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Int. J. Mol. Sci., Volume 26, Issue 3 (February-1 2025) – 530 articles

Cover Story (view full-size image): Transient Receptor Potential (TRP) ion channels play a key role in cancer-induced bone pain (CIBP). They are involved in the pain pathway at different sites both in the peripheral and central nervous system. The acidic tumour environment, caused by the release of protons by osteoclast activity, is a potent activator of TRP channels on primary afferent fibres. They are also expressed in astrocytes and glial cells, where they promote neuroinflammatory processes by interacting with the physiological cross-talk between neurons and immune cells. They also act directly on bone cells by modulating the differentiation of osteoclasts and osteoblasts. Preclinical data suggest a potential role in bone cancer pain management for the modulators of some TRP channels, namely TRPV1, TRPA1, TRPM7, and TRPM8. View this paper
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18 pages, 465 KiB  
Article
Optimising Aripiprazole Long-Acting Injectable: A Comparative Study of One- and Two-Injection Start Regimens in Schizophrenia with and Without Substance Use Disorders and Relationship to Early Serum Levels
by Giada Trovini, Ginevra Lombardozzi, Georgios D. Kotzalidis, Luana Lionetto, Felicia Russo, Angela Sabatino, Elio Serra, Simone Castorina, Giorgia Civita, Sara Frezza, Donatella De Bernardini, Giuseppe Costanzi, Marika Alborghetti, Maurizio Simmaco, Ferdinando Nicoletti and Sergio De Filippis
Int. J. Mol. Sci. 2025, 26(3), 1394; https://doi.org/10.3390/ijms26031394 - 6 Feb 2025
Viewed by 691
Abstract
Aripiprazole as a long-acting injectable (LAI) is initiated in oral aripiprazole-stabilised patients and needs, after first injection, 14 days supplementation of oral aripiprazole (one-injection start, OIS). Recently, an alternative two-injection start (TIS) was advanced, involving two 400 mg injections with a single 20 [...] Read more.
Aripiprazole as a long-acting injectable (LAI) is initiated in oral aripiprazole-stabilised patients and needs, after first injection, 14 days supplementation of oral aripiprazole (one-injection start, OIS). Recently, an alternative two-injection start (TIS) was advanced, involving two 400 mg injections with a single 20 mg oral supplementation of aripiprazole. We tested the two regimens in patients with schizophrenia (SCZ, n = 152, 90 men and 62 women) with (SUD+; n = 93) or without (SUD; n = 59) substance use disorders (SUDs), comparing OIS (n = 66) with TIS (n = 86) and SUD+ vs. SUD. For 26 patients, we measured weekly for one month, aripiprazole + dehydroaripiprazole (active moiety) levels. Patients were followed for three months after LAI with psychopathology and quality-of-life scales (BPRS, CGI-S, ACES, BIS-11, and WHOQOL). All groups improved in psychopathology with no differences between OSI and TIS and between SCZ–SUD+ and SCZ–SUD. The TIS group was associated with serum blood levels of the active moiety within the therapeutic window, while the OIS group showed peaks above the window, possibly exposing patients to toxicity. Treatments were well-tolerated. Here we showed no disadvantages for TIS vs. OIS and possibly increased safety. Shifting the initiation of aripiprazole LAIs to the TIS modality may be safe and pharmacokinetically advantageous. Full article
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14 pages, 2834 KiB  
Article
Complement Factor B Deficiency Is Dispensable for Female Fertility but Affects Microbiome Diversity and Complement Activity
by Manato Sunamoto, Kazunori Morohoshi, Ban Sato, Ryo Mihashi, Masafumi Inui, Mitsutoshi Yamada, Kenji Miyado and Natsuko Kawano
Int. J. Mol. Sci. 2025, 26(3), 1393; https://doi.org/10.3390/ijms26031393 - 6 Feb 2025
Viewed by 426
Abstract
Complement factor B (CFB) is a crucial component for the activation of the alternative pathway due to the formation of the C3 convertase with C3b, which further produces C3b to enhance the overall complement activity. Although Cfb is expressed not only in the [...] Read more.
Complement factor B (CFB) is a crucial component for the activation of the alternative pathway due to the formation of the C3 convertase with C3b, which further produces C3b to enhance the overall complement activity. Although Cfb is expressed not only in the immune tissues, but also in the reproductive tract, the physiological role of the alternative complement pathway in reproduction remains unclear. In this study, we addressed this issue by producing Cfb-knockout (KO) mice and analyzing their phenotypes. Sperm function, number of ovulated oocytes, and litter size were normal in KO mice. In contrast, the diversity of microbiomes in the gut and vaginal tract significantly increased in KO mice. Some serine protease activity in the serum from KO mice was lower than that of wild-type mice. Since the serum from KO mice showed significantly lower activity of the alternative complement pathway, CFB was found to be essential for this pathway. Our results indicate that although the alternative pathway is dispensable for normal fertility and development, it maintains the gut and vaginal microbiomes by suppressing their diversity and activating the alternative complement pathway. Full article
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19 pages, 5241 KiB  
Article
Quantitative Proteomic Analysis of Lysine Malonylation in Response to Salicylic Acid in the Roots of Platycodon grandiflorus
by Wanyue Ding, Yingying Duan, Yuqing Wang, Jizhou Fan, Weiyi Rao and Shihai Xing
Int. J. Mol. Sci. 2025, 26(3), 1392; https://doi.org/10.3390/ijms26031392 - 6 Feb 2025
Viewed by 421
Abstract
Salicylic acid, as a plant hormone, significantly affects the physiological and biochemical indexes of soluble sugar, malondialdehyde content, peroxidase, and superoxide dismutase enzyme activity in Platycodon grandiflorus. Lysine malonylation is a post-translational modification that involves various cellular functions in plants, though it [...] Read more.
Salicylic acid, as a plant hormone, significantly affects the physiological and biochemical indexes of soluble sugar, malondialdehyde content, peroxidase, and superoxide dismutase enzyme activity in Platycodon grandiflorus. Lysine malonylation is a post-translational modification that involves various cellular functions in plants, though it is rarely studied, especially in medicinal plants. In this study, the aim was to perform a comparative quantitative proteomic study of malonylation modification on P. grandiflorus root proteins after salicylic acid treatment using Western blot with specific antibodies, affinity enrichment and LC-MS/MS analysis methods. The analysis identified 1907 malonyl sites for 809 proteins, with 414 proteins and 798 modification sites quantified with high confidence. Post-treatment, 361 proteins were upregulated, and 310 were downregulated. Bioinformatics analysis revealed that malonylation in P. grandiflorus is primarily involved in photosynthesis and carbon metabolism. Physiological and biochemical analysis showed that salicylic acid treatment increased the malondialdehyde levels, soluble protein, superoxide dismutase, and peroxidase activity but did not significantly affect the total saponins content in P. grandiflorus. These findings provide an important basis for exploring the molecular mechanisms of P. grandiflorus following salicylic acid treatment and enhance understanding of the biological function of protein lysine malonylation in plants. Full article
(This article belongs to the Special Issue Advanced Plant Molecular Responses to Abiotic Stresses)
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20 pages, 4383 KiB  
Article
Adsorption of Serum Fetuin onto Octacalcium Phosphate and Its Relation to Osteogenic Property
by Yuki Tsuboi, Ryo Hamai, Kyosuke Okuyama, Kaori Tsuchiya, Yukari Shiwaku, Kensuke Yamauchi and Osamu Suzuki
Int. J. Mol. Sci. 2025, 26(3), 1391; https://doi.org/10.3390/ijms26031391 - 6 Feb 2025
Viewed by 384
Abstract
This study aimed to investigate how the chemical elements in relation to octacalcium phosphate (OCP) hydrolysis affect the osteoblastic differentiation in the presence of serum fetuin. The adsorption of fetuin onto OCP was examined in buffers having different degrees of supersaturation (DS) with [...] Read more.
