Current Issues in Molecular Biology

21 pages, 5298 KB

Open AccessArticle

Degenerative Lumbosacral Spinal Stenosis Alters Neurotrophin-3 and -4 Expression: Impact of Metabolic and Behavioral Factors

by Małgorzata Sobańska, Dawid Sobański, Rafał Staszkiewicz, Paweł Gogol and Beniamin Oskar Grabarek

Curr. Issues Mol. Biol. 2025, 47(11), 962; https://doi.org/10.3390/cimb47110962 - 19 Nov 2025

Abstract

Degenerative lumbosacral spinal stenosis (DLSS) is a progressive condition characterized by narrowing of the spinal canal and subsequent neural compression, often leading to chronic pain and disability. Neurotrophins, particularly neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4), play essential roles in maintaining neuronal integrity and modulating [...] Read more.

Degenerative lumbosacral spinal stenosis (DLSS) is a progressive condition characterized by narrowing of the spinal canal and subsequent neural compression, often leading to chronic pain and disability. Neurotrophins, particularly neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4), play essential roles in maintaining neuronal integrity and modulating nociceptive signaling; however, their involvement in DLSS and potential modulation by systemic and behavioral factors remain poorly understood. This study evaluated NT-3 and NT-4 expression in ligamentum flavum (LF) tissue from 96 patients undergoing surgical decompression for DLSS and compared the results to 85 postmortem control samples. Quantitative analyses were performed using RT-qPCR, ELISA, and immunohistochemistry. NT-3 transcript levels were markedly elevated in stenotic LF samples (fold change: 9.12 ± 0.56; p < 0.05), while NT-4 mRNA expression was significantly reduced (fold change: 0.33 ± 0.07; p < 0.05). At the protein level, both NT-3 (134 ± 5.78 pg/mL) and NT-4 (316.77 ± 8.19 pg/mL) concentrations were significantly increased compared to controls (p < 0.05). Although neurotrophin levels did not correlate directly with pain intensity or morphological severity, elevated NT-3 and NT-4 protein levels were significantly associated with obesity, diabetes, alcohol consumption, and tobacco use (p < 0.05). These findings demonstrate that NT-3 and NT-4 are differentially expressed in the ligamentum flavum of patients with DLSS and are influenced by systemic metabolic disturbances and lifestyle factors, suggesting their potential as biomarkers or therapeutic targets in degenerative spinal disease. Full article

(This article belongs to the Section Molecular Medicine)

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12 pages, 3166 KB

Open AccessArticle

Stachydrine Ameliorates Uterine Hypercontractility in Primary Dysmenorrhea by Targeting the COX-2/PGF2α Pathway

by Yongfeng Cheng, Shuo Chen, Dianjie Cao, Hairu Cheng, Siyuan Chen, Yi Shu, Yue Wang and Zhiwu Chen

Curr. Issues Mol. Biol. 2025, 47(11), 961; https://doi.org/10.3390/cimb47110961 - 19 Nov 2025

Abstract

Primary dysmenorrhea (PDM) is a typical gynecologic disease in which uterine contractions and inflammation cause pain. Stachydrine (Sta) possesses multiple pharmacological activities but its effect on PDM has not yet been clarified. In vitro uterine contraction and oxytocin (OT)-induced PDM mouse models were [...] Read more.

Primary dysmenorrhea (PDM) is a typical gynecologic disease in which uterine contractions and inflammation cause pain. Stachydrine (Sta) possesses multiple pharmacological activities but its effect on PDM has not yet been clarified. In vitro uterine contraction and oxytocin (OT)-induced PDM mouse models were used to evaluate the effect of Sta. Sta (10^−6.5 to 10⁻⁴ mol/L) dose-dependently inhibited spontaneous and OT-induced uterine contractions, with maximum inhibition rates of 47.1% and 40.4%, respectively. This effect was reversed by N-nitro-L-arginine (L-NAME) and indomethacin (Indo), suggesting the involvement of the nitric oxide and prostaglandin pathways. In vivo, Sta (20, 10, 5 mg/kg) significantly reduced writhing episodes, prolonged latency to the first response, and alleviated OT-induced uterine damage and inflammation. Additionally, Sta downregulated cyclooxygenase-2 (COX-2) expression in uterine tissue and decreased serum malondialdehyde (MDA) and prostaglandin F₂α (PGF2α) levels. These findings suggest that Sta alleviates PDM by modulating the COX-2/PGF2α pathway, inhibiting uterine contractions, and reducing inflammation and oxidative stress, making it a promising therapeutic candidate for PDM. Full article

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

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15 pages, 426 KB

Open AccessReview

The Complex Role of MAPK/ERK Signaling Pathway in Different Types of Thrombocytopenia

by Peipei Xue and Maoshan Chen

Curr. Issues Mol. Biol. 2025, 47(11), 960; https://doi.org/10.3390/cimb47110960 - 19 Nov 2025

Abstract

Thrombocytopenia is a common hematological disorder caused by a variety of factors. It often complicates diseases and treatment options for this condition are quite limited. There are no approved drugs for certain types of thrombocytopenia. Therefore, understanding the mechanisms of thrombocytopenia is crucial [...] Read more.

