Current Issues in Molecular Biology

17 pages, 3676 KB

Open AccessArticle

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

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

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

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Abstract

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

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

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

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20 pages, 3442 KB

Open AccessArticle

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

by Mehmet Uğur Karabat and Mehmet Cudi Tuncer

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

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Abstract

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

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

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

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28 pages, 4640 KB

Open AccessArticle

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

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

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

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Abstract

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

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

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

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10 pages, 865 KB

Open AccessArticle

miR-145-5p and miR-148b-3p Expression Is Inversely Associated with Pten Expression in Prostate Pathologies

by Karla Lizbeth Morales Hernández, Noemí García Magallanes, Marco Alvarez Arrazola, Fred Luque Ortega, Martín Irigoyen Arredondo, Fernando Bergez Hernandez and Eliakym Arambula Meraz

Curr. Issues Mol. Biol. 2025, 47(9), 782; https://doi.org/10.3390/cimb47090782 - 22 Sep 2025

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Abstract

Prostate cancer (PCa) represents a significant cause of cancer-associated mortality in the male population worldwide and constitutes a multifactorial disease influenced by genetic and epigenetic factors. Deregulation of genes such as AR and PTEN, as well as alteration in the expression of microRNAs [...] Read more.

Prostate cancer (PCa) represents a significant cause of cancer-associated mortality in the male population worldwide and constitutes a multifactorial disease influenced by genetic and epigenetic factors. Deregulation of genes such as AR and PTEN, as well as alteration in the expression of microRNAs (miRNAs), including miR-145-5p and miR-148b-3p, has been observed in this pathology. This study aimed to explore the correlation between the expression of miR-145-5p, miR-148b-3p, and PTEN in prostate tissue, providing initial insight into their potential interaction in cancer biology. We analyzed 71 samples, comprising 41 from patients with confirmed prostate cancer (PCa group) and 30 from patients with benign prostatic disease (BPD group). Our findings demonstrated a statistically significant association between both miRNAs and the PTEN gene, specifically between miR-148b-3p and PTEN (p = 0.00001) and between miR-145-5p and PTEN (p = 0.0078). These findings support the hypothesis that reduced levels of these miRNAs may be linked to PTEN regulation in prostate pathologies and underscore their potential relevance in PCa biology. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era, 2nd Edition)

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19 pages, 20956 KB

Open AccessArticle

Analysis of Potential Q-Markers for Salt-Processed Alismatis Rhizoma in Diuresis Based on Fingerprinting Technology and Network Analysis

by Lin Yan, Zemin Ou, Yun Wang, Yan Tong, Jinyu Wang and Dewen Liu

Curr. Issues Mol. Biol. 2025, 47(9), 783; https://doi.org/10.3390/cimb47090783 - 21 Sep 2025

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Abstract

Introduction: The ability of salt-processed Alismatis Rhizoma (SAR) (Alisma plantago-aquqtica L.) to nourish Yin and promote urination is stronger than that of Alismatis Rhizoma (AR). However, there are few studies focused on evaluating the quality of its medicinal materials. Objectives: This study [...] Read more.

Introduction: The ability of salt-processed Alismatis Rhizoma (SAR) (Alisma plantago-aquqtica L.) to nourish Yin and promote urination is stronger than that of Alismatis Rhizoma (AR). However, there are few studies focused on evaluating the quality of its medicinal materials. Objectives: This study aimed to identify potential quality markers (Q-markers) for SAR, thereby providing a more reliable basis for its quality control and clinical application. Methods: Q-markers were identified through fingerprinting and chemical pattern recognition analysis of 15 batches of SAR. The diuretic effects of these markers were then verified by network analysis and molecular docking. Results: HPLC fingerprints of 15 SAR batches were established, with similarity analysis showing values > 0.85 (0.852–0.990). Chemical pattern recognition identified six critical compounds contributing to SAR quality: alisol F, alisol C 23-acetate, alisol A, alisol A 24-acetate, alisol B 23-acetate, and an alisol O isomer (VIP > 1.0). Network analysis revealed 76 overlapping targets between these compounds and diuretic-related diseases, with core targets including non-receptor tyrosine kinase (SRC), epidermal growth factor receptor (EGFR), mitogen-activated protein kinase 1 (MAPK1), which were identified through protein–protein interaction (PPI) network analysis, with degrees of 27, 24, and 22, respectively. Key pathways involved were the EGFR tyrosine kinase inhibitor resistance pathway, calcium signaling pathway, tumor necrosis factor signaling pathway, etc. Molecular docking confirmed strong binding interactions between the Q-markers and the hub targets, particularly alisol B 23-acetate with MAPK1 (−60.10 kcal·mol⁻¹) and alisol A 24-acetate with EGFR (−46.14 kcal·mol⁻¹) and SRC (−48.86 kcal·mol⁻¹). The diuretic effects of SAR are likely mediated through anti-inflammatory actions and regulation of water–sodium balance via multi-target and multi-pathway mechanisms. Conclusion: This study provides a robust foundation for quality control and clinical application of SAR, though further in vivo validation is warranted. Full article

(This article belongs to the Section Molecular Pharmacology)

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2 pages, 152 KB

Open AccessRetraction

RETRACTED: Haghmorad et al. Oral Administration of Myelin Oligodendrocyte Glycoprotein Attenuates Experimental Autoimmune Encephalomyelitis through Induction of Th2/Treg Cells and Suppression of Th1/Th17 Immune Responses. Curr. Issues Mol. Biol. 2022, 44, 5728–5740

by Dariush Haghmorad, Bahman Yousefi, Majid Eslami, Ali Rashidy-Pour, Mahdieh Tarahomi, Maryam Jadid Tavaf, Azita Soltanmohammadi, Simin Zargarani, Aleksandr Kamyshnyi and Valentyn Oksenych

Curr. Issues Mol. Biol. 2025, 47(9), 781; https://doi.org/10.3390/cimb47090781 - 20 Sep 2025

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Abstract

The journal retracts the article “Oral Administration of Myelin Oligodendrocyte Glycoprotein Attenuates Experimental Autoimmune Encephalomyelitis through Induction of Th2/Treg Cells and Suppression of Th1/Th17 Immune Responses” [...] Full article

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

22 pages, 1549 KB

Open AccessReview

Natural Products Targeting the Androgen Receptor Signaling Pathway: Therapeutic Potential and Mechanisms

by Sitong Wu, Esveidy Isabel Oceguera Nava, Dennis Ashong, Guanglin Chen and Qiao-Hong Chen

Curr. Issues Mol. Biol. 2025, 47(9), 780; https://doi.org/10.3390/cimb47090780 - 19 Sep 2025

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Abstract

The androgen receptor (AR) signaling pathway is the primary driver of prostate cancer initiation and progression, including the development of castration-resistant prostate cancer (CRPC). Because current AR-targeted therapies inevitably encounter drug resistance, novel strategies to suppress AR signaling are urgently needed. Natural products [...] Read more.