This study aimed to investigate how the chemical elements in relation to octacalcium phosphate (OCP) hydrolysis affect the osteoblastic differentiation in the presence of serum fetuin. The adsorption of fetuin onto OCP was examined in buffers having different degrees of supersaturation (DS) with respect to OCP and hydroxyapatite (HA) at pH 7.4 and 37 °C. The osteoblastic differentiation of mesenchymal stem cells (MSCs) was evaluated in cultures with OCP and 0 to 0.8 mg/mL of fetuin. The amount of fetuin adsorbed increased with increasing DS in the buffer. In the MSC culture, the coexistence of OCP and 0.2–0.4 mg/mL of fetuin close to serum level increased alkaline phosphatase activity; however, the activity was suppressed by 0.2–0.8 mg/mL of fetuin. Transmission electron microscopy revealed de novo crystal formation on OCP in supersaturated buffer and culture media with respect to OCP and HA at lower fetuin concentrations. Infrared spectroscopy and DS estimation indicate that the hydrolysis of OCP with de novo apatite formation was promoted in the culture media at 0.2–0.4 mg/mL of fetuin. These results suggest that OCP may promote osteoblastic differentiation if the suitable conditions are attained regarding the chemical elements and fetuin adsorption around OCP. Full article
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17 pages, 3816 KiB  
Article
SMURF1-Induced Ubiquitination of FTH1 Disrupts Iron Homeostasis and Suppresses Myogenesis
by Xia Xiong, Wen Li, Chunlin Yu, Mohan Qiu, Zengrong Zhang, Chenming Hu, Shiliang Zhu, Li Yang, Han Pen, Xiaoyan Song, Jialei Chen, Bo Xia, Shunshun Han and Chaowu Yang
Int. J. Mol. Sci. 2025, 26(3), 1390; https://doi.org/10.3390/ijms26031390 - 6 Feb 2025
Viewed by 324
Abstract
Ferritin heavy chain 1 (FTH1) is pivotal in the storage, release, and utilization of iron, plays a crucial role in the ferroptosis pathway, and exerts significant impacts on various diseases. Iron influences skeletal muscle development and health by promoting cell growth, ensuring energy [...] Read more.
Ferritin heavy chain 1 (FTH1) is pivotal in the storage, release, and utilization of iron, plays a crucial role in the ferroptosis pathway, and exerts significant impacts on various diseases. Iron influences skeletal muscle development and health by promoting cell growth, ensuring energy metabolism and ATP synthesis, maintaining oxygen supply, and facilitating protein synthesis. However, the precise molecular mechanisms underlying iron’s regulation of skeletal muscle growth and development remain elusive. In this study, we demonstrated that the conditional knockout (cKO) of FTH1 in skeletal muscle results in muscle atrophy and impaired exercise endurance. In vitro studies using FTH1 cKO myoblasts revealed notable decreases in GSH concentrations, elevated levels of lipid peroxidation, and the substantial accumulation of Fe2+, collectively implying the induction of ferroptosis. Mechanistically, E3 ubiquitin-protein ligase SMURF1 (SMURF1) acts as an E3 ubiquitin ligase for FTH1, thereby facilitating the ubiquitination and subsequent degradation of FTH1. Consequently, this activation of the ferroptosis pathway by SMURF1 impedes myoblast differentiation into myotubes. This study identifies FTH1 as a novel regulator of muscle cell differentiation and skeletal muscle development, implicating its potential significance in maintaining skeletal muscle health through the regulation of iron homeostasis. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Skeletal Muscle Metabolism)
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18 pages, 3512 KiB  
Review
Cancer Stem Cells and the Renin–Angiotensin System in the Tumor Microenvironment of Melanoma: Implications on Current Therapies
by Ethan J. Kilmister and Swee T. Tan
Int. J. Mol. Sci. 2025, 26(3), 1389; https://doi.org/10.3390/ijms26031389 - 6 Feb 2025
Viewed by 465
Abstract
Multiple signaling pathways are dysregulated in melanoma, notably the Ras/RAF/MAPK/ERK and PI3K/AKT/mTOR pathways, which can be targeted therapeutically. The high immunogenicity of melanoma has been exploited using checkpoint inhibitors. Whilst targeted therapies and immune checkpoint inhibitors have improved the survival of patients with [...] Read more.
Multiple signaling pathways are dysregulated in melanoma, notably the Ras/RAF/MAPK/ERK and PI3K/AKT/mTOR pathways, which can be targeted therapeutically. The high immunogenicity of melanoma has been exploited using checkpoint inhibitors. Whilst targeted therapies and immune checkpoint inhibitors have improved the survival of patients with advanced melanoma, treatment resistance, their side effect profiles, and the prohibitive cost remain a challenge, and the survival outcomes remain suboptimal. Treatment resistance has been attributed to the presence of cancer stem cells (CSCs), a small subpopulation of pluripotent, highly tumorigenic cells proposed to drive cancer progression, recurrence, metastasis, and treatment resistance. CSCs reside within the tumor microenvironment (TME) regulated by the immune system, and the paracrine renin–angiotensin system, which is expressed in many cancer types, including melanoma. This narrative review discusses the role of CSCs and the paracrine renin–angiotensin system in the melanoma TME, and its implications on the current treatment of advanced melanoma with targeted therapy and immune checkpoint blockers. It also highlights the regulation of the Ras/RAF/MAPK/ERK and PI3K/AKT/mTOR pathways by the renin–angiotensin system via pro-renin receptors, and how this may relate to CSCs and treatment resistance, underscoring the potential for improving the efficacy of targeted therapy and immunotherapy by concurrently modulating the renin–angiotensin system. Full article
(This article belongs to the Special Issue Melanoma: Molecular Mechanisms and Therapy)
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11 pages, 1174 KiB  
Article
Bisabolane Sesquiterpenes with Anti-Chlamydial Activity Isolated from Ligularia narynensis
by Na Gao, Yi-Lin He, Hui-Ming Qi, Hong-Ying Yang, Guo-Li Li, Zhao-Cai Li and Tong Shen
Int. J. Mol. Sci. 2025, 26(3), 1388; https://doi.org/10.3390/ijms26031388 - 6 Feb 2025
Viewed by 303
Abstract
Chlamydia are obligate intracellular bacterial pathogens affecting humans and animals, causing miscarriage, stillbirth, or weak fetuses in the late stages of pregnancy of goats and sheep. Because there is no commercial vaccine for chlamydia in animals, drug treatment has become the most effective [...] Read more.
Chlamydia are obligate intracellular bacterial pathogens affecting humans and animals, causing miscarriage, stillbirth, or weak fetuses in the late stages of pregnancy of goats and sheep. Because there is no commercial vaccine for chlamydia in animals, drug treatment has become the most effective curative method. Natural products, also known as secondary metabolites, are becoming one of the main sources used in new drug development because of their structural diversity and biodiversity. In natural products, plant sources play a major role in the development process of new drugs. In this study, five undescribed highly oxygenated bisabolane sesquiterpenes (Pararubin W, Pararubin X, Pararubin Y., Pararubin Z, and Pararubin AA) were isolated from whole plants of Ligularia narynensis. Their chemical structures were determined via analyses of HRESIMS, IR, 1D, and 2D NMR data, along with the assignment of their relative configurations. These compounds were tested for their anti-chlamydial activity. The results show that compounds 1 and 5 inhibited the growth of Chlamydia abortus in host cells in a dose-dependent manner. Full article
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17 pages, 9073 KiB  
Article
Genetic Diversity and Environmental Adaptation Signatures of the Great Seahorse (Hippocampus kelloggi) in the Coastal Regions of the Indo-Pacific as Revealed by Whole-Genome Re-Sequencing
by Wen-Xin Hao, Ying-Yi Zhang, Xin Wang, Meng Qu, Shi-Ming Wan and Qiang Lin
Int. J. Mol. Sci. 2025, 26(3), 1387; https://doi.org/10.3390/ijms26031387 - 6 Feb 2025
Viewed by 351
Abstract
The great seahorse (Hippocampus kelloggi) is one of the larger species within the seahorse group and is widely distributed in coastal areas of the Indo-Pacific. However, the natural resources of this species continue to decrease, rendering it a vulnerable species that [...] Read more.