Thrombocytopenia is a common hematological disorder caused by a variety of factors. It often complicates diseases and treatment options for this condition are quite limited. There are no approved drugs for certain types of thrombocytopenia. Therefore, understanding the mechanisms of thrombocytopenia is crucial for drug selection and development. The ERK/MAPK signaling pathway plays a significant yet complex role in the formation of megakaryocyte–platelet differentiation and reports on its function are inconsistent. It may be activated, inhibited, or unaffected in different types of thrombocytopenia models. Several drugs targeting the ERK/MAPK signaling pathway have been used for thrombocytopenia in clinical settings, and some small molecule inhibitors have also shown potential therapeutic efficacy for thrombocytopenia through this pathway. In this review, we will summarize both historical and new evidence regarding the roles of the ERK/MAPK signaling pathway in various types of thrombocytopenia and discuss current therapies and future treatment strategies. Full article

(This article belongs to the Section Molecular Medicine)

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30 pages, 796 KB

Open AccessReview

Environmental Stressors and Neuroinflammation: Linking Climate Change to Alzheimer’s Disease

by Mario Caldarelli, Pierluigi Rio, Antonio Gasbarrini, Giovanni Gambassi and Rossella Cianci

Curr. Issues Mol. Biol. 2025, 47(11), 959; https://doi.org/10.3390/cimb47110959 - 18 Nov 2025

Abstract

Environmental exposures are widely recognized as major risk factors for human health. According to projections by the World Health Organization, climate change is expected to cause a significant increase in mortality within the next few decades. Environmental factors, including diet, weather, occupational exposures, [...] Read more.

Environmental exposures are widely recognized as major risk factors for human health. According to projections by the World Health Organization, climate change is expected to cause a significant increase in mortality within the next few decades. Environmental factors, including diet, weather, occupational exposures, and pollutants play a key role in human diseases affecting different systems, such as cardiovascular, pulmonary, gastrointestinal, and neurological. This narrative review explores the relationship between environmental stressors and neuropathological mechanisms, such as microglial and astrocytic activation, oxidative stress, and neuronal injury, involved in neuroinflammation and the associated neurodegeneration. The pathogenesis and progression of Alzheimer’s disease is discussed in detail, establishing a link between environmental stressors and neuroinflammation. A deeper understanding of these neuropathological mechanisms may guide the development of preventive and therapeutic strategies to safeguard brain health in the context of global environmental change. Full article

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

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22 pages, 4663 KB

Open AccessArticle

In Silico Characterization of ADAR1: Structure, Dynamics, and Functional Implications

by Carolyn N. Ashley, Emmanuel Broni, ChaNyah M. Wood and Whelton A. Miller III

Curr. Issues Mol. Biol. 2025, 47(11), 958; https://doi.org/10.3390/cimb47110958 - 18 Nov 2025

Abstract

Adenosine deaminase acting on RNA 1 (ADAR1) is an essential RNA-editing enzyme responsible for the hydrolytic deamination of adenosine to inosine (A-to-I) in double-stranded RNA. This editing mechanism plays a critical role in gene regulation, particularly in neural and immune contexts. Dysregulation of [...] Read more.

Adenosine deaminase acting on RNA 1 (ADAR1) is an essential RNA-editing enzyme responsible for the hydrolytic deamination of adenosine to inosine (A-to-I) in double-stranded RNA. This editing mechanism plays a critical role in gene regulation, particularly in neural and immune contexts. Dysregulation of ADAR1 activity has been implicated in neurological disorders, cancer progression, and immune dysfunction, making ADAR1 an emerging therapeutic target. However, progress in therapeutic development has been hindered by the lack of structural insight into the full-length protein and how its dynamic behavior influences RNA-editing specificity and protein–protein interactions. In this study, we present computational models of the full-length ADAR1p150 isoform generated by homology modeling and further analyzed using molecular dynamics (MD) simulations and principal component analysis (PCA). Our analyses reveal that the dsRBD3 and CDD remain structurally stable, crucial for protein binding and catalytic function, whereas ZBDs and dsRBD1/2 exhibit extensive flexibility, particularly in inter-domain loops, facilitating RNA recognition indicative of conformational selection and fly-casting mechanisms. Free-energy landscape mapping identifies multiple low-energy conformations, highlighting conserved domain cores and flexible loop arrangements. Together, these findings underscore the importance of ADAR1’s dynamic architecture in regulating its function. By linking static structural information with dynamic behavior, the full-length models and dynamic insights presented here provide a valuable framework for future studies of ADAR1 complex formation, editing specificity, and therapeutic targeting. Full article

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

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15 pages, 1235 KB

Open AccessReview

Competition for Chaperones: A Trade-Off Between Thermotolerance and Antiviral Immunity in Plants

by Almas Madirov, Nurgul Iksat, Zhibek Turarbekova, Bakhytbek Abzhalelov and Zhaksylyk Masalimov

Curr. Issues Mol. Biol. 2025, 47(11), 957; https://doi.org/10.3390/cimb47110957 - 18 Nov 2025

Abstract

Molecular chaperones HSP70 and HSP90 represent a critical, yet conflict-ridden, node in plant physiology, particularly under the dual impact of heat stress and viral infection. As key components of both thermotolerance (maintaining proteostasis) and innate immunity (stabilization of NLR receptors), they are simultaneously [...] Read more.