The androgen receptor (AR) signaling pathway is the primary driver of prostate cancer initiation and progression, including the development of castration-resistant prostate cancer (CRPC). Because current AR-targeted therapies inevitably encounter drug resistance, novel strategies to suppress AR signaling are urgently needed. Natural products represent a rich and structurally diverse source of bioactive compounds capable of targeting AR at multiple regulatory levels. This review overviews the interactions between natural products and the AR signaling axis through distinct mechanisms, including inhibition of testosterone production and 5α-reductase activity, direct antagonism of AR, and induction of AR degradation. In addition, several compounds disrupt AR nuclear translocation, downregulate AR splice variants, or suppress AR signaling indirectly through epigenetic regulation, microRNA modulation, or interference with co-regulator networks. Preclinical studies provide compelling evidence that these agents can effectively interrupt AR signaling, thereby suppressing prostate cancer growth. However, challenges remain, particularly the limited pharmacokinetic characterization, lack of in vivo validation, and scarcity of clinical studies. Future research should focus on improving bioavailability, exploring synergistic combinations with existing therapies, and advancing well-designed in vivo and clinical investigations. Collectively, these efforts may establish natural products as lead compounds to modulate AR signaling for prostate cancer prevention and treatment. Full article

(This article belongs to the Special Issue Natural Phytochemicals as Modulators of Cellular Pathways and Therapeutic Targets in Disease Models)

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22 pages, 5983 KB

Open AccessArticle

Bioactive Component Screening and Mechanistic Study of the Anti-Diabetic Activity of Lophatherum gracile Brongn Extract

by Rong Wang, Xuefeng Liu, Kuan Yang, Shaojing Liu, Lili Yu, Yunmei Chen, Nana Wang, Yaqi Hu and Bei Qin

Curr. Issues Mol. Biol. 2025, 47(9), 779; https://doi.org/10.3390/cimb47090779 - 19 Sep 2025

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Abstract

Type 2 diabetes mellitus (T2DM), a metabolic disorder defined by glucose and lipid metabolism dysregulation, has become a major global health issue. Hence, effective measures to prevent T2DM are urgently required. Lophatherum gracile Brongn (LGB) has been used in managing diabetes-related systemic diseases. [...] Read more.

Type 2 diabetes mellitus (T2DM), a metabolic disorder defined by glucose and lipid metabolism dysregulation, has become a major global health issue. Hence, effective measures to prevent T2DM are urgently required. Lophatherum gracile Brongn (LGB) has been used in managing diabetes-related systemic diseases. However, the hypoglycemic bioactive components in LGB and the mechanisms underlying their hypoglycemic activity remain elusive. The current study sought to characterize the bioactive components of LGB and elucidate its mechanism of action against T2DM. Six common characteristic peaks were identified from six batches of LGB, with 39 characteristic chemical components preliminarily identified. Through component–activity correlation analysis, three functional components—namely isoorientin, orientin, and isovitexin—were selected as key candidates. In T2DM mice, LGB effectively improved glucose and lipid metabolic dysfunction. Untargeted metabolomics analysis revealed that LGB modulated pathways related to lipid and carbon metabolism. 16S rRNA gene sequencing and targeted metabolomics analysis revealed that LGB decreased the ratio of Firmicutes to Bacteroidetes and increased the abundance of bacterial groups such as Lactobacillales and Bacteroides. Additionally, LGB elevated the levels of SCFAs, specifically acetic and butyric acid. Moreover, LGB alleviated intestinal inflammation and upregulated the expression of tight junction proteins by inhibiting the LPS/TLR4/NF-κB signaling pathway. This study demonstrated that LGB treated T2DM, with isoorientin, orientin, and isovitexin identified as the main contributing components. The hypoglycemic mechanism is linked to the “gut microbiota−SCFAs−inflammatory response” signaling axis. Full article

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

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17 pages, 2851 KB

Open AccessArticle

Pharmacological Potential of Arthrospira platensis in Mitigating Sub-Chronic Colitis: Redox Homeostasis and Gut Microbiota Modulation

by Meriem Aziez, Betitera Yanat, Cristina Rodriguez-Diaz, Ramona Suharoschi, Romana Vulturar, Simona-Codruta Heghes, Nawel Guenaoui, Awadh M. Ali, Eduardo Garcia-Fuentes and Noureddine Bribi

Curr. Issues Mol. Biol. 2025, 47(9), 778; https://doi.org/10.3390/cimb47090778 - 19 Sep 2025

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Abstract

Inflammatory bowel diseases (IBDs) are complex disorders involving interconnected immune, oxidative, and microbial dysregulations. Arthrospira platensis (Spirulina) is a rich source of bioactive compounds with antioxidant, anti-inflammatory, and immunomodulatory properties. This study investigates the pharmacological efficacy of its aqueous extract (APA) in mitigating [...] Read more.

Inflammatory bowel diseases (IBDs) are complex disorders involving interconnected immune, oxidative, and microbial dysregulations. Arthrospira platensis (Spirulina) is a rich source of bioactive compounds with antioxidant, anti-inflammatory, and immunomodulatory properties. This study investigates the pharmacological efficacy of its aqueous extract (APA) in mitigating 2,4-Dinitrobenzene Sulfonic Acid (DNBS)-induced sub-chronic colitis with a focus on restoring redox balance and modulating gut microbiota composition. APA’s antioxidant capacity was assessed in vitro by 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azino-bis (3-ethylbenzthiazoline-6-sulphonic) acid (ABTS) radical scavenging, and metal chelation assays. In vivo, BALB/c mice received two DNBS inductions to establish sub-chronic colitis and were treated with APA (50, 100, and 200 mg/kg). Therapeutic efficacy was assessed through clinical scoring, histopathological assessment, biochemical analysis, and gut microbiota profiling based on 16S rRNA gene sequencing. APA exhibited strong antioxidant activity and significantly attenuated colitis severity, as evidenced by reduced Disease Activity Index (DAI) scores, decreased colon inflammation, suppression of Myeloperoxidase (MPO)-mediated neutrophil infiltration, and modulation of redox biomarkers. Moreover, metagenomic profiling revealed APA-induced modulation of the gut microbiota, mainly through a decreased abundance of pathogenic genera such as Staphylococcus and Enterobacteriaceae. APA demonstrates potent antioxidant, anti-inflammatory, and microbiota-modulating activities, supporting its potential as a complementary therapy for IBDs and encouraging further clinical studies. Full article

(This article belongs to the Special Issue Microalga Biotechnology and Applications: Molecular and Cellular Mechanisms)

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15 pages, 5753 KB

Open AccessArticle

In Silico Study of Natural Polyphenols as Potential Metabolic Modulators in Mitigating Lipotoxicity in Non-Alcoholic Fatty Liver Disease via Thyroid Hormone Receptor Alpha Activation

by Evangelia K. Konstantinou, Athanasios A. Panagiotopoulos and Maria Dimitriou

Curr. Issues Mol. Biol. 2025, 47(9), 777; https://doi.org/10.3390/cimb47090777 - 19 Sep 2025

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Abstract

Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder described by the deposition of triglycerides in the liver, which primarily occurs due to insulin resistance and obesity. Thyroid hormone receptor alpha (THRA) is involved in metabolic pathways that promote lipolysis, which can prevent [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder described by the deposition of triglycerides in the liver, which primarily occurs due to insulin resistance and obesity. Thyroid hormone receptor alpha (THRA) is involved in metabolic pathways that promote lipolysis, which can prevent the accumulation of liver fat. As a possible treatment for NAFLD, this in silico study examines the binding interactions between THRA and polyphenols and flavonoids present in fruits and vegetables. Including caffeic acid, curcumin, and chlorogenic acid, the binding affinities of the natural substances to THRA were found comparable to the hormone T3, boosting the THRA–TRAP220 complex, promoting fatty acid oxidation, while decreasing lipid accumulation in the liver. Full article

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

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18 pages, 780 KB

Open AccessReview

Anti-TB Drugs for Drug-Sensitive and Drug-Resistant Mycobacterium tuberculosis: A Review

by Kara Lukas, Madeleine T. Dang, Clare Necas and Vishwanath Venketaraman

Curr. Issues Mol. Biol. 2025, 47(9), 776; https://doi.org/10.3390/cimb47090776 - 19 Sep 2025

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Abstract

Tuberculosis (TB) is a global health challenge caused by Mycobacterium tuberculosis, with drug resistance, treatment toxicity, and treatment adherence challenges continuing to impede control efforts. The objective of this review is to explore current advancements in TB treatment, for both drug-sensitive and drug-resistant [...] Read more.

