Current Issues in Molecular Biology

19 pages, 3396 KiB

Open AccessArticle

Ultra-High-Performance Liquid Chromatography–Tandem Mass Spectrometry and Network Pharmacology Reveal the Mechanisms of Rhodiola crenulata in Improving Non-Alcoholic Fatty Liver Disease

by Xin Zeng, Jianwei Wang, Qinyi Xu, Chengdan Deng, Xi Yi, Shang Wang, Ling Yao and Wei Xiang

Curr. Issues Mol. Biol. 2025, 47(5), 324; https://doi.org/10.3390/cimb47050324 - 1 May 2025

Abstract

Rhodiola crenulata (RC) is a traditional herb and functional food that has demonstrated beneficial effects in improving physical function, enhancing work capacity, alleviating fatigue, and preventing altitude sickness. Additionally, RC has shown promising effects in the treatment of non-alcoholic fatty liver disease (NAFLD), [...] Read more.

Rhodiola crenulata (RC) is a traditional herb and functional food that has demonstrated beneficial effects in improving physical function, enhancing work capacity, alleviating fatigue, and preventing altitude sickness. Additionally, RC has shown promising effects in the treatment of non-alcoholic fatty liver disease (NAFLD), although its specific bioactive components and underlying mechanisms remain unclear. In this study, ultra-high-performance liquid chromatography–mass spectrometry (UHPLC-MS) combined with network pharmacology was employed to identify six potential bioactive compounds from the serum of rats treated with RC—Salidroside, Tyrosol, Crenulatin, Catechin gallate, Eriodictyol, and Rhodiooctanoside—that may contribute to its therapeutic effects on NAFLD. The efficacy of these compounds in improving NAFLD was assessed in vitro using HepG2 cells exposed to Palmitic acid (PA), and it was found that Catechin gallate exhibited a significant effect in reducing lipid accumulation in HepG2 cells. Furthermore, based on network pharmacology predictions, molecular docking studies suggested that the primary targets of Catechin gallate in alleviating fatty liver might include ABCB1, DYRK1A, PGD, and FUT4. Molecular dynamics simulations revealed stable binding interactions between Catechin gallate and these four target proteins. This study clarifies the material basis of RC in the treatment of NAFLD and provides a theoretical foundation for the application of RC and Catechin gallate as functional additives for the management of NAFLD. Full article

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

21 pages, 1291 KiB

Open AccessReview

From Lineage to Longevity: A Field Guide to the Key Players in Epigenetic Contribution to Offspring Health

by Razia Zakarya

Curr. Issues Mol. Biol. 2025, 47(5), 323; https://doi.org/10.3390/cimb47050323 - 30 Apr 2025

Abstract

Epidemiological evidence firmly supports the rationale that chronic diseases demonstrate a heritability component. Notwithstanding recent advances in genomic technologies, in a significant proportion of heritable diseases, a candidate gene of interest that explains the entire picture of heritability remains to be identified. Further [...] Read more.

Epidemiological evidence firmly supports the rationale that chronic diseases demonstrate a heritability component. Notwithstanding recent advances in genomic technologies, in a significant proportion of heritable diseases, a candidate gene of interest that explains the entire picture of heritability remains to be identified. Further epidemiological evidence points to environmental risk factors contributing to chronic disease prevalence and severity. The Developmental Origins of Health and Disease hypothesis points to epigenetics as the mechanism modulating gene–environment interactions to elicit disease. Yet the primary effector of epigenetic inheritance remains to be elucidated. This review focuses on key contributors to mammalian development and the epigenetic changes measured therein, to draw attention towards potential molecular candidates underpinning chronic disease heritability. Full article

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

16 pages, 1396 KiB

Open AccessReview

Therapeutic Potential of Alpha-Lipoic Acid: Unraveling Its Role in Oxidative Stress and Inflammatory Conditions

by Aqsa Shahid, Khadeeja Nasir and Madhav Bhatia

Curr. Issues Mol. Biol. 2025, 47(5), 322; https://doi.org/10.3390/cimb47050322 - 30 Apr 2025

Abstract

Alpha-lipoic acid (ALA) is an essential organosulfur compound with a wide range of therapeutic applications, particularly in conditions involving inflammation and oxidative stress. In this review, we describe our current understanding of the multifaceted role of ALA in several inflammatory diseases (acute pancreatitis, [...] Read more.