Molecular chaperones HSP70 and HSP90 represent a critical, yet conflict-ridden, node in plant physiology, particularly under the dual impact of heat stress and viral infection. As key components of both thermotolerance (maintaining proteostasis) and innate immunity (stabilization of NLR receptors), they are simultaneously exploited by viruses to facilitate their own life cycle. This review critically analyzes this “trilemma,” focusing on the hypothesis of competition for a limited chaperone pool. We present mechanistic insights indicating that during heat stress, cellular priority shifts towards maintaining global proteostasis, thereby diverting chaperones from immune functions. This resource-based competition mechanism potentially explains the collapse of ETI-immunity, as NLR receptors, deprived of support from the HSP90-SGT1-RAR1 complex, are destabilized and targeted for degradation. We also integrate adjacent signaling pathways into this model, including hormonal cross-talk (SA, JA) and autophagy. Understanding this trade-off opens new perspectives for molecular breeding and the biotechnological engineering of stress-resilient crop varieties. Full article

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

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56 pages, 606 KB

Open AccessReview

‘‘Non-Invasive Extracellular Vesicle Biomarkers in Endometriosis, Molecular Signatures Linking Pelvic Inflammation, Oocyte Quality, and IVF Outcomes’’

by Charalampos Voros, Fotios Chatzinikolaou, Ioakeim Sapantzoglou, Georgios Papadimas, Spyridon Polykalas, Despoina Mavrogianni, Aristotelis-Marios Koulakmanidis, Diamantis Athanasiou, Vasiliki Kanaka, Maria Kanaka, Kyriakos Bananis, Antonia Athanasiou, Aikaterini Athanasiou, Ioannis Papapanagiotou, Dimitrios Vaitsis, Charalampos Tsimpoukelis, Maria Anastasia Daskalaki, Marianna Theodora, Nikolaos Thomakos, Panagiotis Antsaklis, Dimitrios Loutradis and Georgios Daskalakis Show full author list Hide full author list

Curr. Issues Mol. Biol. 2025, 47(11), 956; https://doi.org/10.3390/cimb47110956 - 17 Nov 2025

Abstract

Endometriosis impairs fertility by interfering with ovarian function, embryonic development, and endometrial receptivity. Extracellular vesicles (EVs) are recognised as non-invasive biomarkers that may indicate biological processes based on their lipid, protein, and microRNA composition. This narrative review synthesises current data on extracellular vesicle [...] Read more.

Endometriosis impairs fertility by interfering with ovarian function, embryonic development, and endometrial receptivity. Extracellular vesicles (EVs) are recognised as non-invasive biomarkers that may indicate biological processes based on their lipid, protein, and microRNA composition. This narrative review synthesises current data on extracellular vesicle (EV) signatures in serum/plasma, menstrual blood, follicular fluid, and uterine fluid in endometriosis patients using assisted reproductive technology (ART). We highlight critical EV-mediated processes, such as progesterone signalling, fibrosis, angiogenesis, inflammation, and metabolism, and their associations with oocyte competence, embryo development, and implantation. Certain EV-miRNA profiles, including miR-22-3p, miR-320a, the miR-200 family, and miR-145-5p, have shown use for diagnostic and prognostic purposes in various investigations. These characteristics are associated with live birth, implantation, and blastocyst quality. We propose a clinical framework that incorporates (i) menstrual-blood EVs for non-invasive endotyping, (ii) serum/plasma EV profiling for baseline risk stratification, and (iii) pre-transfer uterine-fluid EV evaluation to inform embryo-transfer decisions. Translation requires standardisation, cycle phase control, and prior validation. EVs may serve as a beneficial instrument for personalised in vitro fertilisation operations for ladies experiencing infertility due to endometriosis. Full article

(This article belongs to the Section Molecular Medicine)

28 pages, 2012 KB

Open AccessReview

Role of Anti-Inflammatory and Antioxidant Properties of Natural Products in Curing Cardiovascular Diseases

by Amit Kulkarni, Chaitra Chidambar Kulkarni, Seetur Radhakrishna Pradeep, Jagadeesha Poyya, Avinash Kundadka Kudva, Vijay Radhakrishnan and Ajay Sathyanarayanrao Khandagale

Curr. Issues Mol. Biol. 2025, 47(11), 955; https://doi.org/10.3390/cimb47110955 (registering DOI) - 17 Nov 2025

Abstract

Cardiovascular diseases (CVDs) remain a leading cause of mortality worldwide. According to the WHO, every year, there is an increase in the rate of death globally due to CVDs, stroke, and myocardial infarction. Several risk factors contribute to the development of CVDs, one [...] Read more.

