly different molecular pathways to cope with salinity, providing a crucial theoretical foundation for identifying novel salt tolerance genes and developing molecular breeding strategies. Full article

(This article belongs to the Section Molecular Plant Sciences)

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23 pages, 13395 KB

Open AccessArticle

Identification and Validation of Iron Metabolism-Related Biomarkers in Endometriosis: A Mendelian Randomization and Single-Cell Transcriptomics Study

by Juan Du, Zili Lv and Xiaohong Luo

Curr. Issues Mol. Biol. 2025, 47(10), 831; https://doi.org/10.3390/cimb47100831 - 9 Oct 2025

Viewed by 251

Abstract

Studies have shown that the iron concentration in the peritoneal fluid of women is associated with the severity of endometriosis. Therefore, investigation of iron metabolism-related genes (IM-RGs) in endometriosis holds significant implications for both prevention and therapeutic strategies in affected patients. Differentially expressed [...] Read more.

Studies have shown that the iron concentration in the peritoneal fluid of women is associated with the severity of endometriosis. Therefore, investigation of iron metabolism-related genes (IM-RGs) in endometriosis holds significant implications for both prevention and therapeutic strategies in affected patients. Differentially expressed IM-RGs (DEIM-RGs) were identified by intersecting IM-RGs with differentially expressed genes derived from GSE86534. Mendelian randomization analysis was employed to determine DEIM-RGs causally associated with endometriosis, with subsequent verification through sensitivity analyses and the Steiger test. Biomarkers associated with IM-RGs in endometriosis were validated using expression data from GSE86534 and GSE105764. Functional annotation, regulatory network construction, and immunological profiling were conducted for these biomarkers. Single-cell RNA sequencing (scRNA-seq) (GSE213216) was utilized to identify distinctively expressed cellular subsets between endometriosis and controls. Experimental validation of biomarker expression was performed via reverse transcription–quantitative polymerase chain reaction (RT-qPCR). BMP6 and SLC48A1, biomarkers indicative of cellular BMP response, were influenced by a medicus variant mutation that inactivated PINK1 in complex I, concurrently enriched by both biomarkers. The lncRNA NEAT1 regulated BMP6 through hsa-mir-22-3p and hsa-mir-124-3p, while SLC48A1 was modulated by hsa-mir-423-5p, hsa-mir-19a-3p, and hsa-mir-19b-3p. Immune profiling revealed a negative correlation between BMP6 and monocytes, whereas SLC48A1 displayed a positive correlation with activated natural killer cells. scRNA-seq analysis identified macrophages and stromal stem cells as pivotal cellular components in endometriosis, exhibiting altered self-communication networks. RT-qPCR confirmed elevated expression of BMP6 and SLC48A1 in endometriosis samples relative to controls. Both BMP6 and SLC48A1 were consistently overexpressed in endometriosis, reinforcing their potential as biomarkers. Moreover, macrophages and stromal stem cells were delineated as key contributors. These findings provide novel insights into therapeutic and preventive approaches for patients with endometriosis. Full article

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

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15 pages, 2398 KB

Open AccessArticle

IL-2 Receptor Expression in Renal Cell Carcinoma Cells: IL-2 Influences Cell Survival and Induces Cell Death

by Sophie Grigolo, Isabelle Fellay and Luis Filgueira

Curr. Issues Mol. Biol. 2025, 47(10), 830; https://doi.org/10.3390/cimb47100830 - 9 Oct 2025

Viewed by 216

Abstract

Renal cell carcinoma (RCC) is the most common form of kidney cancer in adults. Immunotherapy, such as the application of interleukin-2 (IL-2), is a crucial treatment. It is known that IL-2 is involved in the upregulation of the anti-tumor immune response; however, a [...] Read more.

Renal cell carcinoma (RCC) is the most common form of kidney cancer in adults. Immunotherapy, such as the application of interleukin-2 (IL-2), is a crucial treatment. It is known that IL-2 is involved in the upregulation of the anti-tumor immune response; however, a direct action of IL-2 on RCC cells has not yet been demonstrated. In this project, we aimed to investigate the expression and the functionality of the IL-2Rα, IL-2Rβ, and IL-2Rγ subunits on the four human RCC cell lines A-498, ACHN, Caki-1, and Caki-2. The expression of the three subunit genes was investigated via PCR, agarose gel of PCR products, Western blot, and flow cytometry. IL-2R functionality was assessed in RCC cells cultured with or without rhIL-2 using MTT and BrdU assays to investigate cell viability and proliferation; LDH assays, Live-or-Dye staining, and Annexin V/PI staining to study cell death; and Western blot to detect apoptotic markers, cleaved PARP, and cleaved caspases 3 and 9. Expression of IL-2Rα, IL-2Rβ, and IL-2Rγ subunits in the four cell lines was observed at the protein level with Western blot. Flow cytometry confirmed the cell-surface expression of IL-2Rα, IL-2Rβ, and IL-2Rγ subunits. In addition, we observed that rhIL-2 influenced cell survival/proliferation and cell death, depending on the cell line. We conclude that IL-2R is functional in RCC cells and that rhIL-2 could be used as a therapeutic option to act directly on RCC cells. However, further studies are required to elucidate the signaling pathways triggered by the IL-2-receptor binding on RCC cells. Full article