Tuberculosis (TB) is a global health challenge caused by Mycobacterium tuberculosis, with drug resistance, treatment toxicity, and treatment adherence challenges continuing to impede control efforts. The objective of this review is to explore current advancements in TB treatment, for both drug-sensitive and drug-resistant TB, focusing on pharmacologic regimens, diagnostics, and adjunctive therapies. For drug-sensitive TB, a 4-month rifapentine–moxifloxacin regimen has been proven to be non-inferior to the traditional 6-month standard, while optimized pyrazinamide dosing or faropenem substitution may improve culture conversion and reduce adverse events. In drug-resistant TB, regimens such as the bedaquiline, pretomanid, linezolid, and moxifloxacin have demonstrated efficacy with substantially shorter treatment duration; however, incidents of hepatotoxicity and linezolid-related neuropathy require careful monitoring. Adjunctive therapies, such as metformin, N-Acetylcysteine, aspirin, and statins, show promising effects in modulating host immunity and reducing long-term lung damage. Advances in diagnostics, including whole genome sequencing and CRISPR-based methods, are enabling rapid detection of resistance mutations and directed therapy. Vaccine development has advanced beyond the BCG vaccine to explore vaccines with enhanced immunogenicity or ones that are safe for immunocompromised patients. Implementation strategies such as video directly observed therapy are improving adherence; additionally, community-based, technology-supported interventions significantly improve TB knowledge and compliance. An integrated approach that combines optimized pharmacologic regimens, host-directed therapies, advanced diagnostics, and patient-centered public health strategies is essential to reduce TB incidence, long-term morbidity, and mortality. Full article

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

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24 pages, 1399 KB

Open AccessReview

Combination of the First-in-Class Imipridone ONC201 and Standard Anticancer Therapies as a Rational Approach for Therapeutic Benefit

by Brahmi Shenoy, Miloni Mandani, Meena Chintamaneni and Sonal M. Manohar

Curr. Issues Mol. Biol. 2025, 47(9), 775; https://doi.org/10.3390/cimb47090775 - 18 Sep 2025

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Abstract

The development of drugs for cancer treatment faces critical challenges due to the heterogeneity in cancers, metastatic nature of the disease, lack of efficacy, toxicity, and drug resistance. This makes it quite important to understand the complexities of cancer as well as the [...] Read more.

The development of drugs for cancer treatment faces critical challenges due to the heterogeneity in cancers, metastatic nature of the disease, lack of efficacy, toxicity, and drug resistance. This makes it quite important to understand the complexities of cancer as well as the limitations of druggable targets. ONC201 (also known as dordaviprone/TIC10/Modeyso^TM), a first-in-class member of the imipridone family, has been shown to kill cancer cells selectively. Recently, it has received FDA approval as the first and only treatment for recurrent H3K27M-mutant diffuse midline glioma. The unique pharmacophore, favorable therapeutic index, ability to induce TRAIL and the integrated stress response (ISR), activation of natural killer cells, and ability to diffuse across the blood–brain barrier are the unique characteristics of ONC201. ONC201 has shown effectiveness against various cancers, and this has been evident in many preclinical studies. ONC201 as a single agent, although useful, has some limitations, which could be addressed by using combination strategies. ONC201 has shown synergism with other drugs, leading to greater tumor cell death or reduced tumor growth. Next-generation imipridones, viz. ONC206 and ONC212, are more potent analogs of ONC201 and exhibit similar characteristics. In this review, we discuss the therapeutic potential of ONC201 and its analogs using combination strategies across different cancers. Full article

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

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18 pages, 3893 KB

Open AccessArticle

Metabolome and Transcriptome Analyses of the Molecular Mechanism Underlying Light-Induced Anthocyanin Accumulation in Pepper (Capsicum annuum L.) Peel

by Qinqin He, Liming He, Zongqin Feng, Yunyi Xiao, Qiucheng Qiu, Jiefeng Liu, Hanbing Han and Xinmin Huang

Curr. Issues Mol. Biol. 2025, 47(9), 774; https://doi.org/10.3390/cimb47090774 - 18 Sep 2025

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Abstract

Under light exposure, certain pepper cultivars synthesize large amounts of anthocyanins in their pericarps, with the illuminated areas exhibiting black coloration. However, research on light-induced anthocyanin formation in pepper fruit, particularly the related metabolites and genetic changes, remains limited. To identify the key [...] Read more.

Under light exposure, certain pepper cultivars synthesize large amounts of anthocyanins in their pericarps, with the illuminated areas exhibiting black coloration. However, research on light-induced anthocyanin formation in pepper fruit, particularly the related metabolites and genetic changes, remains limited. To identify the key genes involved in localized anthocyanin synthesis under light conditions, we investigated the black pericarps (light-exposed) and green pericarps of pepper variety MSCJ1 under illumination. Metabolomics analysis identified 579 metabolites in the black and green pepper pericarps, with 50 differentially accumulated metabolites. Petunidin-3-(6″-p-coumaroyl-glucoside) and delphinidin-3-p-coumaroyl-rutinoid accumulation represented the main factor underlying light-induced blackening of the pericarp. RNA-seq identified 121 differentially expressed genes that were significantly enriched in the flavonoid biosynthesis pathway. The genes for phenylalanine ammonia lyase (Capana09g002200, Capna09g002190), cinnamic acid hydroxylase (Capana06g000273), chalcone synthase (Capana05g002274), flavonoid 3-hydroxylase (Capana02g002586), flavonoid 3′-hydroxylase (MSTRG.15987), dihydroflavonol 4-reductase (Capana02g002763), anthocyanin synthase (Capana01g000365), UDP glucosyltransferase (Capana03g000135), and glutathione S-transferase (Capana02g002285) were key genes for anthocyanin synthesis and transport. Transcription factors bHLH (Capana09g001426, Capana09g001427), HSFB3 (Capana05g000086), and TCP4 (Capana07g002142) participated in the regulation of anthocyanin synthesis. These results broaden our understanding of the mechanism of light-induced anthocyanin synthesis in pepper peel. Full article

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

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14 pages, 863 KB

Open AccessReview

Insulin-like Growth Factor 1 (IGF-1) in Hair Regeneration: Mechanistic Pathways and Therapeutic Potential

by Wang-Ju Hsieh, Wei-Yin Qiu, Ivona Percec and Tsong-Min Chang

Curr. Issues Mol. Biol. 2025, 47(9), 773; https://doi.org/10.3390/cimb47090773 - 18 Sep 2025

Viewed by 495

Abstract

IGF-1 (insulin-like growth factor 1) is a growth factor primarily secreted by dermal papilla cells on hair-bearing skin that stimulates hair follicle proliferation and vascularization, and promotes the transition to the anagen growth phase of the hair follicle by activating key pathways such [...] Read more.