The great seahorse (Hippocampus kelloggi) is one of the larger species within the seahorse group and is widely distributed in coastal areas of the Indo-Pacific. However, the natural resources of this species continue to decrease, rendering it a vulnerable species that faces a high risk of extinction. Therefore, there is an urgent need to conduct research on the genetic diversity of this species to protect its genetic resources. In this study, we conducted whole-genome re-sequencing (WGRS) on three H. kelloggi populations from the Red Sea (RS, n = 30), the Andaman Sea (AS, n = 13), and the South China Sea (SCS, n = 13), and a total of 1,398,936 high-quality single-nucleotide polymorphisms (SNPs) were identified. The results indicate that the average observed heterozygosity (Ho) and the average expected heterozygosity (He) for the RS, AS, and SCS populations are 0.2031 and 0.1987, 0.1914 and 0.1822, and 0.2083 and 0.2001, respectively. The three geographic populations exhibit a high degree of genetic differentiation with only a minimal gene flow between them. Consistently, in a population structure analysis, the three groups are also clearly distinguished, which is consistent with the results of the population differentiation coefficient. Demographic analyses revealed that the effective population size (Ne) of the SCS population underwent a dramatic bottleneck during the Last Glacial Maximum (LGM), followed by a substantial recovery, whereas the RS and AS populations maintained stable Ne values throughout this period. To investigate adaptive responses to climate change in the SCS population, we employed selective elimination analysis, which identified 21 candidate genes potentially involved in environmental adaptation. Of particular significance were myo5a, hps4, znf385a, msh3, and pfkfb4, which likely play crucial roles in the adaptive mechanisms of H. kelloggi. This comprehensive study not only illuminates the genetic diversity patterns of H. kelloggi but also provides a valuable foundation for future investigations into the species’ evolutionary adaptations. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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14 pages, 3027 KiB  
Article
Antibiofilm Activities of Halogenated Pyrimidines Against Enterohemorrhagic Escherichia coli O157:H7
by Hyejin Jeon, Yong-Guy Kim, Jin-Hyung Lee and Jintae Lee
Int. J. Mol. Sci. 2025, 26(3), 1386; https://doi.org/10.3390/ijms26031386 - 6 Feb 2025
Viewed by 277
Abstract
Enterohemorrhagic Escherichia coli (EHEC) is a significant public health concern due to its ability to form biofilms, enhancing its resistance to antimicrobials and contributing to its persistence in food processing environments. Traditional antibiotics often fail to target these biofilms effectively, leading to increased [...] Read more.
Enterohemorrhagic Escherichia coli (EHEC) is a significant public health concern due to its ability to form biofilms, enhancing its resistance to antimicrobials and contributing to its persistence in food processing environments. Traditional antibiotics often fail to target these biofilms effectively, leading to increased bacterial resistance. This study aims to explore the efficacy of novel antibiofilm agents, specifically halogenated pyrimidine derivatives, against EHEC. We screened pyrimidine and 31 halogenated pyrimidine derivatives for their antimicrobial and antibiofilm activities against EHEC using biofilm quantification assays, SEM analysis, motility, and curli production assessments. Our findings reveal that certain halogenated pyrimidine derivatives, notably 2-amino-5-bromopyrimidine (2A5BP), 2-amino-4-chloropyrrolo[2,3-d]pyrimidine (2A4CPP), and 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (2,4DC5IPP) at 50 µg/mL, exhibited significant inhibitory effects on EHEC biofilm formation without affecting bacterial growth, suggesting a targeted antibiofilm action. These compounds effectively reduced curli production and EHEC motility, essential factors for biofilm integrity and development. qRT-PCR analysis revealed that two active compounds downregulated the expression of key curli genes (csgA and csgB), leading to reduced bacterial adhesion and biofilm formation. Additionally, in silico ADME–Tox profiles indicated that these compounds exhibit favorable drug-like properties and lower toxicity compared with traditional pyrimidine. This study highlights the potential of halogenated pyrimidine derivatives as effective antibiofilm agents against EHEC, offering a promising strategy for enhancing food safety and controlling EHEC infections. The distinct mechanisms of action of these compounds, particularly in inhibiting biofilm formation and virulence factors without promoting bacterial resistance, underscore their therapeutic potential. Full article
(This article belongs to the Special Issue Mechanisms in Biofilm Formation, Tolerance and Control: 2nd Edition)
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14 pages, 11016 KiB  
Article
Rubiadin Mediates the Upregulation of Hepatic Hepcidin and Alleviates Iron Overload via BMP6/SMAD1/5/9-Signaling Pathway
by Xueting Xie, Linyue Chang, Xinyue Zhu, Fengbei Gong, Linlin Che, Rujun Zhang, Lixin Wang, Chenyuan Gong, Cheng Fang, Chao Yao, Dan Hu, Weimin Zhao, Yufu Zhou and Shiguo Zhu
Int. J. Mol. Sci. 2025, 26(3), 1385; https://doi.org/10.3390/ijms26031385 - 6 Feb 2025
Viewed by 329
Abstract
Iron overload disease is characterized by the excessive accumulation of iron in the body. To better alleviate iron overload, there is an urgent need for safe and effective small molecule compounds. Rubiadin, the active ingredient derived from the Chinese herb Prismatomeris tetrandra, possesses [...] Read more.
Iron overload disease is characterized by the excessive accumulation of iron in the body. To better alleviate iron overload, there is an urgent need for safe and effective small molecule compounds. Rubiadin, the active ingredient derived from the Chinese herb Prismatomeris tetrandra, possesses notable anti-inflammatory and hepatoprotective properties. Nevertheless, its impact on iron metabolism remains largely unexplored. To determine the role of rubiadin on iron metabolism, Western blot analysis, real-time PCR analysis, and the measurement of serum iron were performed. Herein, we discovered that rubiadin significantly downregulated the expression of transferrin receptor 1, ferroportin 1, and ferritin light chain in ferric-ammonium-citrate-treated or -untreated HepG2 cells. Moreover, intraperitoneal administration of rubiadin remarkably decreased serum iron and duodenal iron content and upregulated expression of hepcidin mRNA in the livers of high-iron-fed mice. Mechanistically, bone morphogenetic protein 6 (BMP6) inhibitor LDN-193189 completely reversed the hepcidin upregulation and suppressor of mother against decapentaplegic 1/5/9 (SMAD1/5/9) phosphorylation induced by rubiadin. These results suggested that rubiadin increased hepcidin expression through the BMP6/SMAD1/5/9-signaling pathway. Collectively, our findings uncover a crucial mechanism through which rubiadin modulates iron metabolism and highlight it as a potential natural compound for alleviating iron-overload-related diseases. Full article
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17 pages, 5427 KiB  
Article
The NbCBP1-NbSAMS1 Module Promotes Ethylene Accumulation to Enhance Nicotiana benthamiana Resistance to Phytophthora parasitica Under High Potassium Status
by Sadia Noorin, Youwei Du, Yi Liu, Shuanghong Wang, Yan Wang, Hongchen Jia, Tom Hsiang, Rong Zhang and Guangyu Sun
Int. J. Mol. Sci. 2025, 26(3), 1384; https://doi.org/10.3390/ijms26031384 - 6 Feb 2025
Viewed by 376
Abstract
Potassium (K) fertilization is crucial for plant resistance to pathogens, but the underlying mechanisms remain unclear. Here, we investigate the molecular mechanism by which the addition of K promotes resistance in Nicotiana benthamiana to Phytophthora parasitica. We found that N. benthamiana with [...] Read more.