Alpha-lipoic acid (ALA) is an essential organosulfur compound with a wide range of therapeutic applications, particularly in conditions involving inflammation and oxidative stress. In this review, we describe our current understanding of the multifaceted role of ALA in several inflammatory diseases (acute pancreatitis, arthritis, osteoarthritis, asthma, and sepsis), cardiovascular disorders (CVDs), and neurological conditions. The dual redox nature of ALA, shared with its reduced form dihydrolipoic acid (DHLA), underpins its powerful antioxidant and anti-inflammatory properties, including reactive oxygen species scavenging, metal chelation, and the regeneration of endogenous antioxidants such as glutathione. A substantial body of evidence from preclinical and clinical studies suggests that ALA modulates the key signaling pathways involved in inflammation and cellular stress responses, making it a promising candidate for mitigating inflammation and its systemic consequences. Notably, we also discuss a novel perspective that attributes some of the therapeutic effects of ALA to its ability to release hydrogen sulfide (H₂S), a gaseous signaling molecule. This mechanism may offer further insights into the efficacy of ALA in the treatment of several diseases. Together, these findings support the potential of ALA as a multifunctional agent for managing inflammatory and oxidative stress-related diseases. Full article

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

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29 pages, 1319 KiB

Open AccessReview

The Potential Use of Digital Twin Technology for Advancing CAR-T Cell Therapy

by Sara Sadat Aghamiri and Rada Amin

Curr. Issues Mol. Biol. 2025, 47(5), 321; https://doi.org/10.3390/cimb47050321 - 30 Apr 2025

Abstract

CAR-T cell therapy is a personalized immunotherapy that has shown promising results in treating hematologic cancers. However, its therapeutic efficacy in solid cancers is often limited by tumor evasion mechanisms, resistance pathways, and an immunosuppressive tumor microenvironment. These challenges highlight the need for [...] Read more.

CAR-T cell therapy is a personalized immunotherapy that has shown promising results in treating hematologic cancers. However, its therapeutic efficacy in solid cancers is often limited by tumor evasion mechanisms, resistance pathways, and an immunosuppressive tumor microenvironment. These challenges highlight the need for advanced predictive models to better capture the intricate interactions between CAR-T cells and tumors to enhance their potential. Digital Twins represent a transformative approach for optimizing CAR-T cell therapy by providing a virtual representation of the therapy-tumor trajectory using high-dimensional patient data. In this review, we first define Digital Twins and outline the fundamental steps in their development. We then explore the critical parameters required for designing CAR-T-specific Digital Twins. We examine published case studies demonstrating a few applications of Digital Twins in addressing key challenges in CAR-T cell therapy, including their impact on clinical trials and manufacturing processes. Finally, we discuss the limitations associated with integrating Digital Twins into CAR-T therapy. As Digital Twin technology continues to evolve, the potential to enhance CAR-T therapy through precision modeling and real-time adaptation could redefine the landscape of personalized cancer treatment. Full article

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

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3 pages, 161 KiB

Open AccessEditorial

Editorial for Special Issue “Molecular Research in Osteoarthritis and Osteoarticular Diseases”

by Ye Liu

Curr. Issues Mol. Biol. 2025, 47(5), 320; https://doi.org/10.3390/cimb47050320 - 30 Apr 2025

Abstract

Osteoarthritis is a prevalent and debilitating disorder, affecting over 500 million people, primarily affecting aging adults [...] Full article

(This article belongs to the Special Issue Molecular Research in Osteoarthritis and Osteoarticular Diseases)

24 pages, 10329 KiB

Open AccessArticle

Exploring the Molecular Mechanism of 1,25(OH)₂D₃ Reversal of Sorafenib Resistance in Hepatocellular Carcinoma Based on Network Pharmacology and Experimental Validation

by Zhiyan Long, Xiangyi Wu, Tianxin Luo, Xiaomei Chen, Jian Huang and Shu Zhang

Curr. Issues Mol. Biol. 2025, 47(5), 319; https://doi.org/10.3390/cimb47050319 - 29 Apr 2025

Abstract

Sorafenib is currently the first-line therapeutic agent for advanced hepatocellular carcinoma (HCC). However, sorafenib resistance remains a major clinical challenge. Studies have reported that 1,25-dihydroxyvitamin D3 (1,25(OH)₂D₃) can synergize with multiple chemotherapeutic drugs to enhance their antitumor efficacy, but [...] Read more.