IGF-1 (insulin-like growth factor 1) is a growth factor primarily secreted by dermal papilla cells on hair-bearing skin that stimulates hair follicle proliferation and vascularization, and promotes the transition to the anagen growth phase of the hair follicle by activating key pathways such as PI3K/Akt and MAPK/ERK. IGF-1 also inhibits apoptosis, prolongs the follicular growth phase, and boosts VEGF expression, which supports microcirculation and nutrient delivery to hair follicles. The combined effects of IGF-1 and other growth factors, including VEGF, KGF (FGF-7), and PDGF, further amplify its effects on follicular cell proliferation and tissue repair. IGF-1’s ability to regulate the hair growth cycle and its interactions with other signaling pathways make it a compelling therapeutic target for hair loss disorders. Both preclinical models and clinical evidence highlight IGF-1 as a promising therapeutic option for conditions like androgenetic alopecia (AGA), where IGF-1 levels are typically diminished. While topical IGF-1 treatments have shown efficacy and safety with minimal systemic absorption, additional research is needed to improve delivery methods, such as liposomal gels and exosome-based carriers, and to evaluate long-term effects. Full article

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

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19 pages, 10295 KB

Open AccessArticle

Protective Effect of Hepcidin on Sepsis-Associated Acute Kidney Injury via Activating the Nrf2/GPX4 Signaling Pathway

by Liang-Bo Guo, Shao-Sheng Wu, Feng Xu, Xin-Xing Chen and Heng Fan

Curr. Issues Mol. Biol. 2025, 47(9), 772; https://doi.org/10.3390/cimb47090772 - 18 Sep 2025

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Abstract

Background: Hepcidin not only sustains systemic iron homeostasis but also functions as an antimicrobial peptide. During this study, we sought to analyze the ability of hepcidin to protect against sepsis-associated acute kidney injury (SAKI) and elucidated its underlying mechanisms in mediating ferroptotic pathways. [...] Read more.

Background: Hepcidin not only sustains systemic iron homeostasis but also functions as an antimicrobial peptide. During this study, we sought to analyze the ability of hepcidin to protect against sepsis-associated acute kidney injury (SAKI) and elucidated its underlying mechanisms in mediating ferroptotic pathways. Methods: A SAKI mouse model was created via cecal ligation and puncture (CLP), along with an LPS-induced Human Kidney-2 (HK-2) cell model, to study the protective mechanism of hepcidin against SAKI. Through the analysis of renal injury biomarkers and ferroptosis-related molecules, combined with quantitative detection of nuclear factor-erythroid 2-related factor-2 (Nrf2) nuclear translocation and glutathione peroxidase 4 (GPX4), a regulatory protein of ferroptosis, we uncovered the hepcidin-mediated mechanisms underlying ferroptosis in SAKI. Results: Hepcidin significantly attenuated renal function impairment in mice with SAKI and reduced the sepsis-driven increase in inflammatory mediators. As sepsis was associated with enhanced renal ferroptosis, hepcidin exerted a therapeutic effect by mitigating ferroptosis to a degree comparable with that of the ferroptosis inhibitor Ferrostatin-1 (Fer-1). Furthermore, hepcidin conferred renoprotective effects in SAKI by promoting the nuclear translocation of Nrf2, which in turn mediated the upregulation of the downstream anti-ferroptotic protein GPX4. Importantly, the Nrf2 inhibitor ML385 abrogated both the hepcidin-induced nuclear translocation of Nrf2 and the subsequent increase in GPX4 expression. Conclusions: Protective effects of hepcidin against SAKI are mediated by the Nrf2/GPX4 ferroptosis pathway, underscoring its therapeutic potential for SAKI. Full article

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

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11 pages, 1779 KB

Open AccessArticle

The First Complete Chloroplast Genome Sequence of the Cyrtomium hemionitis Fern

by Junxi Zhao, Panpan Shi, Xiaoxuan Wang, Shuosheng Zhang and Haixian Zhan

Curr. Issues Mol. Biol. 2025, 47(9), 771; https://doi.org/10.3390/cimb47090771 - 18 Sep 2025

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Abstract

Cyrtomium hemionitis is a Cyrtomium fern with potential medicinal value; however, the lack of chloroplast genome data for this species limits its utilization and exploitation. In this study, the Illumina NovoSeq 6000 platform and SPAdes v3.14.1 were used to sequence and assemble the [...] Read more.

Cyrtomium hemionitis is a Cyrtomium fern with potential medicinal value; however, the lack of chloroplast genome data for this species limits its utilization and exploitation. In this study, the Illumina NovoSeq 6000 platform and SPAdes v3.14.1 were used to sequence and assemble the chloroplast genome of C. hemionitis. The chloroplast genome was 151,295 bp in length and exhibited a typical circular, double-stranded, quadripartite plastome architecture, with a GC content of 42.43%. Additionally, it included 30 high-frequency codons, 26 of which ended with A or U. In total, we annotated 130 coding genes, which included 88 protein-coding genes, 8 rRNA genes, and 34 tRNA genes. The IR (inverted repeat) boundaries of the genus Cyrtomium differed from those of common plants, with differences discovered in the JLB (large single-copy, inverted repeat b) and JLA (large single-copy, inverted repeat a) boundaries in this genus. Additionally, the phylogeny of this genus showed that C. hemionitis was more closely related to C. falcatum, whereas Dryopteris crassirhizoma was closely related to the genus Cyrtomium. These findings have significant implications for future research and can serve as a reference for the molecular evolution, systematic development, and utilization of C. hemionitis. Full article

(This article belongs to the Section Molecular Plant Sciences)

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17 pages, 7817 KB

Open AccessArticle

French Maritime Pine Bark Extract Alleviates Lung Injury by Regulating Inflammatory–Oxidative–Apoptotic Pathway and P2X7 Receptor Expression in LPS-Induced Sepsis

by Nergis Ulas, Seckin Ozkanlar, Serkan Yildirim, Omer Aydin and Yunusemre Ozkanlar

Curr. Issues Mol. Biol. 2025, 47(9), 770; https://doi.org/10.3390/cimb47090770 - 18 Sep 2025

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Abstract

Introduction: Sepsis is a dysregulated systemic immune response to infection which may result in mortality. It may also lead to organ injury, including injury to the lung. French maritime pine bark extract (MPBE) has been proposed to prevent/treat various inflammatory diseases due to [...] Read more.