Cardiovascular diseases (CVDs) remain a leading cause of mortality worldwide. According to the WHO, every year, there is an increase in the rate of death globally due to CVDs, stroke, and myocardial infarction. Several risk factors contribute to the development of CVDs, one of which is hypoxia, defined as a reduction in oxygen levels. This major stressor affects aerobic species and plays a crucial role in the development of cardiovascular disease. Research has uncovered the “hypoxia-inducible factors (HIFs) switch” and investigated the onset, progression, acute and chronic effects, and adaptations of hypoxia, particularly at high altitudes. The hypoxia signalling pathways are closely linked to natural rhythms such as the circadian rhythm and hibernation. In addition to genetic and evolutionary factors, epigenetics also plays an important role in postnatal cardiovascular responses to hypoxia. Oxidized LDL-C initiates atherosclerosis amidst oxidative stress, inflammation, endothelial dysfunction, and vascular remodelling in CVD pathogenesis. Anti-inflammatory and antioxidant biomarkers are needed to identify individuals at risk of cardiovascular events and enhance risk prediction. Among these, C-reactive protein (CRP) is a recognized marker of vascular inflammation in coronary arteries. Elevated pro-atherogenic oxidized LDL (oxLDL) expression serves as an antioxidant marker, predicting coronary heart disease in apparently healthy men. Natural antioxidants and anti-inflammatory molecules protect the heart by reducing oxidative stress, enhancing vasodilation, and improving endothelial function. For instance, the flavonoid quercetin exerts antioxidant and anti-inflammatory effects primarily by activating the Nrf2/HO-1 signaling pathway, thereby enhancing cellular antioxidant defense and reducing reactive oxygen species. Carotenoids, such as astaxanthin, exhibit potent antioxidant activity by scavenging free radicals and preserving mitochondrial integrity. The alkaloid berberine mediates cardiovascular benefits through activation of AMO-activated protein kinase (AMPK) and inhibition of nuclear factor kappa B [NF-kB] signalling, improving lipid metabolism and suppressing inflammatory cytokines. Emerging evidence highlights microRNAs (miRNAs) as potential regulators of oxidative stress via endothelial nitric oxide synthase (eNOS) and silent mating-type information regulation 2 homolog (SIRT1). While the exact mechanisms remain unclear, their benefits are likely to include antioxidant and anti-inflammatory effects, notably reducing the susceptibility of low-density lipoproteins to oxidation. Additionally, the interactions between organs under hypoxia signalling underscore the need for a comprehensive regulatory framework that can support the identification of therapeutic targets, advance clinical research, and enhance treatments, including FDA-approved drugs and those in clinical trials. Promising natural products, including polysaccharides, alkaloids, saponins, flavonoids, and peptides, as well as traditional Indian medicines, have demonstrated anti-hypoxic properties. Their mechanisms of action include increasing haemoglobin, glycogen, and ATP levels, reducing oxidative stress and lipid peroxidation, preserving mitochondrial function, and regulating genes related to apoptosis. These findings emphasise the importance of anti-hypoxia research for the development of effective therapies to combat this critical health problem. A recent approach to controlling CVDs involves the use of antioxidant and anti-inflammatory therapeutics through low-dose dietary supplementation. Despite their effectiveness at low doses, further research on ROS, antioxidants, and nutrition, supported by large multicentre trials, is needed to optimize this strategy. Full article

(This article belongs to the Special Issue Cardiovascular Disease: From Molecular Mechanisms to Therapeutic Innovations)

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4 pages, 170 KB

Open AccessEditorial

Editorial for the Special Issue “Early Molecular Diagnosis and Comprehensive Treatment of Tumors”

by Yao-Chou Tsai and Chan-Yen Kuo

Curr. Issues Mol. Biol. 2025, 47(11), 954; https://doi.org/10.3390/cimb47110954 - 17 Nov 2025

Abstract

Cancer is one of the leading causes of morbidity and mortality worldwide, and it poses a persistent challenge to modern medicine [...] Full article

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

21 pages, 4779 KB

Open AccessArticle

Integrating Network Pharmacology and Metabolomics to Elucidate the Mechanism of Cryptotanshinone Against Platelet Aggregation

by Jielan Huang, Zhenjie Liu, Baolin Wang, Haixin Qiu, Qiujie Chen, Jinyan Xian, Shen Liu, Xiaoxiu Shi, Ting Xia, Xiaoqing Tan, Wenhui Jiang, Yuanle Shen, Liuping Wang and Jianfang Feng

Curr. Issues Mol. Biol. 2025, 47(11), 953; https://doi.org/10.3390/cimb47110953 (registering DOI) - 17 Nov 2025

Abstract

Cryptotanshinone (CTS), an antiplatelet compound from Salvia miltiorrhiza, exhibits in vitro potency comparable to aspirin. This study integrated network pharmacology and metabolomics to elucidate its underlying mechanisms. An acute blood stasis model was induced in Sprague-Dawley rats using epinephrine and ice-water immersion. [...] Read more.

Cryptotanshinone (CTS), an antiplatelet compound from Salvia miltiorrhiza, exhibits in vitro potency comparable to aspirin. This study integrated network pharmacology and metabolomics to elucidate its underlying mechanisms. An acute blood stasis model was induced in Sprague-Dawley rats using epinephrine and ice-water immersion. Animals were assigned to seven groups. Platelet aggregation was measured turbidimetrically using arachidonic acid (AA) and adenosine diphosphate (ADP) as agonists. Core targets were predicted by network pharmacology, differential metabolites were screened, and pathways were enriched using untargeted metabolomics. Integrated analysis identified shared pathways and key targets, validated by molecular docking. AA- and ADP-induced aggregation was significantly increased in model rats versus the blank group. CTS at all doses markedly inhibited aggregation in a dose-dependent manner. Network pharmacology identified 15 core targets. Metabolomics identified 51 differential metabolites enriched in seven pathways, including glycerophospholipid and butanoate metabolism. Integrated analysis revealed five common pathways: linoleic acid metabolism, arginine biosynthesis, AA metabolism, glutathione metabolism, and drug metabolism—and four key targets (CYP3A4, NOS3, PTGS2, and GSTP1). Molecular docking showed strong binding energies (<−9 kcal/mol) between CTS and these targets. CTS inhibits platelet aggregation by regulating CYP3A4, NOS3, PTGS2, and GSTP1 and intervening in five metabolic pathways, supporting its potential as an anti-platelet agent. Full article

(This article belongs to the Special Issue Therapeutic Effects of Natural Bioactive Compounds in the Management of Human Diseases: 2nd Edition)

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13 pages, 577 KB

Open AccessArticle

Maternal and Fetal SERPINA3 Polymorphisms and Risk of Preeclampsia: A Dyad and Triad Based Case-Control Study

by Hsi-Hsuan Yang, Claire Baldauf, Trevor A. Pickering, Håkon K. Gjessing, Sue Ann Ingles and Melissa Lee Wilson

Curr. Issues Mol. Biol. 2025, 47(11), 952; https://doi.org/10.3390/cimb47110952 - 17 Nov 2025

Abstract

Serine protease inhibitor A3 (SERPINA3), also called α-1-antichymotrypsin, is a serine protease involved in placental dysfunction. This study examines SERPINA3 polymorphisms and haplotypes for associations with maternal hypertensive disorders of pregnancy (HDPs) and preeclampsia with severe features (sPE) or Hemolysis, Elevated Liver Enzymes, [...] Read more.