Sorafenib is currently the first-line therapeutic agent for advanced hepatocellular carcinoma (HCC). However, sorafenib resistance remains a major clinical challenge. Studies have reported that 1,25-dihydroxyvitamin D3 (1,25(OH)₂D₃) can synergize with multiple chemotherapeutic drugs to enhance their antitumor efficacy, but the combinatorial effect between 1,25(OH)₂D₃ and sorafenib has not yet been investigated. This study aimed to investigate the potential molecular mechanism by which 1,25(OH)₂D₃ reverses sorafenib resistance in hepatocellular carcinoma using network pharmacology, molecular docking, and experimental validation. We predicted a web-based pharmacological approach to predict potential targets of 1,25(OH)₂D₃ and its derivatives, as well as sorafenib resistance genes in hepatocellular carcinoma from public databases. We then constructed 1,25(OH)₂D₃ chemo-sensitizing expression profiles through intersection analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were employed to predict the potential pathways involved in 1,25(OH)₂D₃ chemosensitization, followed by molecular docking analysis and analysis of molecular dynamics simulations. Finally, experimental validation were conducted to elucidate the potential mechanisms by which 1,25(OH)₂D₃ enhances the sensitivity of HCC to sorafenib. Compound and target screening identified 730 predicted targets of 1,25(OH)₂D₃ and its derivatives, 1144 genes associated with sorafenib resistance in hepatocellular carcinoma, and 56 potential chemosensitization targets from the intersection analysis. KEGG analysis suggested that the chemosensitization effect of 1,25(OH)₂D₃ might be mediated by the FoxO signaling pathway. Molecular docking showed that both 1,25(OH)₂D₃ and its derivatives could stably bind to FOXO3A, a key gene in the FoxO family, and molecular dynamics simulation analysis further indicated that the two bind well together. In vitro experiments demonstrated the synergistic effects of 1,25(OH)₂D₃ and sorafenib, significantly inhibiting the viability and colony formation rate of sorafenib-resistant hepatocellular carcinoma cells. Additionally, the combination treatment promoted apoptosis and inhibited autophagy. Furthermore, the combination modulated the FOXO3A/FOXM1 signaling axis. This study reveals that 1,25(OH)₂D₃ enhances the chemosensitivity of hepatocellular carcinoma (HCC) to sorafenib, with underlying mechanisms potentially involving the targeted modulation of the FOXO3A/FOXM1 signaling axis and the reversal of sorafenib-resistant phenotypes through the regulation of apoptotic and autophagic pathways. Full article

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

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4 pages, 150 KiB

Open AccessEditorial

Editorial for the Special Issue “Aging, Age-Related Changes in the Brain and the Progression of Alzheimer’s Disease”

by A. N. M. Mamun-Or-Rashid

Curr. Issues Mol. Biol. 2025, 47(5), 318; https://doi.org/10.3390/cimb47050318 - 29 Apr 2025

Abstract

Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive decline, memory impairment, and synaptic dysfunction [...] Full article

(This article belongs to the Special Issue Aging, Age-Related Changes in the Brain and the Progression of Alzheimer’s Disease)

19 pages, 1175 KiB

Open AccessReview

Applications of Growth Factors in Implant Dentistry

by Balen Hamid Qadir, Mohammed Aso Abdulghafor, Mohammed Khalid Mahmood, Faraedon Mostafa Zardawi, Mohammed Taib Fatih, Handren Ameer Kurda, Zana Fuad Noori, Herve Tassery, Delphine Tardivo, Arthur Falguiere, Vincent Romao and Romain Lan

Curr. Issues Mol. Biol. 2025, 47(5), 317; https://doi.org/10.3390/cimb47050317 - 28 Apr 2025

Abstract

Growth factors are proteins that play an essential part in tissue regeneration and development. They attach surface receptors to mediate their actions on cells. Signaling systems within cells are activated when growth factors bind to their associated receptors. These signaling cascades control the [...] Read more.

Growth factors are proteins that play an essential part in tissue regeneration and development. They attach surface receptors to mediate their actions on cells. Signaling systems within cells are activated when growth factors bind to their associated receptors. These signaling cascades control the transcription of genes involved in cellular functions like proliferation, differentiation, migration, protein synthesis, and metabolism. This narrative review provides a comprehensive update on the use of growth factors in implant dentistry with a special emphasis on human clinical trials. Since wound healing and osseointegration are pre-requisites of successful implantation and growth factors are important components of homeostasis and wound healing, this review first starts with the basic biology of wound healing. Then, it presents the specific role of growth factors in wound healing and tissue regeneration. Finally, the PubMed database was searched using relevant keywords with some filters related to the research question. Out of the initial 44 records, all the clinical human studies (n = 29) with the actual dental implant placement and its assessment were included. These results of the published and relevant literature over the last 25 years on different applications of growth factors in the field of implant dentistry are critically discussed. Full article

(This article belongs to the Section Bioorganic Chemistry and Medicinal Chemistry)

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20 pages, 3325 KiB

Open AccessArticle

Evaluation of Sapindus mukorossi Gaertn Flower Water Extract on In Vitro Anti-Acne Activity

by Zibing Zhao, Aohuan Zhang, Liya Song, Congfen He and Huaming He

Curr. Issues Mol. Biol. 2025, 47(5), 316; https://doi.org/10.3390/cimb47050316 - 28 Apr 2025

Abstract

Background: Sapindus mukorossi Gaertn is a deciduous tree with saponins as the main active ingredients and has been utilized in medicine and cosmetic industries. Currently, the investigations of S. mukorossi mainly focus on the pericarp and seed kernel parts, while other parts [...] Read more.