Introduction: Sepsis is a dysregulated systemic immune response to infection which may result in mortality. It may also lead to organ injury, including injury to the lung. French maritime pine bark extract (MPBE) has been proposed to prevent/treat various inflammatory diseases due to its strong anti-inflammatory and antioxidant effects. This study evaluates the protective and therapeutic effects of MPBE on lung injury induced by intraperitoneal E. coli lipopolysaccharide (LPS) in rats. Materials and Methods: The study design was as follows: Control, MPBE20, MPBE50, LPS, LPS+MPBE20 and LPS+MPBE50. Blood and lung tissue samples were collected 6 h after the LPS induction following a 10-day administration of MPBE. Results: LPS-induced sepsis was confirmed by the overproduction of IL-1β and TNF-α in bloodstream compared to the Control (p < 0.001). Lung injury was determined by severe histopathological changes and neutrophil infiltration in the lung tissue following intraperitoneal LPS injection. In lung tissue, MPBE improved the levels of P2X7R, TLR4, NLRP3, IL-1β, TNF-α, JNK, H2AX, 8-OHdG, MDA, GSH, Caspase-1 and Caspase-3, and pathological changes in MPBE+LPS groups compared to the LPS group. Conclusions: MPBE appears to regulate P2X7R signaling and the inflammatory–apoptotic pathway by protecting the lung from oxidative cell damage in LPS-induced sepsis in vivo. Full article

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

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16 pages, 2937 KB

Open AccessArticle

The Analysis of Solanum lycopersicum Sap Dark Proteome Reveals Ordered and Disordered Protein Abundance

by Francisco Antonio Reyes-Soria, Francisco Guillén-Chable, Enrique Castaño de la Serna, Lorenzo Felipe Sánchez-Teyer, Miguel Angel Herrera-Alamillo, Alejandro Pereira-Santana and Luis Carlos Rodriguez-Zapata

Curr. Issues Mol. Biol. 2025, 47(9), 769; https://doi.org/10.3390/cimb47090769 - 18 Sep 2025

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Abstract

Protein identity and functional roles within the cell provide the landscape of proteomics and other high-throughput technologies. However, not all protein sequences are cataloged with an identity or a functional protein family. The lack of identity and functional role of a set of [...] Read more.

Protein identity and functional roles within the cell provide the landscape of proteomics and other high-throughput technologies. However, not all protein sequences are cataloged with an identity or a functional protein family. The lack of identity and functional role of a set of proteins are collectively named as the dark proteome. Key structural features are, for example, ordered sequences (with a defined structural arrangement) and disordered sequences (presenting one or more intrinsically disordered stretches). Here, we reanalyzed eight proteomic datasets and the subset of the “unknown” proteome of S. lycopersicum to describe if there is a relationship between disorder, length, and tissue-specific abundance of proteins with key structural features in the relation of ordered/disordered abundance in the protein sequences. Intriguingly, we unveil that from the S. lycopersicum proteome, the “unknown” subset represents around 10% only. We further cataloged dark proteome in terms of ordered and disordered sequences and found that proteins with disorder represent around 23% of the total “unknown” proteins. Also, we describe an amino acid composition and sequence length enrichment both, in the ordered and disordered fraction of the dark proteome. Finally, we describe that proteins within the dark proteome can be related to a specific location and abundance in an organ or tissue. An unknown protein sequence presenting a combination of specific length and degree of disorder can be explored with other biotechnological alternatives to improve responses or tolerate abiotic stress, also serving as sensors during development or ripening stages. These findings suggest an opportunity to study “protein darkness” in terms of disorder and functional associations. Full article

(This article belongs to the Special Issue Technological Advances Around Next-Generation Sequencing Application)

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27 pages, 1769 KB

Open AccessReview

Beyond Purification: Evolving Roles of Fusion Tags in Biotechnology

by Tsutomu Arakawa and Teruo Akuta

Curr. Issues Mol. Biol. 2025, 47(9), 768; https://doi.org/10.3390/cimb47090768 - 17 Sep 2025

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Abstract

Genetic fusion of a tag sequence to a target protein, or protein of interest (POI), is one of the most widely used technologies for recombinant expression. Tag-fusion proteins can enhance soluble expression, prolong half-life, increase binding avidity, and facilitate protein purification or refolding. [...] Read more.

Genetic fusion of a tag sequence to a target protein, or protein of interest (POI), is one of the most widely used technologies for recombinant expression. Tag-fusion proteins can enhance soluble expression, prolong half-life, increase binding avidity, and facilitate protein purification or refolding. In addition, tag-fusion proteins can be used to identify POI-binding partners through pull-down or immunoprecipitation assays. Beyond these classical applications, tags have evolved to serve as multifunctional tools, enabling real-time imaging, spatial localization, targeted delivery, and regulation of protein activity in living systems. Some engineered tags also allow conditional control, such as pH or ligand-dependent stabilization, thus expanding their utility in synthetic biology and therapeutic design. Here, we summarize protein-based and peptide-based tags, as well as methods for tag removal. While not fully comprehensive, this review aims to help researchers design suitable tag formats for specific goals. Full article

(This article belongs to the Special Issue Recombinant Proteins for Molecular Biology Research: Technologies and Applications)

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24 pages, 2508 KB

Open AccessReview

Mechanistic Insights into the Abiotic Stress Adaptation of Salix Species: A Comprehensive Review of Physiological, Molecular, and Sex-Dimorphic Responses

by Pengcheng Sun, Fangjing Fan, Yinggao Liu and Fuyuan Zhu

Curr. Issues Mol. Biol. 2025, 47(9), 767; https://doi.org/10.3390/cimb47090767 - 17 Sep 2025

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Abstract

As key species for ecological restoration, Salix spp. thrive in harsh environments, including high-altitude regions, arid zones, and saline–alkaline soils, demonstrating remarkable resilience to abiotic stressors. Recent advances in genomics, transcriptomics, and functional gene research have shed light on the mechanisms underlying Salix [...] Read more.

As key species for ecological restoration, Salix spp. thrive in harsh environments, including high-altitude regions, arid zones, and saline–alkaline soils, demonstrating remarkable resilience to abiotic stressors. Recent advances in genomics, transcriptomics, and functional gene research have shed light on the mechanisms underlying Salix species’ responses to drought, salinity, heavy metals, and low-temperature stresses. This review systematically synthesizes the physiological, biochemical, and molecular adaptations of Salix to abiotic stress, with a particular focus on underexplored areas such as sex-dimorphic regulation and integrated hormone-ROS signaling pathways. We emphasize the dynamic interplay between transcription factors, hormonal crosstalk, and ROS signaling that underpins the stress response, highlighting sex-specific variations that modulate adaptive capacity. Moreover, we discuss the synergistic roles of exogenous additives and rhizosphere microorganisms in enhancing stress resistance. This comprehensive analysis provides critical insights for breeding stress-resilient Salix cultivars and for future research into stress adaptation mechanisms in woody plants. Full article

(This article belongs to the Special Issue New Advances in Plant Responses to Environmental Stresses)

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21 pages, 3927 KB

Open AccessReview

Mechanisms Linking Obesity with Non-Alcoholic Fatty Liver Disease (NAFLD) and Cardiovascular Diseases (CVDs)—The Role of Oxidative Stress

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

Curr. Issues Mol. Biol. 2025, 47(9), 766; https://doi.org/10.3390/cimb47090766 - 16 Sep 2025

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Abstract

Obesity concerns a wide range of the population, tending to become a major factor for diseases’ progression and fatality rate increases, with implications concerning the cardiovascular system’s deterioration. Obesity is closely linked with metabolic derangements concerning lipid storage and circulation, and the cellular [...] Read more.