Potassium (K) fertilization is crucial for plant resistance to pathogens, but the underlying mechanisms remain unclear. Here, we investigate the molecular mechanism by which the addition of K promotes resistance in Nicotiana benthamiana to Phytophthora parasitica. We found that N. benthamiana with high K content (HK, 52.3 g/kg) produced more ethylene in response to P. parasitica infection, compared to N. benthamiana with low-K content (LK, 22.4 g/kg). An exogenous ethylene application effectively increased resistance in LK N. benthamiana to the level under HK status, demonstrating the involvement of ethylene in the HK-associated resistance in N. benthamiana. Further, transcriptome analysis showed that NbSAMS1, encoding ethylene biosynthesis, was induced to upregulate P. parasitica about five times higher in HK than in LK N. benthamiana. NbSAMS1 overexpression enhanced resistance in LK plants, whereas NbSAMS1 silencing reduced resistance in HK plants, confirming its importance in conferring resistance. Furthermore, we identified a calcium-binding protein, NbCBP1, which interacted with NbSAMS1, promoting its expression in HK N. benthamiana. Silencing NbCBP1 compromised resistance in HK N. benthamiana, whereas its overexpression improved resistance in LK N. benthamiana. Notably, NbCBP1 protected NbSAMS1 from degradation by the 26S proteasome, thereby sustaining ethylene accumulation in HK N. benthamiana in response to P. parasitica infection. Thus, our research elucidated some mechanisms of the NbCBP1-NbSAMS1 module associated with disease resistance in HK N. benthamiana. Full article
(This article belongs to the Section Molecular Plant Sciences)
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19 pages, 3754 KiB  
Article
Differential Regulation of miRNA and Protein Profiles in Human Plasma-Derived Extracellular Vesicles via Continuous Aerobic and High-Intensity Interval Training
by Zhenghao Wang, Yiran Ou, Xinyue Zhu, Ye Zhou, Xiaowei Zheng, Meixia Zhang, Sheyu Li, Shao-Nian Yang, Lisa Juntti-Berggren, Per-Olof Berggren and Xiaofeng Zheng
Int. J. Mol. Sci. 2025, 26(3), 1383; https://doi.org/10.3390/ijms26031383 - 6 Feb 2025
Viewed by 406
Abstract
Both continuous aerobic training (CAT) and high-intensity interval training (HIIT) are recommended to promote health and prevent diseases. Exercise-induced circulating extracellular vesicles (EX-EVs) have been suggested to play essential roles in mediating organ crosstalk, but corresponding molecular mechanisms remain unclear. To assess and [...] Read more.
Both continuous aerobic training (CAT) and high-intensity interval training (HIIT) are recommended to promote health and prevent diseases. Exercise-induced circulating extracellular vesicles (EX-EVs) have been suggested to play essential roles in mediating organ crosstalk, but corresponding molecular mechanisms remain unclear. To assess and compare the systemic effects of CAT and HIIT, five healthy male volunteers were assigned to HIIT and CAT, with a 7-day interval between sessions. Plasma EVs were collected at rest or immediately after each training section, prior to proteomics and miRNA profile analysis. We found that the differentially expressed (DE) miRNAs in EX-EVs were largely involved in the regulation of transcriptional factors, while most of the DE proteins in EX-EVs were identified as non-secreted proteins. Both CAT and HIIT play common roles in neuronal signal transduction, autophagy, and cell fate regulation. Specifically, CAT showed distinct roles in cognitive function and substrate metabolism, while HIIT was more associated with organ growth, cardiac muscle function, and insulin signaling pathways. Interestingly, the miR-379 cluster within EX-EVs was specifically regulated by HIIT, involving several biological functions, including neuroactive ligand–receptor interaction. Furthermore, EX-EVs likely originate from various tissues, including metabolic tissues, the immune system, and the nervous system. Our study provides molecular insights into the effects of CAT and HIIT, shedding light on the roles of EX-EVs in mediating organ crosstalk and health promotion. Full article
(This article belongs to the Special Issue Molecular Insights into the Role of Exercise in Disease and Health)
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48 pages, 2940 KiB  
Review
Molecular Regulation of Palatogenesis and Clefting: An Integrative Analysis of Genetic, Epigenetic Networks, and Environmental Interactions
by Hyuna Im, Yujeong Song, Jae Kyeom Kim, Dae-Kyoon Park, Duk-Soo Kim, Hankyu Kim and Jeong-Oh Shin
Int. J. Mol. Sci. 2025, 26(3), 1382; https://doi.org/10.3390/ijms26031382 - 6 Feb 2025
Viewed by 450
Abstract
Palatogenesis is a complex developmental process requiring temporospatially coordinated cellular and molecular events. The following review focuses on genetic, epigenetic, and environmental aspects directing palatal formation and their implication in orofacial clefting genesis. Essential for palatal shelf development and elevation (TGF-β, BMP, FGF, [...] Read more.
Palatogenesis is a complex developmental process requiring temporospatially coordinated cellular and molecular events. The following review focuses on genetic, epigenetic, and environmental aspects directing palatal formation and their implication in orofacial clefting genesis. Essential for palatal shelf development and elevation (TGF-β, BMP, FGF, and WNT), the subsequent processes of fusion (SHH) and proliferation, migration, differentiation, and apoptosis of neural crest-derived cells are controlled through signaling pathways. Interruptions to these processes may result in the birth defect cleft lip and/or palate (CL/P), which happens in approximately 1 in every 700 live births worldwide. Recent progress has emphasized epigenetic regulations via the class of non-coding RNAs with microRNAs based on critically important biological processes, such as proliferation, apoptosis, and epithelial–mesenchymal transition. These environmental risks (maternal smoking, alcohol, retinoic acid, and folate deficiency) interact with genetic and epigenetic factors during palatogenesis, while teratogens like dexamethasone and TCDD inhibit palatal fusion. In orofacial cleft, genetic, epigenetic, and environmental impact on the complex epidemiology. This is an extensive review, offering current perspectives on gene-environment interactions, as well as non-coding RNAs, in palatogenesis and emphasizing open questions regarding these interactions in palatal development. Full article
(This article belongs to the Special Issue Gene Regulatory and Signaling Pathways in Palatogenesis)
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22 pages, 13927 KiB  
Article
Discovery of TRPV4-Targeting Small Molecules with Anti-Influenza Effects Through Machine Learning and Experimental Validation
by Yan Sun, Jiajing Wu, Beilei Shen, Hengzheng Yang, Huizi Cui, Weiwei Han, Rongbo Luo, Shijun Zhang, He Li, Bingshuo Qian, Lingjun Fan, Junkui Zhang, Tiecheng Wang, Xianzhu Xia, Fang Yan and Yuwei Gao
Int. J. Mol. Sci. 2025, 26(3), 1381; https://doi.org/10.3390/ijms26031381 - 6 Feb 2025
Viewed by 392
Abstract
Transient receptor potential vanilloid 4 (TRPV4) is a calcium-permeable cation channel critical for maintaining intracellular Ca2+ homeostasis and is essential in regulating immune responses, metabolic processes, and signal transduction. Recent studies have shown that TRPV4 activation enhances influenza A virus infection, promoting [...] Read more.