Background: Sapindus mukorossi Gaertn is a deciduous tree with saponins as the main active ingredients and has been utilized in medicine and cosmetic industries. Currently, the investigations of S. mukorossi mainly focus on the pericarp and seed kernel parts, while other parts are yet to be studied and developed. This study aimed to investigate the anti-acne potential of S. mukorossi flower water extract (SMFW) by in vitro experiments. Methods and Results: The DPPH, ABTS, superoxide anion radical scavenging assay, and FRAP assay revealed the strong antioxidant activities of SMFW. The antibacterial activity of SMFW against Cutibacterium acnes has been evaluated with an inhibition diameter of 14.08 ± 0.63 mm. Furthermore, SMFW significantly inhibited the secretion of pro-inflammatory cytokines (TNF-α, IL-6, and IL-β) in lipopolysaccharide (LPS)-stimulated THP-1 macrophages. Transcriptome analysis showed that SMFW treatment reversed 448 LPS-upregulated DEGs and 349 LPS-downregulated DEGs, and KEGG enrichment analysis indicated that SMFW might exert its anti-inflammatory effect via NOD-like receptor and JAK-STAT signaling pathways. Conclusions: SMFW exhibited antioxidant, antibacterial, and anti-inflammatory properties in in vitro experiments. RNA-seq analysis indicated that SMFW may alleviate inflammation by regulating the NOD-like receptor and JAK-STAT signaling pathways. In summary, SMFW has shown potential for anti-acne efficacy and can be used as a natural raw material in cosmetics. Full article

(This article belongs to the Section Bioorganic Chemistry and Medicinal Chemistry)

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15 pages, 4721 KiB

Open AccessArticle

A Multi-Model Machine Learning Framework for Identifying Raloxifene as a Novel RNA Polymerase Inhibitor from FDA-Approved Drugs

by Nhung Thi Hong Van and Minh Tuan Nguyen

Curr. Issues Mol. Biol. 2025, 47(5), 315; https://doi.org/10.3390/cimb47050315 - 28 Apr 2025

Abstract

RNA-dependent RNA polymerase (RdRP) represents a critical target for antiviral drug development. We developed a multi-model machine learning framework combining five traditional algorithms (ExtraTreesClassifier, RandomForestClassifier, LGBMClassifier, BernoulliNB, and BaggingClassifier) with a CNN deep learning model to identify potential RdRP inhibitors among FDA-approved drugs. [...] Read more.

RNA-dependent RNA polymerase (RdRP) represents a critical target for antiviral drug development. We developed a multi-model machine learning framework combining five traditional algorithms (ExtraTreesClassifier, RandomForestClassifier, LGBMClassifier, BernoulliNB, and BaggingClassifier) with a CNN deep learning model to identify potential RdRP inhibitors among FDA-approved drugs. Using the PubChem dataset AID 588519, our ensemble models achieved the highest performance with accuracy, ROC-AUC, and F1 scores higher than 0.70, while the CNN model demonstrated complementary predictive value with a specificity of 0.77 on external validation. Molecular docking studies with the norovirus RdRP (PDB: 4NRT) identified raloxifene as a promising candidate, with a binding affinity (−8.8 kcal/mol) comparable to the positive control (−9.2 kcal/mol). The molecular dynamics simulation confirmed stable binding with RMSD values of 0.12–0.15 nm for the protein–ligand complex and consistent hydrogen bonding patterns. Our findings suggest that raloxifene may possess RdRP inhibitory activity, providing a foundation for its experimental validation as a potential broad-spectrum antiviral agent. Full article

(This article belongs to the Special Issue Molecular Biology of Viral Replication and Associated Disease Outcomes)

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17 pages, 9247 KiB

Open AccessArticle

Network Pharmacology and In Vitro Experimental Validation Reveal the Anti-Inflammatory and Anti-Apoptotic Effects of Lotus Leaf Extract in Treating Inflammatory Diarrhea in Pigs

by Yu Zheng, Jiana Zheng, Jiao Wang, Junxin Li, Jiali Liu, Bohan Zheng, Qinjin Li, Xiaohong Huang and Zhaoyan Lin

Curr. Issues Mol. Biol. 2025, 47(5), 314; https://doi.org/10.3390/cimb47050314 - 28 Apr 2025

Abstract

The objective of this research was to investigate the efficacy of lotus leaf in the prevention and treatment of inflammatory diarrhea in pigs, utilizing network pharmacology and in vitro methodologies. Initially, LC-MS was employed to analyze the constituents of lotus leaf extract (LLE); [...] Read more.