Obesity concerns a wide range of the population, tending to become a major factor for diseases’ progression and fatality rate increases, with implications concerning the cardiovascular system’s deterioration. Obesity is closely linked with metabolic derangements concerning lipid storage and circulation, and the cellular metabolism affecting most of the internal organs, especially liver and cellular function. In this current study, an analysis of the linking mechanisms between obesity, lipid deterioration, liver, and lipid tissue homeostasis will be performed, with special attention to the pathophysiological characteristics of these detrimental effects on the NAFLD (non-alcoholic fatty liver disease) and the cellular function of the endothelial blood cells, with special reference to the additional burdening of obesity on the autonomous nervous system signaling, and the resulting hypertension. Despite the very complex and pluripotent pathogenic mechanisms with which obesity is intervening in these processes, it could be safely deduced that metabolic and lipid transport manipulation could serve as a crucial factor towards the cellular and tissue function improvement, as the interlinkages in the mechanisms, although highly analyzed, have not been completely deciphered until now. Full article

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

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42 pages, 1810 KB

Open AccessReview

Reactive Sulfur Species and Protein Persulfidation: An Emerging Redox Axis in Human Health and Disease

by Celia María Curieses Andrés, Fernando Lobo, José Manuel Pérez de la Lastra, Elena Bustamante Munguira, Celia Andrés Juan and Eduardo Pérez Lebeña

Curr. Issues Mol. Biol. 2025, 47(9), 765; https://doi.org/10.3390/cimb47090765 - 16 Sep 2025

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Abstract

Reactive sulfur species (RSS)—hydrogen sulfide (H₂S), low-molecular-weight persulfides/polysulfides and protein persulfidation—constitute a third redox axis alongside ROS and RNS. Nanomolar H₂S, produced by trans-sulfuration (CBS/CSE) and 3-MST, is oxidized by sulfide–quinone reductase to persulfides that fuel the respiratory chain [...] Read more.

Reactive sulfur species (RSS)—hydrogen sulfide (H₂S), low-molecular-weight persulfides/polysulfides and protein persulfidation—constitute a third redox axis alongside ROS and RNS. Nanomolar H₂S, produced by trans-sulfuration (CBS/CSE) and 3-MST, is oxidized by sulfide–quinone reductase to persulfides that fuel the respiratory chain while curbing superoxide. Reversible persulfidation reprograms cysteine sensors in metabolism (GAPDH), inflammation (NLRP3, p47^phox) and transcription (Keap1/NRF2), linking RSS to energy balance, vasodilation, innate immunity and neuroplasticity. Disrupted sulfur signaling—deficit or overload—contributes to heart failure, sarcopenia, neurodegeneration, cancer and post-COVID syndromes. Therapeutically, slow-release donors (SG1002, GYY4137), mitochondria-targeted vectors (AP39), photo- or thiol-activated “smart” scaffolds, diet-derived polysulfides/isothiocyanates and microbiota engineering aim to restore the protective RSS window. Key challenges are a narrow therapeutic margin and real-time quantification of persulfide fluxes. Harnessing RSS therefore offers a route to rebalance redox homeostasis across diverse chronic diseases. Full article

(This article belongs to the Special Issue Mechanistic Insights into the Antioxidant Activity of Bioorganic Molecules: A Chemical Perspective)

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20 pages, 4318 KB

Open AccessArticle

IDO Activation Affects BDNF/TrkB Signaling Pathway, Oxidative Stress, and Mitochondrial Enzymatic Activities in Temporal Lobe Epilepsy

by Jingwen Xu, Liping Wei, Junling Fu, Ziting Kong and Lun Cai

Curr. Issues Mol. Biol. 2025, 47(9), 764; https://doi.org/10.3390/cimb47090764 - 16 Sep 2025

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Abstract

Indoleamine 2,3-dioxygenase (IDO) activation by seizures elevates toxic tryptophan metabolites linked to seizure exacerbation. Brain-derived neurotrophic factor (BDNF)/tyrosine kinase B (TrkB) signaling, oxidative stress, and mitochondrial respiratory chain complex dysfunction contribute to temporal lobe epilepsy (TLE), but their regulatory links remain unclear. Male [...] Read more.

Indoleamine 2,3-dioxygenase (IDO) activation by seizures elevates toxic tryptophan metabolites linked to seizure exacerbation. Brain-derived neurotrophic factor (BDNF)/tyrosine kinase B (TrkB) signaling, oxidative stress, and mitochondrial respiratory chain complex dysfunction contribute to temporal lobe epilepsy (TLE), but their regulatory links remain unclear. Male Kunming mice were grouped into Control, Control + 1-Methyl-DL-tryptophan (1-MT), TLE, and TLE + 1-MT. TLE was induced with 300 mg/kg pilocarpine. Two weeks after modeling, 1-MT (50 mg/kg) was administered twice daily for two weeks in 1-MT groups. Assessments included video monitoring to record seizure frequency and duration; Nissl and Fluoro-Jade B (FJB) staining to evaluate neuronal damage; real-time quantitative PCR (qRT-PCR) and Western blot to detect IDO, BDNF, and TrkB expression; assays for the following oxidative stress markers: malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT); and detection of mitochondrial complex I/IV activities. Results showed TLE mice had significantly increased IDO expression, BDNF/TrkB over-activation, elevated oxidative stress, impaired mitochondrial complex I/IV activities, severe neuronal damage, and increased seizure frequency/duration. 1-MT intervention reversed all these pathological changes, restoring levels to near-control status. This indicates IDO activation promotes TLE progression, which is associated with modulation of the BDNF/TrkB signaling pathway, exacerbation of oxidative stress, and impairment of mitochondrial complex I/IV activities—supporting IDO as a potential therapeutic target for TLE. Full article

(This article belongs to the Section Molecular Medicine)

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38 pages, 4420 KB

Open AccessArticle

Uncovering the Tumorigenic Blueprint of PFOS and PFOA Through Multi-Organ Transcriptomic Analysis of Biomarkers, Mechanisms, and Therapeutic Targets

by Krisha Mathur, Aleezah Khaliq, Stephanie Park, Nathan Chu, Vaishnavi M. Burra, Norah Kanukolanu, Ellen Costello and Sivanesan Dakshanamurthy

Curr. Issues Mol. Biol. 2025, 47(9), 763; https://doi.org/10.3390/cimb47090763 - 15 Sep 2025

Viewed by 716

Abstract

Per- and polyfluoroalkyl substances (PFASs), called forever chemicals, persist in the environment and bioaccumulate, posing significant health risks. While epidemiological studies have linked exposure to specific PFAS types, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS), to an increased incidence of various cancers, [...] Read more.