Transient receptor potential vanilloid 4 (TRPV4) is a calcium-permeable cation channel critical for maintaining intracellular Ca2+ homeostasis and is essential in regulating immune responses, metabolic processes, and signal transduction. Recent studies have shown that TRPV4 activation enhances influenza A virus infection, promoting viral replication and transmission. However, there has been limited exploration of antiviral drugs targeting the TRPV4 channel. In this study, we developed the first machine learning model specifically designed to predict TRPV4 inhibitory small molecules, providing a novel approach for rapidly identifying repurposed drugs with potential antiviral effects. Our approach integrated machine learning, virtual screening, data analysis, and experimental validation to efficiently screen and evaluate candidate molecules. For high-throughput virtual screening, we employed computational methods to screen open-source molecular databases targeting the TRPV4 receptor protein. The virtual screening results were ranked based on predicted scores from our optimized model and binding energy, allowing us to prioritize potential inhibitors. Fifteen small-molecule drugs were selected for further in vitro and in vivo antiviral testing against influenza. Notably, glecaprevir and everolimus demonstrated significant inhibitory effects on the influenza virus, markedly improving survival rates in influenza-infected mice (protection rates of 80% and 100%, respectively). We also validated the mechanisms by which these drugs interact with the TRPV4 channel. In summary, our study presents the first predictive model for identifying TRPV4 inhibitors, underscoring TRPV4 inhibition as a promising strategy for antiviral drug development against influenza. This pioneering approach lays the groundwork for future clinical research targeting the TRPV4 channel in antiviral therapies. Full article
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29 pages, 12007 KiB  
Article
Molecular Simulation of the Binding of Amyloid Beta to Apolipoprotein A-I in High-Density Lipoproteins
by Chris J. Malajczuk and Ricardo L. Mancera
Int. J. Mol. Sci. 2025, 26(3), 1380; https://doi.org/10.3390/ijms26031380 - 6 Feb 2025
Viewed by 291
Abstract
Disrupted clearance of amyloid beta (Aβ) from the brain enhances its aggregation and formation of amyloid plaques in Alzheimer’s disease. The most abundant protein constituent of circulating high-density lipoprotein (HDL) particles, apoA-I, readily crosses the blood–brain barrier from periphery circulation, exhibits low-micromolar binding [...] Read more.
Disrupted clearance of amyloid beta (Aβ) from the brain enhances its aggregation and formation of amyloid plaques in Alzheimer’s disease. The most abundant protein constituent of circulating high-density lipoprotein (HDL) particles, apoA-I, readily crosses the blood–brain barrier from periphery circulation, exhibits low-micromolar binding affinity for soluble, neurotoxic forms of Aβ, and modulates Aβ aggregation and toxicity in vitro. Its highly conserved N-terminal sequence, 42LNLKLLD48 (‘LN’), has been proposed as a binding region for Aβ. However, high-resolution structural characterisation of the mechanism of HDL–Aβ interaction is very difficult to attain. Molecular dynamics simulations were conducted to investigate for the first time the interaction of Aβ and the ‘LN’ segment of apoA-I. Favourable binding of Aβ by HDLs was found to be driven by hydrophobic and hydrogen-bonding interactions predominantly between the ‘LN’ segment of apoA-I and Aβ. Preferential binding of Aβ may proceed in small, protein-rich HDLs whereby solvent-exposed hydrophobic ‘LN’ segments of apoA-I interact specifically with Aβ, stabilising it on the HDL surface in a possibly non-amyloidogenic conformation, facilitating effective Aβ clearance. These findings rationalise the potentially therapeutic role of HDLs in reducing Aβ aggregation and toxicity, and of peptide mimics of the apoA-I interacting region in blocking Aβ aggregation. Full article
(This article belongs to the Special Issue Advances in Protein Dynamics)
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30 pages, 1219 KiB  
Review
Antioxidant and Anti-Inflammatory Effects of Bioactive Compounds in Atherosclerosis
by Ştefan Horia Roşian, Ioana Boarescu and Paul-Mihai Boarescu
Int. J. Mol. Sci. 2025, 26(3), 1379; https://doi.org/10.3390/ijms26031379 - 6 Feb 2025
Viewed by 429
Abstract
Atherosclerosis, a chronic inflammatory disease characterized by the accumulation of lipids and immune cells within arterial walls, remains a leading cause of cardiovascular morbidity and mortality worldwide. Oxidative stress and inflammation are central to its pathogenesis, driving endothelial dysfunction, foam cell formation, and [...] Read more.
Atherosclerosis, a chronic inflammatory disease characterized by the accumulation of lipids and immune cells within arterial walls, remains a leading cause of cardiovascular morbidity and mortality worldwide. Oxidative stress and inflammation are central to its pathogenesis, driving endothelial dysfunction, foam cell formation, and plaque instability. Emerging evidence highlights the potential of bioactive compounds with antioxidant and anti-inflammatory properties to mitigate these processes and promote vascular health. This review explores the mechanisms through which bioactive compounds—such as polyphenols, carotenoids, flavonoids, omega-3 fatty acids, coenzyme Q10, and other natural compounds—modulate oxidative stress and inflammation in atherosclerosis. It examines their effects on key molecular pathways, including the inhibition of reactive oxygen species (ROS) production, suppression of nuclear factor-κB (NF-κB), and modulation of inflammatory cytokines. By integrating current knowledge, this review underscores the therapeutic potential of dietary and supplemental bioactive compounds as complementary strategies for managing atherosclerosis, paving the way for future research and clinical applications. Full article
(This article belongs to the Special Issue Effects of Bioactive Compounds in Oxidative Stress and Inflammation)
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16 pages, 1891 KiB  
Article
Mitochondrial COX3 and tRNA Gene Variants Associated with Risk and Prognosis of Idiopathic Pulmonary Fibrosis
by Li-Na Lee, I-Shiow Jan, Wen-Ru Chou, Wei-Lun Liu, Yen-Liang Kuo, Chih-Yueh Chang, Hsiu-Ching Chang, Jia-Luen Liu, Chia-Lin Hsu, Chia-Nan Lin, Ke-Yun Chao, Chi-Wei Tseng, I-Hsien Lee, Jann-Tay Wang and Jann-Yuan Wang
Int. J. Mol. Sci. 2025, 26(3), 1378; https://doi.org/10.3390/ijms26031378 - 6 Feb 2025
Viewed by 352
Abstract
Idiopathic pulmonary fibrosis (IPF) has been associated with mitochondrial dysfunction. We investigated whether mitochondrial DNA variants in peripheral blood leukocytes (PBLs), which affect proteins of the respiratory chain and mitochondrial function, could be associated with an increased risk and poor prognosis of IPF. [...] Read more.
Idiopathic pulmonary fibrosis (IPF) has been associated with mitochondrial dysfunction. We investigated whether mitochondrial DNA variants in peripheral blood leukocytes (PBLs), which affect proteins of the respiratory chain and mitochondrial function, could be associated with an increased risk and poor prognosis of IPF. From 2020 to 2022, we recruited 36 patients (age: 75.3 ± 8.5; female: 19%) with IPF, and 80 control subjects (age: 72.3 ± 9.0; female: 27%). The mitochondrial genome of peripheral blood leukocytes was determined using next-generation sequencing. During a 45-month follow-up, 10 (28%) patients with IPF remained stable and the other 26 (72%) progressed, with 12 (33%) mortalities. IPF patients had more non-synonymous (NS) variants (substitution/deletion/insertion) in mitochondrial COX3 gene (coding for subunit 3 of complex IV of the respiratory chain), and more mitochondrial tRNA variants located in the anticodon (AC) stem, AC loop, variable loop, T-arm, and T-loop of the tRNA clover-leaf structure in PBLs than the control group. The succumbed IPF patients were older, had lower initial diffusion capacity, and higher initial fibrosis score on high-resolution computerized tomography (HRCT) than the alive group. NS variants in mitochondrial COX3 gene and tRNA variants in PBLs were associated with shorter survival. Our study shows that (1) leukocyte mitochondrial COX3 NS variants are associated with risk and prognosis of IPF; (2) leukocyte mitochondrial tRNA variants located in the AC stem, AC loop, variable loop, T-arm, and T-loop of the tRNA clover-leaf structure are associated with risk, and the presence of tRNA variants is associated with poor prognosis of IPF. Full article
(This article belongs to the Special Issue Advanced Molecular Research in Lung Diseases)
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28 pages, 3097 KiB  
Review
Epigenetic Regulation by lncRNA GAS5/miRNA/mRNA Network in Human Diseases
by Lam Ngoc Thao Nguyen, Jaeden S. Pyburn, Nhat Lam Nguyen, Madison B. Schank, Juan Zhao, Ling Wang, Tabitha O. Leshaodo, Mohamed El Gazzar, Jonathan P. Moorman and Zhi Q. Yao
Int. J. Mol. Sci. 2025, 26(3), 1377; https://doi.org/10.3390/ijms26031377 - 6 Feb 2025
Viewed by 304
Abstract
The interplay between long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) is crucial in the epigenetic regulation of mRNA and protein expression, impacting the development and progression of a plethora of human diseases, such as cancer, cardiovascular disease, inflammatory-associated diseases, and viral infection. Among [...] Read more.