The objective of this research was to investigate the efficacy of lotus leaf in the prevention and treatment of inflammatory diarrhea in pigs, utilizing network pharmacology and in vitro methodologies. Initially, LC-MS was employed to analyze the constituents of lotus leaf extract (LLE); then, the TCMSP database was utilized to identify the active components and their corresponding targets. The GeneCards database was consulted to identify disease-related targets pertinent to inflammatory diarrhea in pigs. A drug ingredient–disease target network was constructed using Cytoscape software. Subsequently, the STRING database facilitated protein interaction analysis, which was also visualized through Cytoscape. Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were conducted based on the genes shared between disease and LLE targets. Molecular docking of the active ingredients with key targets was performed using Autodock Vina. Subsequently, an in vitro LPS-induced inflammation model was established using IPEC-J2 cells to validate the predictions made through network pharmacology. Verification was conducted via flow cytometry and Western blot analysis. The LC-MS assay and TCMSP retrieval results revealed that Quercetin, Nuciferine, Kaempferol, Leucodelphinidin, and Catechin were identified as the main compounds of LLE, associated with 181 potential targets. A total of 5995 targets were linked to inflammatory diarrhea in pigs, with 159 overlapping targets identified between the bioactive compounds and the disease. Notable key targets included TNF-α, IL-6, caspase-3, TP53, and AKT, which are integral to inflammation and apoptosis processes. GO functional annotation indicated significant enrichment in biological processes such as gene expression regulation and transcription from RNA polymerase II promoters. KEGG pathway analysis highlighted critical pathways, including TNF signaling and apoptosis. Furthermore, molecular docking analyses demonstrated that the bioactive components of lotus leaf exhibited a strong binding affinity for essential targets, including AKT1, BAX, caspase-3, CCL2, IL-6, IL-10, MPK14, NOS3, PTGS1, and TNF-α. In vitro experiments confirmed that LLE significantly inhibited LPS-induced apoptosis in IPEC-J2 cells and suppressed the activation of the TNF-α-mediated apoptosis pathway. This study offers novel insights into the therapeutic potential of Chinese medicine and its constituents in addressing inflammatory diarrhea in pigs. Full article

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

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16 pages, 2719 KiB

Open AccessArticle

A Transcriptomic Study on the Toxic Effects of Iodide (I⁻) Wet Deposition on Pepper (Capsicum annuum) Leaves

by Rui Yu, Zhu-Ling Ma, Min Wang and Jie Jin

Curr. Issues Mol. Biol. 2025, 47(5), 313; https://doi.org/10.3390/cimb47050313 - 28 Apr 2025

Abstract

Radioactive iodine (¹²⁹I), released into the environment from human nuclear activities, poses significant health risks to the biosphere due to its long half-life and mobility. This study investigates the toxic effects of wet-deposited iodine on the growth of chili pepper seedlings [...] Read more.

Radioactive iodine (¹²⁹I), released into the environment from human nuclear activities, poses significant health risks to the biosphere due to its long half-life and mobility. This study investigates the toxic effects of wet-deposited iodine on the growth of chili pepper seedlings (Capsicum annuum L.) under soil cultivation conditions. Using sodium iodide (NaI) as the exposure agent, transcriptomic analysis was conducted to evaluate the molecular responses of chili pepper leaves to iodine at concentrations of 2, 4, and 8 ppm. The study identified 2440 and 1543 differentially expressed genes (DEGs) in leaves exposed to 2 ppm vs. 4 ppm iodine and 2 ppm vs. 8 ppm iodine, respectively. GO enrichment analysis showed that DEGs at 4 ppm were significantly associated with protein–chromophore linkage, extracellular region, and iron ion binding, while those at 8 ppm were enriched in defense response, cell wall components, and iron ion binding. Iodine stress disrupted key pathways associated with photosynthesis, antioxidant defense, and cuticle biosynthesis. In particular, the downregulation of key genes related to protein–chromophore binding, lipid metabolism, and cell wall organization indicated reduced photosynthetic efficiency and weakened stress resistance. This study provides molecular-level insights into the ecological risks of iodine stress in plants and offers a scientific basis for managing iodine contamination and breeding iodine-tolerant chili pepper cultivars. Full article

(This article belongs to the Special Issue Functional Genomics and Comparative Genomics Analysis in Plants, 3rd Edition)

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22 pages, 8254 KiB

Open AccessArticle

Poria cocos Ethanol Extract Restores MK-801-Induced Cytoskeleton Regulation in Neuro2A and IMR-32 Cells and Locomotor Hyperactivity in C57BL/6 Mice by Modulating the Rho Signaling Pathway

by Ya-Ying Chang, Cheng-Wei Lu, Tzu-Yu Lin, I-Shiang Tzeng, Yi-Chyan Chen and Mao-Liang Chen

Curr. Issues Mol. Biol. 2025, 47(5), 312; https://doi.org/10.3390/cimb47050312 - 28 Apr 2025

Abstract

Poria cocos extract attenuates MK-801-induced hyperactivity via RhoA/ROCK1 pathway modulation in mice. Background/Objectives: Poria cocos (P. cocos), a traditional East Asian medicinal mushroom, serves as a medicine and nutritional supplement, has been used to improve sleep and mood. Its bioactive compounds [...] Read more.