Per- and polyfluoroalkyl substances (PFASs), called forever chemicals, persist in the environment and bioaccumulate, posing significant health risks. While epidemiological studies have linked exposure to specific PFAS types, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS), to an increased incidence of various cancers, specific tumorigenesis mechanisms are unknown. Here, we investigated the potential molecular markers and signatures of perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) tumorigenesis. We performed a comprehensive transcriptomic analysis across multiple species and tissue types (N = 529) using PFOS and PFOA-exposed RNA-Seq samples. Conserved signatures demonstrate significant disruptions in seven key carcinogenic characteristics including metabolic reprogramming, epigenetic modifications, immune suppression, oxidative stress, and genomic instability. Tumorigenic markers such as SERPINE1, FN1, PLIN2, ALDOA, TRIB3, and TSC22D3 and their associated pathways may act independently or synergistically to promote a pro-tumorigenic environment. Additionally, PPARα, LARP1, ACOX1, MYC, and MYCN were identified as key upstream regulators supporting disruptions in lipid metabolism, oxidative stress, and uncontrolled cell proliferation. In liver samples, low concentrations of PFOS and PFOA were sufficient to exhibit tumorigenic signatures associated with tumorigenesis initiation and development. Inferred mechanisms of ccRCC initiation and development were linked to lipid metabolism dysregulation and immunosuppressive signaling. In prostate and testicular xenograft tumor models, carcinogenic mechanisms for tumor progression and promotion were hypothesized. Receptor-mediated signaling and protein synthesis was disrupted in prostate cancer and epigenetic alterations and ECM remodeling observed in testicular cancer. We also explored potential therapeutic rescue strategies, including chemopreventive agents for early intervention. All our findings provide hypotheses for PFOS/PFOA-induced tumorigenesis; however, experimental studies are required to establish translational relevance. All the R codes developed in this study are publicly available. Full article

(This article belongs to the Special Issue Genomic Analysis of Common Disease, 2nd Edition)

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12 pages, 2898 KB

Open AccessArticle

Field-Deployable Detection of Chestnut Blight Pathogen Cryphonectria parasitica Using Enzyme-Mediated Duplex Exponential Amplification

by Shuai Wang, Zhongwei Feng, Yiming Liu, Changyun Tang, Kai Guo and Jiafu Hu

Curr. Issues Mol. Biol. 2025, 47(9), 762; https://doi.org/10.3390/cimb47090762 - 15 Sep 2025

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Abstract

Chestnut blight caused by Cryphonectria parasitica poses a major threat to chestnut plantations worldwide. Rapid, field-deployable diagnostic tools are essential for effective disease surveillance and management. Here, we developed and validated an enzyme-mediated duplex exponential amplification (EmDEA) assay for the specific and sensitive [...] Read more.

Chestnut blight caused by Cryphonectria parasitica poses a major threat to chestnut plantations worldwide. Rapid, field-deployable diagnostic tools are essential for effective disease surveillance and management. Here, we developed and validated an enzyme-mediated duplex exponential amplification (EmDEA) assay for the specific and sensitive detection of C. parasitica. The assay successfully distinguished C. parasitica from non-target fungal species with a detection limit of 10 pg of genomic DNA per reaction. Application to naturally infected bark samples yielded results consistent with those of conventional qPCR. The complete workflow, including crude DNA extraction and fluorescence-based detection under isothermal conditions, was completed within 35 min. Our findings demonstrate that the EmDEA assay is a sensitive, robust, and field-adaptable tool that can be used for the early detection of chestnut blight, with significant potential for deployment in resource-limited environments. Full article

(This article belongs to the Section Molecular Plant Sciences)

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21 pages, 1652 KB

Open AccessArticle

Comparative Molecular Profiling and Bioactivity Analysis of Algerian Propolis: Antioxidant, Antibacterial Activities, and In Silico NRF2-KEAP1 Pathway Modulation

by Amel Reguig, Ahmed Messai, Ibtissam Kahina Bedaida, Diana C. G. A. Pinto, Chawki Bensouici, Abdelmoneim Tarek Ouamane, Artur M. S. Silva and Jean-Philippe Roy

Curr. Issues Mol. Biol. 2025, 47(9), 761; https://doi.org/10.3390/cimb47090761 - 15 Sep 2025

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Abstract

Propolis, a natural bee-derived product rich in diverse phytochemicals with potential therapeutic benefits, remains underexplored in Algeria. This study investigated the molecular profile, antioxidant capacity, and antibacterial activity of propolis sourced from two bioclimatically distinct Algerian regions (humid subtropical Batna and hot desert [...] Read more.

Propolis, a natural bee-derived product rich in diverse phytochemicals with potential therapeutic benefits, remains underexplored in Algeria. This study investigated the molecular profile, antioxidant capacity, and antibacterial activity of propolis sourced from two bioclimatically distinct Algerian regions (humid subtropical Batna and hot desert Biskra) using electrospray ionization mass spectrometry, ultra-high-performance liquid chromatography with diode array detection, and gas chromatography–mass spectrometry. Significant regional variations were observed, with propolis extract 2 (PE2) exhibiting a higher bioactive content, including a constituent not previously reported in propolis. Antioxidant assays (2,2-diphenyl-1-picrylhydrazyl, 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid), ferric reducing antioxidant power, and phenanthroline) demonstrated that PE2 consistently outperformed propolis extract 1 and the reference standards (DPPH IC₅₀: 27.74 µg/mL; FRAP: 5.16 µg/mL). Antibacterial testing demonstrated potent bactericidal effects, particularly for PE2, with minimum inhibitory concentration values equivalent to the minimum bactericidal concentrations required against Staphylococcus aureus ATCC 25923 (18.75 µg/mL) and Escherichia coli ATCC 25922 (133 µg/mL). Molecular docking identified nine bioactive compounds with high KEAP1 binding affinity, with 1,3-O-caffeoyl-dihydrocaffeoylglycerol (first time reported in propolis) showing the strongest binding affinity (−11.02 Kcal/mol). In silico pharmacokinetic predictions further verified its drug-like properties. These findings suggest the tested Algerian propolis samples, as a source of natural alternative antioxidants and antimicrobials, provide a basis for future research in drug discovery and development. 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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21 pages, 910 KB

Open AccessReview

The Diverse Roles of Mitochondria in Regulating Cancer Metastasis

by Shiyu Tang and Biao Yang

Curr. Issues Mol. Biol. 2025, 47(9), 760; https://doi.org/10.3390/cimb47090760 - 15 Sep 2025

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Abstract

Metastasis is the primary cause of cancer-related deaths. As a multi-step process, tumor metastasis encompasses several key aspects. Tumor cells first traverse the basement membrane and subsequently invade the surrounding vascular or lymphatic systems, ultimately leading to secondary colonization. Throughout the progression of [...] Read more.

Metastasis is the primary cause of cancer-related deaths. As a multi-step process, tumor metastasis encompasses several key aspects. Tumor cells first traverse the basement membrane and subsequently invade the surrounding vascular or lymphatic systems, ultimately leading to secondary colonization. Throughout the progression of metastasis, tumor cells can overcome selective pressures and transition between different cellular states, depending on the diverse functions of mitochondria. Mitochondria not only function as energy generators but also co-evolve with host cells, acting as critical signaling hubs in various biological pathways. Under sustained stress conditions such as nutrient deficiency, cellular stress, and the reprogramming of gene expression, alterations in mitochondrial morphology and function can prevent cell death and facilitate the targeted transformation of oncogenes, tumor progression, and the emergence of invasive cell phenotypes. The multifaceted roles of mitochondria enable tumor cells to evade unfavorable environments and establish colonies in more conducive sites. In summary, this review consolidates the complex interactions between mitochondria and cancer while elucidating their significant role in cancer metastasis and therapeutic responses. Full article

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

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15 pages, 782 KB

Open AccessReview

Emerging Therapeutic Strategies for HPV-Related Cancers: From Gene Editing to Precision Oncology

by Muharrem Okan Cakir, Guldide Kayhan, Betul Yilmaz, Mustafa Ozdogan and G. Hossein Ashrafi

Curr. Issues Mol. Biol. 2025, 47(9), 759; https://doi.org/10.3390/cimb47090759 - 15 Sep 2025

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Abstract

Human papillomavirus (HPV) is a major etiological factor in cervical, anal, and oropharyngeal cancers. Although prophylactic vaccines have substantially reduced infection rates, effective therapeutic options for established HPV-associated malignancies remain limited. This review provides an up-to-date overview of emerging strategies to treat HPV-driven [...] Read more.