The interplay between long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) is crucial in the epigenetic regulation of mRNA and protein expression, impacting the development and progression of a plethora of human diseases, such as cancer, cardiovascular disease, inflammatory-associated diseases, and viral infection. Among the many lncRNAs, growth arrest-specific 5 (GAS5) has garnered substantial attention for its evident role in the regulation of significant biological processes such as proliferation, differentiation, senescence, and apoptosis. Through miRNA-mediated signaling pathways, GAS5 modulates disease progression in a cell-type-specific manner, typically by influencing proteins involved in inflammation and cell death. While GAS5 is recognized as a tumor suppressor in cancer, recent reports highlight its broader regulatory capacity in non-cancerous diseases. Its modulation of protein expression through the GAS5/miRNA network has been shown to both mitigate and exacerbate disease, depending on the specific context. Furthermore, the therapeutic potential of GAS5 manipulation, via knockdown or overexpression, offers promising avenues for targeted interventions across human diseases. This review explores the dualistic impacts of the GAS5/miRNA network in conditions such as cancer, cardiovascular disease, viral infections, and inflammatory disorders. Through the evaluation of current evidence, we aim to provide insight into GAS5’s biological functions and its implications for future research and therapeutic development. Full article
(This article belongs to the Special Issue Role of MicroRNAs in Human Diseases)
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32 pages, 1452 KiB  
Review
Modification in Structures of Active Compounds in Anticancer Mitochondria-Targeted Therapy
by Agnieszka Pyrczak-Felczykowska and Anna Herman-Antosiewicz
Int. J. Mol. Sci. 2025, 26(3), 1376; https://doi.org/10.3390/ijms26031376 - 6 Feb 2025
Viewed by 458
Abstract
Cancer is a multifaceted disease characterised by uncontrolled cellular proliferation and metastasis, resulting in significant global mortality. Current therapeutic strategies, including surgery, chemotherapy, and radiation therapy, face challenges such as systemic toxicity and tumour resistance. Recent advancements have shifted towards targeted therapies that [...] Read more.
Cancer is a multifaceted disease characterised by uncontrolled cellular proliferation and metastasis, resulting in significant global mortality. Current therapeutic strategies, including surgery, chemotherapy, and radiation therapy, face challenges such as systemic toxicity and tumour resistance. Recent advancements have shifted towards targeted therapies that act selectively on molecular structures within cancer cells, reducing off-target effects. Mitochondria have emerged as pivotal targets in this approach, given their roles in metabolic reprogramming, retrograde signalling, and oxidative stress, all of which drive the malignant phenotype. Targeting mitochondria offers a promising strategy to address these mechanisms at their origin. Synthetic derivatives of natural compounds hold particular promise in mitochondrial-targeted therapies. Innovations in drug design, including the use of conjugates and nanotechnology, focus on optimizing these compounds for mitochondrial specificity. Such advancements enhance therapeutic efficacy while minimizing systemic toxicity, presenting a significant step forward in modern anticancer strategies. Full article
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21 pages, 5178 KiB  
Article
The Disruptions of Sphingolipid and Sterol Metabolism in the Short Fiber of Ligon-Lintless-1 Mutant Revealed Obesity Impeded Cotton Fiber Elongation and Secondary Cell Wall Deposition
by Huidan Tian, Qiaoling Wang, Xingying Yan, Hongju Zhang, Zheng Chen, Caixia Ma, Qian Meng, Fan Xu and Ming Luo
Int. J. Mol. Sci. 2025, 26(3), 1375; https://doi.org/10.3390/ijms26031375 - 6 Feb 2025
Viewed by 374
Abstract
Boosting evidence indicated lipids play important roles in plants. To explore lipid function in cotton fiber development, the lipid composition and content were detected by untargeted and targeted lipidomics. Compared with rapid elongation fibers, the lipid intensity of 16 sub-classes and 56 molecular [...] Read more.
Boosting evidence indicated lipids play important roles in plants. To explore lipid function in cotton fiber development, the lipid composition and content were detected by untargeted and targeted lipidomics. Compared with rapid elongation fibers, the lipid intensity of 16 sub-classes and 56 molecular species decreased, while only 7 sub-classes and 26 molecular species increased in the fibers at the stage of secondary cell wall deposition. Unexpectedly, at the rapid elongation stage, 20 sub-classes and 60 molecular species increased significantly, while only 5 sub-classes and 8 molecular species decreased in the ligon lintless-1 (li-1) mutant compared with its wild-type Texas Maker-1 (TM-1). Particularly, campesteryl, sitosteryl, and total steryl ester increased by 21.8-, 48.7-, and 45.5-fold in the li-1 fibers, respectively. All the molecular species of sphingosine-1-P, phytoceramide-OHFA, and glucosylceramide increased while all sphingosine, phytosphingosine, and glycosyl inositol phospho ceramides decreased in the li-1 fibers. Similarly, the different expression genes between the mutant and wild type were enriched in many pathways involved in the lipid metabolism. Furthermore, the number of lipid droplets also increased in the li-1 leaf and fiber cells when compared with the wild type. These results illuminated that fiber cell elongation being blocked in the li-1 mutant was not due to a lack of lipids, but rather lipid over-accumulation (obesity), which may result from the disruption of sphingolipid and sterol metabolism. This study provides a new perspective for further studying the regulatory mechanisms of fiber development. Full article
(This article belongs to the Section Molecular Plant Sciences)
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11 pages, 4355 KiB  
Case Report
Peripheral Blood Mononuclear Cells Cytokine Profile in a Patient with Toxic Epidermal Necrolysis Triggered by Lamotrigine and COVID-19: A Case Study
by Margarita L. Martinez-Fierro, Idalia Garza-Veloz, Sidere Monserrath Zorrilla-Alfaro, Andrés Eduardo Campuzano-Garcia and Monica Rodriguez-Borroel
Int. J. Mol. Sci. 2025, 26(3), 1374; https://doi.org/10.3390/ijms26031374 - 6 Feb 2025
Viewed by 299
Abstract
Stevens–Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN) is a severe mucocutaneous reaction often induced by medications. The co-occurrence of SJS/TEN and COVID-19 presents a unique challenge due to overlapping inflammatory pathways. This case study examined the cytokine profile of a patient with both TEN [...] Read more.