Poria cocos extract attenuates MK-801-induced hyperactivity via RhoA/ROCK1 pathway modulation in mice. Background/Objectives: Poria cocos (P. cocos), a traditional East Asian medicinal mushroom, serves as a medicine and nutritional supplement, has been used to improve sleep and mood. Its bioactive compounds may regulate calcium signaling and Rho family proteins, which are linked to cytoskeletal remodeling and psychiatric symptoms. This study investigated the effects of P. cocos ethanol extract (PCEE) on Rho signaling, cytoskeleton dynamics, and behavior in MK-801-treated cells and mice. Methods: PCEE components were analyzed using HPLC. IMR-32 and Neuro2A cells were treated with MK-801 and PCEE to assess changes in F-actin (via fluorescence staining), cell migration (wound healing and Transwell assays), and Rho signaling proteins (by immunoblotting). In vivo, C57BL/6 mice received MK-801 to induce hyperactivity, followed by PCEE treatment. RhoA/ROCK1 pathway protein levels in the prefrontal cortex were analyzed. Results: PCEE reversed MK-801-induced inhibition of cell migration, F-actin disruption, and dysregulation of Rho-related proteins (RhoGDI1, RhoA, CDC42, Rac1, ROCK1, MLC2, PFN1). In mice, PCEE significantly reduced MK-801-induced hyperactivity and normalized RhoA/ROCK1 signaling in the brain. Conclusion: PCEE modulates cytoskeletal dynamics by regulating RhoA/ROCK1 signaling and attenuates MK-801-induced behavioral and molecular changes, suggesting its therapeutic potential for psychosis with fewer adverse effects. Full article

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

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16 pages, 1242 KiB

Open AccessArticle

A Novel Application of RNA In Situ Hybridization in the Analysis of Vitamin D Receptor Expression in Psoriatic Skin Tissue Following Etanercept Treatment

by Max Lundgren, Alexandra Kuliszkiewicz, Martin Gillstedt, Azin Jasmin Zanghaneh and Amra Osmancevic

Curr. Issues Mol. Biol. 2025, 47(5), 311; https://doi.org/10.3390/cimb47050311 - 28 Apr 2025

Abstract

Psoriasis is a chronic inflammatory skin disease marked by abnormal keratinocyte proliferation and immune dysregulation. The vitamin D receptor (VDR) plays a crucial role in regulating skin cell growth and immune responses, but its expression in psoriatic skin and modulation by treatment remain [...] Read more.

Psoriasis is a chronic inflammatory skin disease marked by abnormal keratinocyte proliferation and immune dysregulation. The vitamin D receptor (VDR) plays a crucial role in regulating skin cell growth and immune responses, but its expression in psoriatic skin and modulation by treatment remain unclear. This study aimed to analyze VDR mRNA expression in psoriatic skin tissue before and after etanercept therapy using RNAscope, an RNA in situ hybridization technique that, to the best of our knowledge, has not previously been applied in psoriasis research. Two bio-naïve adult patients with moderate to severe plaque psoriasis received etanercept (50 mg weekly) for 12 weeks. Skin biopsies from lesional and perilesional areas were collected at baseline and post-treatment. VDR expression was assessed in different epidermal layers and the dermis using a semi-quantitative scoring system. In one patient, a statistically significant decrease in VDR expression was observed in the perilesional dermis after treatment (p < 0.001), though this preliminary finding warrants careful interpretation given the very limited cohort size. Both patients exhibited a non-significant trend toward increased VDR expression in the lesional epidermis post-treatment. These preliminary findings suggest that etanercept may modulate VDR expression in psoriatic skin, but individual variability and the small sample size preclude definitive conclusions. The study primarily demonstrates the feasibility of using RNAscope for VDR analysis in patients with psoriasis, an approach that may be novel in this context, and underscores the need for larger investigations to confirm these preliminary findings and further clarify the role of VDR in disease pathogenesis and treatment response. Full article

(This article belongs to the Section Bioorganic Chemistry and Medicinal Chemistry)

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16 pages, 750 KiB

Open AccessReview

Harnessing Exosomes: A Brief Overview of Nature’s Nanocarriers and a Glimpse into Their Implications in Pituitary Neuroendocrine Tumors (PitNETs)

by Ligia Gabriela Tataranu

Curr. Issues Mol. Biol. 2025, 47(5), 310; https://doi.org/10.3390/cimb47050310 - 28 Apr 2025

Abstract

The study of exosomes is currently an area of major interest in the scientific world, especially after the discovery of their function as natural nanocarriers. Their intrinsic features in regulating intricate intracellular pathways have put them in the spotlight in the last decade, [...] Read more.