Serine protease inhibitor A3 (SERPINA3), also called α-1-antichymotrypsin, is a serine protease involved in placental dysfunction. This study examines SERPINA3 polymorphisms and haplotypes for associations with maternal hypertensive disorders of pregnancy (HDPs) and preeclampsia with severe features (sPE) or Hemolysis, Elevated Liver Enzymes, and Low Platelet (HELLP) syndrome in mother–baby dyads (HDP) and mother–father–baby triads (sPE/HELLP). This retrospective case–control study examined two patient cohorts, HDPs and severe PE/HELLP syndrome. The HDP population included cases (n = 142) and controls (n = 168) of mother–baby dyads recruited from a large, urban, safety-net hospital in Los Angeles. The sPE/HELLP syndrome population included cases (n = 189) and controls (n = 28) of mother–father–baby triads recruited through HELLP syndrome research websites. Cases were verified by medical chart abstraction when possible. Two SERPINA3 SNPs, rs4934 and rs1884082, were genotyped from saliva samples, mouthwash, or buccal swabs. The Haplin package in R was used to perform genetic association analyses. No evidence of increased risk related to individual SERPINA3 SNPs or haplotypes for the developing HDPs or sPE/HELLP was found in individual nor combined cohorts. In the HDP cohort, the g-a haplotype (relative to T-G haplotype) was borderline significant for increased risk of HDPs when carried by the child (double dose: RR = 1.58, 95% CI: (1.00, 2.52), p = 0.05). We observed significant parent-of-origin (PoO) effects in the combined cohort: specifically, an increased risk of HDPs/sPE/HELLP if the mother carries a double copy for both rs4934 (RR = 3.03, 95% CI (1.50, 6.09), p < 0.01) and rs1884082 (RR = 2.38, 95% CI (1.22, 4.71), p = 0.01). A reduced risk of HDPs/sPE/HELLP was observed for rs4934 (RR = 0.54, 95% CI (0.31, 0.98), p = 0.04) and rs1884082 (RR = 0.52, 95% CI (0.30, 0.91), p = 0.02) with child carriage of the maternally inherited allele. In contrast, child carriage of a paternally inherited copy of the variant allele for rs4934 increased risk of HDPs/sPE/HELLP (RR = 1.54, 95% CI (1.09, 2.20), p = 0.02). There was no evidence that SERPINA3 gene polymorphisms and haplotypes were associated with risk of HDPs or sPE/HELLP. However, significant PoO effects were observed in the combined cohort analysis, with child carriage of rs4934 that is maternally inherited decreasing HDPs/sPE/HELLP risk while a paternally inherited copy increases risk, suggesting a role for maternal–fetal genomic incompatibility. Full article

(This article belongs to the Special Issue Advanced Molecular Research on Hypertensive Disorders of Pregnancy (HDPs))

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15 pages, 4408 KB

Open AccessArticle

Integrated Transcriptomic and Metabolomic Analyses Reveal Key Responses of Cotton to Salt Stress Post-Germination

by Yanzhen Liu, Yaxin Shi, Ren Xiang, Jianduo Bai, Jingshun Wang and Xianliang Zhang

Curr. Issues Mol. Biol. 2025, 47(11), 951; https://doi.org/10.3390/cimb47110951 - 15 Nov 2025

Abstract

Salt stress is a major environmental constraint that severely limits cotton seed germination. However, the regulatory mechanisms governing salt stress responses during the post-germination stage remain largely unclear. Here, we employed an integrated transcriptomic and metabolomic approach to investigate salt-responsive mechanisms in the [...] Read more.

Salt stress is a major environmental constraint that severely limits cotton seed germination. However, the regulatory mechanisms governing salt stress responses during the post-germination stage remain largely unclear. Here, we employed an integrated transcriptomic and metabolomic approach to investigate salt-responsive mechanisms in the salt-tolerant cotton cultivar ST022-1056m5 (ST) following exposure to 150 mM NaCl. Our analysis identified 4368 differentially expressed genes (DEGs) and 441 differentially accumulated metabolites (DAMs) under salt stress conditions. Multi-omics integration revealed that alpha-linolenic acid and linoleic acid metabolic pathways were particularly responsive to salt stress. In the α-linolenic acid pathway, salt stress triggered substantial accumulation of jasmonic acid (JA) precursors and concurrent upregulation of key JA biosynthetic genes. Simultaneously, the linoleic acid metabolism pathway exhibited increased metabolite levels and enhanced the relative gene expression. These findings provide compelling evidence that alpha-linolenic acid and linoleic acid metabolism pathways collectively modulate post-germination salt stress responses in cotton, offering new insights into the molecular mechanisms underlying salt tolerance and presenting potential targets for breeding resilient cotton varieties. Full article

(This article belongs to the Section Molecular Plant Sciences)

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17 pages, 6149 KB

Open AccessArticle

Divergent Tissue and Circulatory Expression of miR-10a in Canine Hepatocellular Carcinoma: Comparative Insights from Human HCC

by Most Shumi Akhter Shathi, Mohammad Arif, Nobuhiro Nozaki, Yutaro Ide, Yoshiyuki Akiyama, Shaohsu Wang, Masashi Takahashi and Naoki Miura

Curr. Issues Mol. Biol. 2025, 47(11), 950; https://doi.org/10.3390/cimb47110950 - 15 Nov 2025

Abstract

Canine hepatocellular carcinoma (HCC), the most common primary liver malignancy in dogs, shares many clinicopathological and molecular similarities with human HCC. However, its molecular characteristics remain insufficiently defined, and reliable diagnostic biomarkers are lacking. Elucidating dysregulated microRNAs (miRNAs) may aid in both disease [...] Read more.