Stevens–Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN) is a severe mucocutaneous reaction often induced by medications. The co-occurrence of SJS/TEN and COVID-19 presents a unique challenge due to overlapping inflammatory pathways. This case study examined the cytokine profile of a patient with both TEN (triggered by lamotrigine) and COVID-19. The clinical history of the patient, including lamotrigine exposure and COVID-19 diagnosis, was documented. A 13-cytokine profile assessment was performed in peripheral blood mononuclear cells from the patient and their parents by using quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). A 6-year-old male patient developed lamotrigine-induced TEN with concomitant COVID-19 affecting 90% of the body surface area. Compared with their parents, who were positive for COVID-19, IL-6, IL-4, and IL-12 were modulated (downregulated) by TEN. The cytokine profile showed elevated levels of IL-1α, IL-1β, IL-5, IL-8, NF-κβ, and interferons (IFN; α, β, and γ), indicating a robust antiviral response. The immune profile suggested a hyperactivated immune state that contributed to the severity of the patient’s clinical manifestations, leading to death 18 days after hospitalization. Understanding the immune response is important for developing future targeted therapeutic strategies and improving patient outcomes. Further research is needed to explore the interaction between drug-induced SJS/TEN and infections. Full article
(This article belongs to the Special Issue Targeted Therapy for Immune Diseases)
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26 pages, 2623 KiB  
Review
The Role of Gut Microbiota-Derived Trimethylamine N-Oxide in the Pathogenesis and Treatment of Mild Cognitive Impairment
by Haihua Xie, Jia Jiang, Sihui Cao, Xuan Xu, Jingyin Zhou, Ruhan Zhang, Bo Huang, Penghui Lu, Liang Peng and Mi Liu
Int. J. Mol. Sci. 2025, 26(3), 1373; https://doi.org/10.3390/ijms26031373 - 6 Feb 2025
Viewed by 406
Abstract
Mild cognitive impairment (MCI) represents a transitional stage between normal aging and dementia, often considered critical for dementia prevention. Despite its significance, no effective clinical treatment for MCI has yet been established. Emerging evidence has demonstrated a strong association between trimethylamine-N-oxide (TMAO), a [...] Read more.
Mild cognitive impairment (MCI) represents a transitional stage between normal aging and dementia, often considered critical for dementia prevention. Despite its significance, no effective clinical treatment for MCI has yet been established. Emerging evidence has demonstrated a strong association between trimethylamine-N-oxide (TMAO), a prominent metabolite derived from the gut microbiota, and MCI, highlighting its potential as a biomarker and therapeutic target. TMAO has been implicated in increasing MCI risk through its influence on factors such as hypertension, cardiovascular disease, depression, diabetes, and stroke. Moreover, it contributes to MCI by promoting oxidative stress, disrupting the blood–brain barrier, impairing synaptic plasticity, inducing inflammation, causing mitochondrial metabolic disturbances, and facilitating abnormal protein aggregation. This review further explores therapeutic strategies targeting TMAO to mitigate MCI progression. Full article
(This article belongs to the Section Molecular Microbiology)
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24 pages, 1083 KiB  
Review
Correlations Between Gut Microbiota Composition, Medical Nutrition Therapy, and Insulin Resistance in Pregnancy—A Narrative Review
by Robert-Mihai Enache, Oana Alexandra Roşu, Monica Profir, Luciana Alexandra Pavelescu, Sanda Maria Creţoiu and Bogdan Severus Gaspar
Int. J. Mol. Sci. 2025, 26(3), 1372; https://doi.org/10.3390/ijms26031372 - 6 Feb 2025
Viewed by 392
Abstract
Many physiological changes accompany pregnancy, most of them involving metabolic perturbations. Alterations in microbiota composition occur both before and during pregnancy and have recently been correlated with an important role in the development of metabolic complications, such as insulin resistance and gestational diabetes [...] Read more.
Many physiological changes accompany pregnancy, most of them involving metabolic perturbations. Alterations in microbiota composition occur both before and during pregnancy and have recently been correlated with an important role in the development of metabolic complications, such as insulin resistance and gestational diabetes mellitus (GDM). These changes may be influenced by physiological adaptations to pregnancy itself, as well as by dietary modifications during gestation. Medical nutritional therapy (MNT) applied to pregnant women at risk stands out as one of the most important factors in increasing the microbiota’s diversity at both the species and genus levels. In this review, we discuss the physiological changes during pregnancy and their impact on the composition of the intestinal microbiota, which may contribute to GDM. We also discuss findings from previous studies regarding the effectiveness of MNT in reducing insulin resistance. In the future, additional studies should aim to identify specific gut microbial profiles that serve as early indicators of insulin resistance during gestation. Early diagnosis, achievable through stool analysis or metabolite profiling, may facilitate the timely implementation of dietary or pharmaceutical modifications, thereby mitigating the development of insulin resistance and its associated sequelae. Full article
(This article belongs to the Special Issue Molecular Insight into Gestational Diabetes Mellitus)
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14 pages, 4642 KiB  
Article
Dynamics of Immune Cell Infiltration and Fibroblast-Derived IL-33/ST2 Axis Induction in a Mouse Model of Post-Surgical Lymphedema
by Kazuhisa Uemura, Kei-ichi Katayama, Toshihiko Nishioka, Hikaru Watanabe, Gen Yamada, Norimitsu Inoue and Shinichi Asamura
Int. J. Mol. Sci. 2025, 26(3), 1371; https://doi.org/10.3390/ijms26031371 - 6 Feb 2025
Viewed by 315
Abstract
Lymphedema is an intractable disease most commonly associated with lymph node dissection for cancer treatment and can lead to a decreased quality of life. Type 2 T helper (Th2) lymphocytes have been shown to be important in the progression of lymphedema. The activation [...] Read more.
Lymphedema is an intractable disease most commonly associated with lymph node dissection for cancer treatment and can lead to a decreased quality of life. Type 2 T helper (Th2) lymphocytes have been shown to be important in the progression of lymphedema. The activation of IL-33 and its receptor, the suppression of tumorigenicity 2 (ST2) signaling pathway, induces the differentiation of Th2 cells, but its involvement in lymphedema remains unclear. In the present study, we analyzed the dynamics of immune cell infiltration, including the IL-33/ST2 axis, in a mouse tail lymphedema model. Neutrophil infiltration was first detected in the lymphedema tissue on postoperative day (POD) 2. Macrophage infiltration increased from POD 2 to 5. The number of CD4+ T cells, including 50% Tregs, gradually increased from POD 14. The mRNA expression of ll13 and Ifng increased on POD 21. The expression of IL-33 was induced in fibroblast nuclei within dermal and subcutaneous tissues from POD 2, and the expression of the Il1rl1 gene encoding ST2 increased from POD 7. We demonstrated the infiltration process from innate to acquired immune cells through the development of a mouse tail lymphedema. The IL-33/ST2 axis was found to be induced during the transition from innate to acquired immunity. Full article
(This article belongs to the Special Issue Lymphedema: From Mechanism to Treatment)
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20 pages, 10581 KiB  
Article
Phylogeny of Camphora and Cinnamomum (Lauraceae) Based on Plastome and Nuclear Ribosomal DNA Data
by Jian Xu, Haorong Zhang, Fan Yang, Wen Zhu, Qishao Li, Zhengying Cao, Yu Song and Peiyao Xin
Int. J. Mol. Sci. 2025, 26(3), 1370; https://doi.org/10.3390/ijms26031370 - 6 Feb 2025
Viewed by 328
Abstract
Camphora Fabr. is a genus in the family Lauraceae, comprising over 20 tropical and subtropical tree species. Since the genera Camphora and Cinnamomum Schaeff. were described, there has been a long-lasting controversy regarding the phylogenetic relationships among taxa in both genera. In particular, [...] Read more.