The study of exosomes is currently an area of major interest in the scientific world, especially after the discovery of their function as natural nanocarriers. Their intrinsic features in regulating intricate intracellular pathways have put them in the spotlight in the last decade, and it has been considered that by harnessing them, the future of cellular communication and therapeutic innovation will experience a breakthrough, leading to pioneering research. However, it has been demonstrated that exosomes have various important roles, from conferring resistance to viral infections of the human placenta to transfer of oncogenic signals between cells, reshaping cellular metabolism, promoting angiogenesis, mediating immune evasion, serving as biomarkers in cancer diagnosis and prognosis, and having implications in the therapeutic management of certain diseases. Besides the general overview of exosomes as nature’s nanocarriers and their functions, this article aims to discuss their implications in PitNETs, especially since there have been many recent studies regarding the clinical benefits of biomolecular medicine. Full article

(This article belongs to the Special Issue Exosomes in Tissue Regeneration and Disease Therapy)

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21 pages, 6859 KiB

Open AccessReview

Targeting SHP2 with Natural Products: Exploring Saponin-Based Allosteric Inhibitors and Their Therapeutic Potential

by Dong-Oh Moon

Curr. Issues Mol. Biol. 2025, 47(5), 309; https://doi.org/10.3390/cimb47050309 - 27 Apr 2025

Abstract

SHP2, a non-receptor protein tyrosine phosphatase, plays a pivotal role in regulating intracellular signaling pathways, particularly the RAS/MAPK and PI3K/AKT cascades, which are critical for cellular proliferation, differentiation, and survival. Aberrant SHP2 activity, often driven by gain-of-function mutations, is implicated in oncogenesis and [...] Read more.

SHP2, a non-receptor protein tyrosine phosphatase, plays a pivotal role in regulating intracellular signaling pathways, particularly the RAS/MAPK and PI3K/AKT cascades, which are critical for cellular proliferation, differentiation, and survival. Aberrant SHP2 activity, often driven by gain-of-function mutations, is implicated in oncogenesis and drug resistance, making it an attractive therapeutic target. Traditional inhibitors targeting SHP2’s catalytic site face limitations such as poor selectivity and low bioavailability. Recent advancements in allosteric inhibitors, specifically targeting SHP2’s tunnel site, offer improved specificity and pharmacokinetics. Natural products, especially saponins with their unique structural diversity, have emerged as promising candidates for SHP2 inhibition. This review explores the structural and functional dynamics of SHP2, highlights the potential of saponin-based inhibitors, and discusses their mechanisms of action, including their interactions with key residues in the tunnel site. The therapeutic potential of saponins is further emphasized by their ability to overcome the limitations of catalytic inhibitors and their applicability in combination therapies. Future directions include structural optimization to improve pharmacokinetics and the development of innovative strategies such as PROTACs to enhance the clinical utility of saponin-based SHP2 inhibitors. Full article

(This article belongs to the Special Issue Molecular Insights into Food-Derived Natural Products and Their Biological Activities—2nd Edition)

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15 pages, 4748 KiB

Open AccessArticle

Fraxin Alleviates Atherosclerosis by Inhibiting Oxidative Stress and Inflammatory Responses via the TLR4/PI3K/Akt Pathway

by Yaru Wang, Bailing Wei, Mingyang Leng, Jiali He, Yicheng Zhao, Haohao Xia, Haibin Luo and Xue Bai

Curr. Issues Mol. Biol. 2025, 47(5), 308; https://doi.org/10.3390/cimb47050308 - 27 Apr 2025

Abstract

Fraxin is a bioactive compound derived from Cortex Fraxini. It is known for its diverse biological activities and numerous benefits, including anti-inflammatory, antioxidant, analgesic, antimicrobial, antiviral, and immunomodulatory effects. Despite growing interest in natural compounds for cardiovascular diseases Fraxin’s atheroprotective properties and molecular [...] Read more.