Canine hepatocellular carcinoma (HCC), the most common primary liver malignancy in dogs, shares many clinicopathological and molecular similarities with human HCC. However, its molecular characteristics remain insufficiently defined, and reliable diagnostic biomarkers are lacking. Elucidating dysregulated microRNAs (miRNAs) may aid in both disease characterization and comparative oncology research. Small RNA sequencing datasets from canine HCC were analyzed to identify significantly dysregulated miRNAs with high expression and biomarker potential. The top candidate was validated in clinical tissues, cell lines, patient’s plasma and plasma exosomes using RT-qPCR. Comparative analyses were conducted using human HCC datasets (TCGA and GEO), followed by target prediction and functional enrichment to identify conserved molecular pathways. Among the 59 differentially expressed miRNAs, cfa-miR-10a showed the highest average expression level and yet was significantly downregulated in canine HCC tissues. RT-qPCR confirmed reduced expression of cfa-miR-10a in canine HCC tissues, whereas plasma exosomes showed significant enrichment, demonstrating excellent diagnostic performance (AUC = 0.94). The mature sequence of cfa-miR-10a is highly conserved with hsa-miR-10a-5p. TCGA datasets confirmed downregulation of hsa-miR-10a-5p in HCC tissues, whereas a GEO dataset showed no significant change in serum exosome levels. Target prediction and functional annotation identified 59 overlapping genes, with the Proteoglycans in cancer pathways being conserved in both species, mediated by ACTG1, SDC1, FRS2, and WNT9B. Collectively, these findings demonstrate distinct intra-tumoral and exosomal expression pattern of miR-10a in canine HCC and support its potential as a non-invasive biomarker with translational relevance. Full article

(This article belongs to the Special Issue Innovative Therapeutics and Biomarkers in Hepatocellular Carcinoma Research)

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13 pages, 1848 KB

Open AccessArticle

Photodynamic Therapy Modulates pri-miRNA Expression in C. albicans-Infected HEK-293 Cells: An In Vitro Study

by Cinzia Casu, Andrea Butera, Alessandra Scano, Andrea Scribante, Valentino Natoli, Mara Pinna, Sara Fais and Germano Orrù

Curr. Issues Mol. Biol. 2025, 47(11), 949; https://doi.org/10.3390/cimb47110949 - 14 Nov 2025

Abstract

Oral infections caused by Candida spp. represent a major health concern due to the increasing resistance of these fungi to conventional antifungal agents. Photodynamic therapy (PDT) is a treatment based on the use of light at a specific wavelength that activates a photosensitizer [...] Read more.

Oral infections caused by Candida spp. represent a major health concern due to the increasing resistance of these fungi to conventional antifungal agents. Photodynamic therapy (PDT) is a treatment based on the use of light at a specific wavelength that activates a photosensitizer (PS) in the presence of oxygen. The activated PS selectively binds to infected cells and induces apoptosis through the generation of reactive oxygen species (ROS). Previous biomolecular studies on Candida albicans have demonstrated that its infection triggers characteristic molecular signals, such as miRNA-146a and miRNA-155, which serve as inflammatory markers. This in vitro study aimed to evaluate the impact of PDT on the expression of their primary transcripts (pri-miRNAs) in a cell culture model of C. albicans infection. Human embryonic kidney (HEK-293) cells were infected with a multidrug-resistant strain of C. albicans (CA97) and subsequently exposed to curcumin-based PDT activated by blue light (470 nm). The expression of pri-miRNAs 146a and 155 was assessed before and after PDT treatment for each experimental group. The expression levels of pri-miRNAs increased approximately 2- to 3.5-fold following C. albicans infection but returned to baseline values after PDT treatment. The evaluation of pri-miRNAs 146a/155 may serve as a valuable research tool for monitoring early inflammatory responses induced by Candida infection, as well as a sensitive biomarker for assessing the effectiveness of photodynamic therapy in an in vitro cell culture model. Full article

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

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19 pages, 4476 KB

Open AccessArticle

Unveiling Let-7a’s Therapeutic Role in Ewing Sarcoma Through Molecular Docking and Deformation Energy Analysis

by Mubashir Hassan, Amal Malik, Saba Shahzadi and Andrzej Kloczkowski

Curr. Issues Mol. Biol. 2025, 47(11), 948; https://doi.org/10.3390/cimb47110948 - 14 Nov 2025

Abstract

Ewing sarcoma is a pediatric malignant cancer that usually develops in bones and soft tissues. The current study investigates the function of hsa-let-7a as a target molecule in the pathophysiology of Ewing sarcoma using computational approaches. To anticipate complementary sites, miRNA and mRNA [...] Read more.