Human papillomavirus (HPV) is a major etiological factor in cervical, anal, and oropharyngeal cancers. Although prophylactic vaccines have substantially reduced infection rates, effective therapeutic options for established HPV-associated malignancies remain limited. This review provides an up-to-date overview of emerging strategies to treat HPV-driven tumours. Key approaches include immune checkpoint inhibitors, therapeutic vaccines such as VGX-3100 and PRGN-2012, and gene-editing tools like CRISPR/Cas9. Epigenetic drugs, particularly histone deacetylase inhibitors, show promise in reactivating silenced tumour suppressor genes and enhancing antitumour immunity. In addition, natural bioactive compounds and plant-derived molecules are being explored as complementary anti-HPV agents, while drug repurposing and combination therapies offer cost-effective opportunities to broaden treatment options. We also highlight the role of patient-derived organoid models as powerful platforms for personalized drug screening and functional assessment. By integrating these therapeutic innovations with precision oncology approaches, this review outlines a multidimensional framework aimed at improving clinical outcomes and quality of life for patients with HPV-associated cancers. Full article

(This article belongs to the Special Issue Molecular Mechanism of HPV’s Involvement in Cancers)

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26 pages, 4310 KB

Open AccessReview

Intracellular Mis-Localization of Modified RNA Molecules and Non-Coding RNAs: Facts from Hematologic Malignancies

by Argiris Symeonidis, Argyri Chroni, Irene Dereki, Dionysios Chartoumpekis and Argyro Sgourou

Curr. Issues Mol. Biol. 2025, 47(9), 758; https://doi.org/10.3390/cimb47090758 - 14 Sep 2025

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Abstract

The intracellular topography of RNA molecules, encompassing ribonucleotides with biochemical modifications, such as N6-methyladenosine (m6A), 5-methylcytosine (m5C), adenosine to inosine (A → I) editing, and isomerization of uridine to pseudouridine (Ψ), as well as of non-coding RNA molecules, is currently studied within the [...] Read more.

The intracellular topography of RNA molecules, encompassing ribonucleotides with biochemical modifications, such as N6-methyladenosine (m6A), 5-methylcytosine (m5C), adenosine to inosine (A → I) editing, and isomerization of uridine to pseudouridine (Ψ), as well as of non-coding RNA molecules, is currently studied within the frame of the epigenome. Circulating RNA molecules in the intracellular space that have incorporated information by carrying specific modifications depend on the balanced activity and correct subcellular installation of their modifying enzymes, the “writers”, “readers” and “erasers”. Modifications are critical for RNA translocation from the nucleus to the cytoplasm, for stability and translation efficiency, and for other, still-uncovered functions. Moreover, trafficking of non-coding RNA molecules depends on membrane transporters capable of recognizing signal sequences and RNA recognition-binding proteins that can facilitate their transport to different intracellular locations, guiding the establishment of interconnection possibilities with different macromolecular networks. The potential of long non-coding RNAs to form multilayer molecular connections, as well as the differential topology of micro-RNAs in cell nuclei, compared to cytoplasm, has been recognized by several studies. The study of the intercellular compartmentalization of these molecules has recently become feasible thanks to technological progress; however, a wealth of information has not yet been produced that would lead to safe conclusions regarding non-coding RNA’s contributions to the early steps of pathogenesis and disease progression in hematological malignancies. Both, the bone marrow, as the main hematopoietic tissue, and the lymphoid tissues are composed of cells with highly reactive potential to signals affecting the epigenome and initiating cascade pathways in response. Independently or in combination with coexistent driver genetic mutations, especially mutations of enzymes involved in epigenomic surveillance, intracellular microenvironmental alterations within the cell nuclear, cytoplasmic, and mitochondrial compartments can lead to disorganization of hematopoietic stem cells’ epigenomes, promoting the generation of hematological malignancies. In this review, we discuss the various intracellular processes that, when disrupted, may result in the ectopic placement of RNA molecules, either inducing specific modifications or non-coding molecules or promoting hematological malignant phenotypes. The crosstalk between mitochondrial and nuclear genomes and the complex regulatory effects of mis-localized RNA molecules are highlighted. This research approach may constitute a field for new, more specifically targeted therapies in hematology based on RNA technology. Full article

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

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16 pages, 3814 KB

Open AccessArticle

Let-7c/RUNX1 Axis Promotes Cervical Cancer: A Bioinformatic Analysis

by Ana Elvira Zacapala-Gómez, Gabriela Hernández-Galicia, Francisco Israel Torres-Rojas, Christian Johana Baños-Hernández, Julio Ortiz-Ortiz, Hilda Jiménez-Wences, Gabriela Elizabeth Campos-Viguri, Verónica Antonio-Véjar, Judit Alarcón-Millán and Eric Genaro Salmerón-Bárcenas

Curr. Issues Mol. Biol. 2025, 47(9), 757; https://doi.org/10.3390/cimb47090757 - 13 Sep 2025

Viewed by 352

Abstract

Background: Cervical cancer (CC) ranks as the third most common cancer in incidence and mortality in females worldwide. Let-7c is a tumor suppressor miRNA, and its role has been little studied in CC. Runt-related transcription factor 1 (RUNX1) is upregulated in several human [...] Read more.

Background: Cervical cancer (CC) ranks as the third most common cancer in incidence and mortality in females worldwide. Let-7c is a tumor suppressor miRNA, and its role has been little studied in CC. Runt-related transcription factor 1 (RUNX1) is upregulated in several human cancers, such as colorectal cancer. It is a transcription factor that promotes cell proliferation, metastasis, chemotherapy resistance and angiogenesis in colorectal cancer. In this study, we performed a bioinformatic analysis to understand how Let-7c and RUNX1 are involved in the development of CC. Methods: We performed a bioinformatic analysis of Let-7c in CC using GSE and TCGA datasets from GEO, KM-plotter, miRPathDB and Enrich databases. Then, we conducted a comprehensive analysis of RUNX1’s role in CC using TCGA, GSE and HPA datasets from OncoDB, CISTROME, ExPASy, Alibaba, ALGGEN, ENCODE, IGV, GEO, KM-plotter and DiseaseMeth databases. Results: We found that Let-7c expression is decreased in CC. Interestingly, we identified a transcription factor known as RUNX1, as a potential target of Let-7c. Finally, we suggest that RUNX1 could regulate the expression of several genes, promoting CC. Conclusions: The Let-7c/RUNX1 axis promotes CC. Full article

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

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