Fraxin is a bioactive compound derived from Cortex Fraxini. It is known for its diverse biological activities and numerous benefits, including anti-inflammatory, antioxidant, analgesic, antimicrobial, antiviral, and immunomodulatory effects. Despite growing interest in natural compounds for cardiovascular diseases Fraxin’s atheroprotective properties and molecular targets have not yet been fully elucidated. To address this gap, our research employed an integrated approach combining network pharmacology, molecular docking simulations, and in vitro biological validation to systematically unravel Fraxin’s therapeutic mechanisms against atherosclerosis (AS). The results showed that 84 potential targets for Fraxin against AS were predicted through public databases, and the key target TLR4 was identified by protein–protein interaction and molecular docking analysis. GO enrichment and KEGG pathway analysis revealed that these potential targets were significantly enriched in the PI3K-Akt and oxidative stress responses pathways. Subsequently conducted in vitro studies validated that Fraxin modulates the TLR4/PI3K/Akt signaling pathway to suppress reactive oxygen species generation and downregulate pro-inflammatory cytokines including Il1b, Il6, and Tnf thereby slowing atherosclerotic disease advancement. This investigation methodically delineates Fraxin’s therapeutic targets and underlying molecular mechanisms in AS management, establishing a scientific foundation for its potential translation into clinical practice. Full article

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

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22 pages, 294 KiB

Open AccessReview

CRISPR-Cas9 and Its Bioinformatics Tools: A Systematic Review

by Alicja Jasieniecka and Inês Domingues

Curr. Issues Mol. Biol. 2025, 47(5), 307; https://doi.org/10.3390/cimb47050307 - 27 Apr 2025

Abstract

CRISPR-Cas9 has revolutionized genetic research with bioinformatics tools essential for tasks like guide RNA design, off-target prediction, and data analysis. This systematic review summarizes the functionality and key features of such tools. Studies published after 2012 were selected through searches in PubMed, Google [...] Read more.

CRISPR-Cas9 has revolutionized genetic research with bioinformatics tools essential for tasks like guide RNA design, off-target prediction, and data analysis. This systematic review summarizes the functionality and key features of such tools. Studies published after 2012 were selected through searches in PubMed, Google Scholar, and other sources, with the final search conducted on 9 November 2024. Seven studies met the criteria, describing around 45 tools, including databases and functional programs. Tools like CRISPResso, CHOPCHOP, and Cas-OFFinder were commonly highlighted, with a major focus on single-guide RNA (sgRNA) design and optimization. Some tools provided specific solutions, while others offered broader functionality, but most lacked experimental validation. Several tools were developed by the authors of the studies, introducing potential bias. Findings highlight a need for integrated platforms that combine functionalities, reducing reliance on fragmented workflows. Current tools often address narrow tasks, complicating their practical application. Future development should focus on comprehensive, multitasking tools to improve accessibility and streamline research processes. Limitations include the descriptive nature of most studies, potential author bias, and challenges in comparing tools objectively. Nonetheless, this review underscores bioinformatics’ critical role in CRISPR research and emphasizes the need for innovative, standardized platforms. This study received no funding and was not registered. Full article

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

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31 pages, 4089 KiB

Open AccessArticle

A Pilot Investigation of Circulating miRNA Expression in Individuals Exposed to Aluminum and Welding Fumes

by Gözde Öztan, Halim İşsever, Tuğçe İşsever, Fatma Oğuz, Sevgi Canbaz, Canan Küçükgergin and Kazım Yalçın Arga

Curr. Issues Mol. Biol. 2025, 47(5), 306; https://doi.org/10.3390/cimb47050306 - 26 Apr 2025

Abstract

The objectives of this study comprise the identification of key miRNAs and their target genes associated with severe tolerance in individuals exposed to aluminum and welding fumes, and the elucidation of the underlying regulatory mechanisms. In this study, the levels of seven miRNAs [...] Read more.

The objectives of this study comprise the identification of key miRNAs and their target genes associated with severe tolerance in individuals exposed to aluminum and welding fumes, and the elucidation of the underlying regulatory mechanisms. In this study, the levels of seven miRNAs (hsa-miR-19a-3p, hsa-miR-130b-3p, hsa-miR-25-3p, hsa-miR-363-3p, hsa-miR-92a-3p, hsa-miR-24-3p, and hsa-miR-19b-3p) were analyzed using both hsa-miR-16-5p and RNU6 (U6 snRNA) as reference miRNAs to validate normalization reliability. The qRT-PCR method was used on blood serum samples from 16 workers who were exposed to aluminum, 16 workers who were exposed to welding fumes, and 16 healthy controls who were not exposed to aluminum or welding fumes. We determined heavy metal levels from serum samples of workers exposed to aluminum and welding fumes and control groups using the ICP-OES method. The expression levels of hsa-miR-19a-3p and hsa-miR-19b-3p in aluminum-exposed and control groups were found to be statistically significant (p < 0.05). When workers exposed to welding fumes were compared with the those in the control groups, the expression levels of hsa-miR-19a-3p, hsa-miR-130b-3p, hsa-miR-92a-3p, and hsa-miR-24-3p were observed to be statistically significant (p < 0.05). This study shows that the identification of miRNAs and target genes in different biological functions and pathways plays an important role in understanding the molecular mechanisms of responses to heavy metal toxicity. We share the view that the study will make a significant contribution to the literature in that seven candidate miRNAs can be used as possible biomarkers for exposure to aluminum and welding fumes in humans. Full article

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

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