Ewing sarcoma is a pediatric malignant cancer that usually develops in bones and soft tissues. The current study investigates the function of hsa-let-7a as a target molecule in the pathophysiology of Ewing sarcoma using computational approaches. To anticipate complementary sites, miRNA and mRNA sequences were retrieved from the miRBase and NCBI databases. The three-dimensional structures of both hsa-let-7a and mRNA_EWSR1 were predicted through MC-Fold and RNAComposer, respectively. Furthermore, online HNADOCK and PatchDock docking servers were utilized to check the docking energy values and interactive behavior between miRNA and mRNA. The generated docked results showed good binding score values and interaction profiles between nucleotides of hsa-let-7a and mRNA of EWSR1. Moreover, both docking complexes were also studied using anisotropic network model analysis, which involved plotting correlation, inter-nucleotide distance fluctuations, and deformation energy graphs. The predicted heatmap graph also highlighted the significance of hsa-let-7a in various cellular signaling pathways, which may be interconnected with Ewing sarcoma, making it a potential therapeutic target. Together, this study offers computational insights that highlight hsa-let-7a as a promising therapeutic candidate for Ewing sarcoma, based on miRNA-driven predictive modeling. Full article

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

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13 pages, 2298 KB

Open AccessArticle

Study on the Protective Mechanism of Dihydromyricetin Against Aflatoxin B₁-Induced Injury in Madin–Darby Canine Kidney Cells

by He Zhai, Liuwei Xie, Baoan Li, Mingqiang Song, Xiao Li, Shu Xu, Yao Wang and Chao Xu

Curr. Issues Mol. Biol. 2025, 47(11), 947; https://doi.org/10.3390/cimb47110947 - 13 Nov 2025

Abstract

Aflatoxin B₁ (AFB₁) is a common contaminant in canine diets that can cause significant damage to metabolic organs with prolonged exposure. Dihydromyricetin (DMY), a flavonoid compound abundant in Ampelopsis grossedentata, is widely used in functional foods due to its [...] Read more.

Aflatoxin B₁ (AFB₁) is a common contaminant in canine diets that can cause significant damage to metabolic organs with prolonged exposure. Dihydromyricetin (DMY), a flavonoid compound abundant in Ampelopsis grossedentata, is widely used in functional foods due to its diverse biological activities. This study aimed to investigate the mechanism by which DMY alleviates AFB1-induced damage in MDCK cells. Four experimental groups were established: a control group with culture medium only (CON group), a group treated with 5 μg/mL AFB1 (AFB1 group), and two treatment groups treated with 5 μg/mL AFB1 combined with either 25 mmol/L or 50 mmol/L DMY—concentrations with more robust and stable protective effects than 100 mmol/L DMY, as confirmed by experimental screening. The results showed that AFB₁ significantly reduced MDCK cell viability at concentrations of 5–30 μg/mL (p < 0.01), while DMY at 25–100 mmol/L markedly improved cell viability (p < 0.01). AFB₁ treatment led to a significant increase in reactive oxygen species (ROS), malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) levels, along with a reduction in superoxide dismutase (SOD) and catalase (CAT) activities (p < 0.01). 25 mmol/L and 50 mmol/L DMY treatment reversed these effects, decreasing ROS, MDA, TNF-α, IL-6, and IL-1β levels while increasing SOD and CAT activities (p < 0.01). Furthermore, 25 mmol/L and 50 mmol/L DMY improved mitochondrial membrane potential (p < 0.01), counteracting AFB₁’s inhibitory effects on autophagy-related proteins by promoting p-AMPK and Beclin-1 expression while inhibiting p-mTOR, p53, and p62 expression (p < 0.05). In conclusion, DMY mitigates AFB₁-induced damage in MDCK cells by enhancing anti-inflammatory and antioxidant defenses and promoting autophagy, providing a theoretical foundation for future treatment strategies for canine kidney damage. Full article

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

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20 pages, 3768 KB

Open AccessArticle

Effects of Exogenous Spermidine on Germination and Seedling Growth of Rice Under Salt Stress: Physiological and Transcriptomic Insights

by Biaoxin Fei, Jian Liu, Baolai Mao, Ruixiang Wang, Yifan Meng, Haidong Huang, Xin Lu, Fei Zhao and Yongbo Duan

Curr. Issues Mol. Biol. 2025, 47(11), 946; https://doi.org/10.3390/cimb47110946 - 13 Nov 2025

Abstract

Salt stress severely impairs rice (Oryza sativa L.) germination and seedling establishment. Exogenous spermidine (Spd) has been shown to regulate stress tolerance in plants, but whether it acts during rice germination and seedling establishment under salt stress remains unclear. Here, rice seeds [...] Read more.

Salt stress severely impairs rice (Oryza sativa L.) germination and seedling establishment. Exogenous spermidine (Spd) has been shown to regulate stress tolerance in plants, but whether it acts during rice germination and seedling establishment under salt stress remains unclear. Here, rice seeds (cv. Jindao 919) were exposed to 75 mM NaCl with different Spd concentrations (0–1.4 mM), and physiological, biochemical, and transcriptomic responses were evaluated. The findings showed that salt stress had a pronounced inhibitory effect on both seed germination and seedling development. Exogenous Spd effectively alleviated these negative effects, with the most significant improvements observed at 1.0–1.2 mM: germination rate increased by 3.98–8.52%, seedling root length increased by 17.74–37.68%, soluble sugar content increased by 29.83–230%, and SOD and POD activities increased by 29.81–40.3% and 18.45–44.0%, respectively, while MDA content decreased by 36.28–40.3%. Further transcriptomic analysis identified a total of 1835 differentially expressed genes (DEGs). KEGG enrichment analysis revealed these genes were concentrated in key pathways including terpenoid biosynthesis, phenylpropanoid biosynthesis, and amino sugar and nucleotide sugar metabolism, thus alleviating the negative impact of salt stress on rice germination and seedling development. These pathways are closely related to gibberellin metabolism, lignin biosynthesis, and amino sugar metabolism, further revealing the regulatory role of Spd. Overall, 1.0–1.2 mM Spd was most effective in alleviating salt stress by synergistically regulating antioxidant defense, osmoregulation, and metabolic reprogramming, enhancing rice’s overall stress tolerance. This study provides theoretical guidance for precise regulation of Spd concentration to improve rice performance in saline-alkaline soils, and reveals the sustained promoting effects of Spd across various developmental stages of rice and its underlying molecular mechanisms. Full article