(This article belongs to the Section Molecular Medicine)

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13 pages, 1462 KB

Open AccessArticle

Regulation of PD-L1 Protein Expression by the E3 Ubiquitin Ligase GP78

by Madhumita Chatterjee, Julio M. Pimentel, Jun-Ying Zhou, Thamarahansi Mugunamalwaththa, Zhe Yang, Avraham Raz and Gen Sheng Wu

Curr. Issues Mol. Biol. 2025, 47(10), 829; https://doi.org/10.3390/cimb47100829 - 9 Oct 2025

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Abstract

Immune checkpoint inhibitors (ICIs), including PD-L1 inhibitors, have been approved by the FDA for the treatment of cancers; however, only a small number of cancer patients benefit from these ICIs. Furthermore, the development of drug resistance to this type of treatment is often [...] Read more.

Immune checkpoint inhibitors (ICIs), including PD-L1 inhibitors, have been approved by the FDA for the treatment of cancers; however, only a small number of cancer patients benefit from these ICIs. Furthermore, the development of drug resistance to this type of treatment is often inevitable. The mechanisms of resistance to PD-L1 inhibitors can be attributed, in part, to an incomplete understanding of the regulation of PD-L1 protein expression. In this study, we identified the role of the E3 ligase GP78, also known as the Autocrine Motility Factor Receptor (AMFR), in the regulation of PD-L1 protein levels. We show that GP78 physically interacts with PD-L1, which is confirmed by IP and Western blotting and is supported by molecular modelling using AlphaFold2. Our modeling studies predict that the interface amino acids of the Ig1 domain of PD-L1 interact with the RING domain and a β-hairpin preceding the CUE domain of GP78. The crystal structure of the PD-1/PD-L1 complex reveals that the interaction with PD-1 is mediated by the Ig1 domain of PD-L1. Furthermore, proteasomal degradation of PD-L1 has been observed via GP78-mediated K48-linked ubiquitination, indicating a key regulatory role for GP78 in the downregulation of PD-L1. Because GP78 expression is inversely correlated with PD-L1 levels in cancer, these findings may have clinical implications for predicting tumor immune evasion and patient response to PD-1/PD-L1 blockade therapies. Taken together, these findings identify a previously unknown mechanism by which GP78 targets PD-L1 for ubiquitination and subsequent degradation in cancer cells, and suggest that blocking the interaction between PD-L1 and PD-1 by an E3 ligase is a novel strategy to improve immunotherapies for cancer patients. Full article

(This article belongs to the Section Molecular Medicine)

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14 pages, 4433 KB

Open AccessArticle

Saucerneol D Suppresses the Growth of Helicobacter pylori and Their Virulence Factors

by Su Man Kim, Hyun Jun Woo, Zhongduo Yang, Tiankun Zhao, Ji Yeong Yang and Sa-Hyun Kim

Curr. Issues Mol. Biol. 2025, 47(10), 828; https://doi.org/10.3390/cimb47100828 - 9 Oct 2025

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Abstract

Helicobacter pylori infects the human stomach and causes various gastrointestinal diseases. Saucerneol D is a type of lignan, which is a polyphenol compound that exists naturally in plants, and it is abundant in flaxseed, sesame seeds, whole grains, vegetables, and fruits. Saucerneol D [...] Read more.

Helicobacter pylori infects the human stomach and causes various gastrointestinal diseases. Saucerneol D is a type of lignan, which is a polyphenol compound that exists naturally in plants, and it is abundant in flaxseed, sesame seeds, whole grains, vegetables, and fruits. Saucerneol D is found in Saurus chinensis extract and has been reported to exert a variety of effects, such as antioxidant and anti-inflammatory abilities. However, its antibacterial effect against H. pylori has not been reported; therefore, we analyzed the effect of saucerneol D on H. pylori in the present study. Changes in the expression of pathogenic factors and gene transcription in H. pylori were observed after treatment with saucerneol D using Western blotting and RT-PCR. It was confirmed that saucerneol D suppressed the growth of H. pylori by decreasing the expression of the genes dnaN and polA, which are required for bacterial replication. Saucerneol D also reduced the secretion of the major pathogenic toxin protein, CagA, by downregulating the expression of type IV secretion system-composing proteins. Furthermore, saucerneol D reduced ammonia production by inhibiting the expression of urease proteins, which are essential for the survival of H. pylori in the acidic gastric environment. Additionally, saucerneol D decreased the expression of flaB, potentially reducing motility. Finally, it was confirmed that the expression of the sabA gene, associated with cell adhesion, was reduced. These results suggest that saucerneol D inhibits the growth of H. pylori and the expression of several pathogenic factors, indicating that saucerneol D has an antimicrobial effect against H. pylori. Full article