(This article belongs to the Section Molecular Plant Sciences)

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29 pages, 5088 KB

Open AccessHypothesis

Molecular Mechanism for the Selective Presentation of Antigenic Peptides by Major Histocompatibility Complex Class I and Class II Molecules: A Hypothesis

by Bao Ting Zhu

Curr. Issues Mol. Biol. 2025, 47(11), 945; https://doi.org/10.3390/cimb47110945 - 13 Nov 2025

Abstract

The major histocompatibility complex (MHC) class I and class II molecules (abbreviated as MHC-I and MHC-II, respectively) are specialized in antigen presentation. Unlike the T cell receptors (TCRs), which have great variability, the MHC-I and MHC-II molecules essentially have no variability at all. [...] Read more.

The major histocompatibility complex (MHC) class I and class II molecules (abbreviated as MHC-I and MHC-II, respectively) are specialized in antigen presentation. Unlike the T cell receptors (TCRs), which have great variability, the MHC-I and MHC-II molecules essentially have no variability at all. It is apparent that the MHC-I and MHC-II molecules per se do not have the built-in ability to distinguish the huge populations of self-peptides from antigenic non-self-peptides. At present, the precise mechanism underlying the selective presentation of antigenic peptides by both MHC-I and MHC-II molecules is unclear. For an MHC-II molecule to gain the ability to selectively present antigenic (mostly foreign) peptides, it is hypothesized herein that all naïve CD4⁺ T cells in the body will release extracellular vesicles (EVs), which are specially designed for antigen-presenting cells (APCs); these EVs contain mRNAs that will be delivered to APCs and translated into an intracellular version of the TCR proteins (iTCR^II), which will help select antigenic peptides for presentation by the MHC-II molecules. Similarly, it is hypothesized that the fully activated CD4⁺ T cells will also release EVs, and these EVs contain different mRNAs for another intracellular version of the TCR proteins (iTCR^I), which will help pathogen-infected somatic cells to select the antigenic peptides (mostly from invading pathogens) for presentation by the MHC-I molecules. Understandably, while the iTCR^II proteins will work closely with the MHC-II molecules in the exogenous endocytic pathway, the iTCR^I proteins will work closely with the MHC-I molecules in the endogenous pathway. In this paper, a few other related hypotheses are also proposed, which jointly offer a plausible mechanistic explanation for the selective presentation of antigenic peptides by both MHC-I and MHC-II molecules. While the proposed hypotheses are partly supported by some experimental observations, it is hoped that these hypotheses will promote discussion and experimental testing of the mechanisms underlying the complex process of selective antigen presentation. Full article

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

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63 pages, 695 KB

Open AccessReview

Perfluoroalkyl Substances (PFAS) and Lipid Metabolism in Experimental Animal Models: A Scoping Review on the Mechanisms Behind the Induced Hepatotoxicity

by Gabriele Tancreda, Luca Campisi, Matteo Sarti, Luisa Pozzo and Andrea Vornoli

Curr. Issues Mol. Biol. 2025, 47(11), 944; https://doi.org/10.3390/cimb47110944 - 13 Nov 2025

Abstract

Per and polyfluoroalkyl substances (PFAS) are a class of synthetic, persistent environmental pollutants detected in biological systems and increasingly recognized for their harmful effects on human health. The liver, being a central organ in the metabolism of xenobiotics, is profoundly affected by these [...] Read more.

Per and polyfluoroalkyl substances (PFAS) are a class of synthetic, persistent environmental pollutants detected in biological systems and increasingly recognized for their harmful effects on human health. The liver, being a central organ in the metabolism of xenobiotics, is profoundly affected by these compounds and is a main target of PFAS-induced toxicity. The purpose of the present Scoping Review is to investigate the multiple and complex mechanisms behind PFAS hepatotoxicity, taking into consideration evidence from preclinical in vivo models. Using electronic databases (PubMed and Google Scholar), a total of 38 studies were found eligible to be extensively explored to gather information regarding PFAS toxicity toward hepatic lipid metabolism, oxidative stress, injury and inflammation. Moreover, the parental exposure of these chemicals on the offspring will be discussed as well. As illustrated in the proposed graphical abstract, PFAS exposure has been linked to the triggering of oxidative stress phenomena, mitochondrial dysfunction and hepatic inflammatory infiltrate with sex specific effects in rodents. The predominant effects manifest as the overproduction of reactive oxygen species (ROS), the disruption of hepatic lipid metabolism, and the activation of several nuclear transcription factors involved in lipid regulation, with PPAR-α being the most prominent. Considering their strong bioaccumulative properties and persistence in both the environment and the human body, legacy and emerging PFAS should be regarded as potent toxicants with a distinctive role in the onset of metabolic diseases and as a pressing issue to be addressed within regulatory policies. Full article

(This article belongs to the Special Issue Advances in Molecular Biology Methods in Hepatology Research, 2nd Edition)

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