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

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17 pages, 1659 KB

Open AccessReview

Beyond the Cup: Coffee Extracts as Modulators of Periodontal Inflammation and Bone Remodeling

by Janvi Mody, Deamah Aleisa, Harshal Modh, Purnima Sainani, Serge Dibart and Weiyuan Ma

Curr. Issues Mol. Biol. 2025, 47(10), 827; https://doi.org/10.3390/cimb47100827 - 8 Oct 2025

Viewed by 323

Abstract

Alveolar bone loss is a defining feature of periodontitis and a principal cause of tooth loss worldwide. Driven by a dysregulated host immune response to chronic bacterial infection, periodontitis initiates a cascade of inflammatory events that lead to an imbalance in bone remodeling, [...] Read more.

Alveolar bone loss is a defining feature of periodontitis and a principal cause of tooth loss worldwide. Driven by a dysregulated host immune response to chronic bacterial infection, periodontitis initiates a cascade of inflammatory events that lead to an imbalance in bone remodeling, favoring osteoclastic activity. While conventional periodontal therapies aim to control infection and inflammation, they often fall short in preserving bone integrity. As a result, interest has grown in adjunctive strategies targeting molecular pathways involved in bone metabolism. Among potential candidates, coffee, a globally consumed beverage often perceived as detrimental to health, has gained attention for its complex array of bioactive compounds, including caffeine, chlorogenic acids, and polyphenols. These compounds have demonstrated anti-inflammatory, antioxidant, and osteo-modulatory effects in various biological contexts. Despite coffee’s reputation as a potential health risk, its complex composition presents a paradox, necessitating an investigation into how its bioactive constituents may mitigate periodontal tissue destruction. The novelty of this short review lies in its integration of in vitro, animal, and epidemiologic evidence to delineate the dose- and context-dependent effects of coffee polyphenols, particularly chlorogenic and ferulic acids, on periodontal inflammation and alveolar bone remodeling, with special emphasis on osteoclast-related mechanisms that have not been synthesized previously. Caffeine can influence osteoblast and osteoclast activity in a dose-dependent manner, while chlorogenic acids (CGA) and polyphenols exert radical-scavenging and cytokine-suppressing activity that may reduce inflammatory bone loss. However, their efficacy is influenced by coffee species, cultivation, roasting, and extraction methods. This review evaluates current evidence and proposes directions for optimizing coffee-based formulations to support alveolar bone preservation in periodontitis. 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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19 pages, 2337 KB

Open AccessArticle

Equal Prevalence of Genotypes ON1 and BA of Human Orthopneumovirus in Riyadh, Saudi Arabia, in 2022

by Anwar Ahmed, Abdulkarim Alhetheel, Fahad N. Almajhdi, Shama Parveen, Muslim M. AlSaadi and Khalid F. Al-Mobaireek

Curr. Issues Mol. Biol. 2025, 47(10), 826; https://doi.org/10.3390/cimb47100826 - 8 Oct 2025

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Abstract

Human orthopneumovirus (HOPV) is a major cause of acute respiratory tract infection (ARI) in children around the world. The present study was conceptualized to detect and characterize human orthopneumovirus in 640 NPAs collected from symptomatic ARI pediatric patients younger than 2 years of [...] Read more.

Human orthopneumovirus (HOPV) is a major cause of acute respiratory tract infection (ARI) in children around the world. The present study was conceptualized to detect and characterize human orthopneumovirus in 640 NPAs collected from symptomatic ARI pediatric patients younger than 2 years of age. The samples were collected from a hospital in Riyadh, Saudi Arabia, during winter 2022. Orthopneumovirus was detected in 98 (15.31%) of the 640 NPAs. No significant difference in the prevalence of HOPV-A (49%) and HOPV-B (51%) was observed during the study period as they circulated at similar frequencies. The HOPV-A strains (33) and HOPV-B strains (47) clustered into ON1 and BA genotype, respectively. The ON1 genotypes were further categorized into the subgenotype GA-2.3 and three different lineages, GA-2.3.5, GA-2.3.6a, and GA-2.3.6b, whereas the BA genotypes were categorized into the GB-5.0 subgenotype, entirely belonging to the GB-5.0.5a lineage. This is the first report to characterize orthopneumovirus strains from Saudi Arabia using a recently reported method. Several mutations, a few N-/O-glycosylation sites, and some purifying selections were observed in both the ON1 and BA genotypes. The present study demonstrates the equal prevalence of the ON1 and BA genotypes, in contrast to earlier reports on HOPV-A prevalence in the region. Understanding the change in the genotype distribution of HOPV requires the uninterrupted surveillance and genetic characterization of HOPV in circulating respiratory infections. These findings may contribute to a better understanding of HOPV evolution and the dynamics of its distribution at the local and global levels, resulting in improved understanding of epidemics. Full article

(This article belongs to the Section Molecular Microbiology)

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Curr. Issues Mol. Biol., Volume 47, Issue 10 (October 2025) – 69 articles

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