Camphora Fabr. is a genus in the family Lauraceae, comprising over 20 tropical and subtropical tree species. Since the genera Camphora and Cinnamomum Schaeff. were described, there has been a long-lasting controversy regarding the phylogenetic relationships among taxa in both genera. In particular, phylogenetic inferences derived from plastid data remain debated, with varying hypotheses proposed and occasional disputes concerning the monophyly of Camphora taxa. To further investigate the relationships, We analyzed plastomes and nuclear ribosomal cistron sequences (nrDNA) of 22 Camphora taxa, 15 Cinnamomum taxa, and 13 representative taxa of related genera. The Camphora plastomes range from 152,745 to 154,190 bp, with a GC content of 39.1% to 39.2%. A total of 128 genes were identified in the Camphora plastomes, including 84 protein-coding genes, 8 rRNA genes, and 36 tRNA genes. A total of 1130 SSR loci were detected from plastomes of Camphora, and A/T base repeats looked like the most common. Comparative analyses revealed that the plastomes of Camphora exhibit high similarity in overall structure. The loci ycf1, ycf2, trnK (UUU), psbJ-psbL, and ccsA-ndhD were identified as candidate DNA barcodes for these taxa. Plastome phylogenetic analysis revealed that Camphora is not monophyletic, whereas the nrDNA dataset supported the monophyly of Camphora. We propose that intergeneric hybridization may underlie the observed discordance between plastid and nuclear data in Camphora, and we recommend enhanced taxonomic sampling and precise species identification to improve phylogenetic resolution and accuracy. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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20 pages, 11711 KiB  
Article
CITE-Seq Analysis Reveals a Differential Natural Killer Cell SPON2 Expression in Cardiovascular Disease Patients Impacted by Human-Cytomegalovirus Serostatus and Diabetes
by Sujit Silas Armstrong, Daniel G. Chen, Sunil Kumar, James R. Heath, Matthew J. Feinstein, John R. Greenland, Daniel R. Calabrese, Lewis L. Lanier, Klaus Ley and Avishai Shemesh
Int. J. Mol. Sci. 2025, 26(3), 1369; https://doi.org/10.3390/ijms26031369 - 6 Feb 2025
Viewed by 475
Abstract
Coronary artery disease (CAD) is linked to atherosclerosis plaque formation. In pro-inflammatory conditions, human Natural Killer (NK) cell frequencies in blood or plaque decrease; however, NK cells are underexplored in CAD pathogenesis, inflammatory mechanisms, and CAD comorbidities, such as human cytomegalovirus (HCMV) infection [...] Read more.
Coronary artery disease (CAD) is linked to atherosclerosis plaque formation. In pro-inflammatory conditions, human Natural Killer (NK) cell frequencies in blood or plaque decrease; however, NK cells are underexplored in CAD pathogenesis, inflammatory mechanisms, and CAD comorbidities, such as human cytomegalovirus (HCMV) infection and diabetes. Analysis of PBMC CITE-seq data from sixty-one CAD patients revealed higher blood NK cell SPON2 expression in CAD patients with higher stenosis severity. Conversely, NK cell SPON2 expression was lower in pro-inflammatory atherosclerosis plaque tissue with an enriched adaptive NK cell gene signature. In CAD patients with higher stenosis severity, peripheral blood NK cell SPON2 expression was lower in patients with high HCMV-induced adaptive NK cell frequencies and corresponded to lower PBMC TGFβ transcript expression with dependency on diabetes status. These results suggest that high NK cell SPON2 expression is linked to atherosclerosis pro-homeostatic status and may have diagnostic and prognostic implications in cardiovascular disease. Full article
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17 pages, 9918 KiB  
Article
Aspirin Foliar Spray-Induced Changes in Light Energy Use Efficiency, Chloroplast Ultrastructure, and ROS Generation in Tomato
by Julietta Moustaka, Ilektra Sperdouli, Emmanuel Panteris, Ioannis-Dimosthenis S. Adamakis and Michael Moustakas
Int. J. Mol. Sci. 2025, 26(3), 1368; https://doi.org/10.3390/ijms26031368 - 6 Feb 2025
Viewed by 328
Abstract
Aspirin (Asp) is extensively used in human health as an anti-inflammatory, antipyretic, and anti-thrombotic drug. In this study, we investigated if the foliar application of Asp on tomato plants has comparable beneficial effects on photosynthetic function to that of salicylic acid (SA), with [...] Read more.
Aspirin (Asp) is extensively used in human health as an anti-inflammatory, antipyretic, and anti-thrombotic drug. In this study, we investigated if the foliar application of Asp on tomato plants has comparable beneficial effects on photosynthetic function to that of salicylic acid (SA), with which it shares similar physiological characteristics. We assessed the consequences of foliar Asp-spray on the photosystem II (PSII) efficiency of tomato plants, and we estimated the reactive oxygen species (ROS) generation and the chloroplast ultrastructural changes. Asp acted as an osmoregulator by increasing tomato leaf water content and offering antioxidant protection. This protection kept the redox state of plastoquinone (PQ) pull (qp) more oxidized, increasing the fraction of open PSII reaction centers and enhancing PSII photochemistry (ΦPSII). In addition, Asp foliar spray decreased reactive oxygen species (ROS) formation, decreasing the excess excitation energy on PSII. This resulted in a lower singlet oxygen (1O2) generation and a lower quantum yield for heat dissipation (ΦNPQ), indicating the photoprotective effect provided by Asp, especially under excess light illumination. Simultaneously, we observed a decrease in stomatal opening by Asp, which reduced the transpiration. Chloroplast ultrastructural data revealed that Asp, by offering a photoprotective effect, decreased the need for the photorespiration process, which reduces photosynthetic performance. It is concluded that Asp shares similar physiological characteristics with SA, having an equivalent beneficial impact to SA by acting as a biostimulant of the photosynthetic function for an enhanced crop yield. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Plant Abiotic Stress Tolerance)
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28 pages, 7769 KiB  
Article
Impact of African-Specific ACE2 Polymorphisms on Omicron BA.4/5 RBD Binding and Allosteric Communication Within the ACE2–RBD Protein Complex
by Victor Barozi and Özlem Tastan Bishop
Int. J. Mol. Sci. 2025, 26(3), 1367; https://doi.org/10.3390/ijms26031367 - 6 Feb 2025
Viewed by 531
Abstract
Severe acute respiratory symptom coronavirus 2 (SARS-CoV-2) infection occurs via the attachment of the spike (S) protein’s receptor binding domain (RBD) to human ACE2 (hACE2). Natural polymorphisms in hACE2, particularly at the interface, may alter RBD–hACE2 interactions, potentially affecting viral infectivity across populations. [...] Read more.
Severe acute respiratory symptom coronavirus 2 (SARS-CoV-2) infection occurs via the attachment of the spike (S) protein’s receptor binding domain (RBD) to human ACE2 (hACE2). Natural polymorphisms in hACE2, particularly at the interface, may alter RBD–hACE2 interactions, potentially affecting viral infectivity across populations. This study identified the effects of six naturally occurring hACE2 polymorphisms with high allele frequency in the African population (S19P, K26R, M82I, K341R, N546D and D597Q) on the interaction with the S protein RBD of the BA.4/5 Omicron sub-lineage through post-molecular dynamics (MD), inter-protein interaction and dynamic residue network (DRN) analyses. Inter-protein interaction analysis suggested that the K26R variation, with the highest interactions, aligns with reports of enhanced RBD binding and increased SARS-CoV-2 susceptibility. Conversely, S19P, showing the fewest interactions and largest inter-protein distances, agrees with studies indicating it hinders RBD binding. The hACE2 M82I substitution destabilized RBD–hACE2 interactions, reducing contact frequency from 92 (WT) to 27. The K341R hACE2 variant, located distally, had allosteric effects that increased RBD–hACE2 contacts compared to WThACE2. This polymorphism has been linked to enhanced affinity for Alpha, Beta and Delta lineages. DRN analyses revealed that hACE2 polymorphisms may alter the interaction networks, especially in key residues involved in enzyme activity and RBD binding. Notably, S19P may weaken hACE2–RBD interactions, while M82I showed reduced centrality of zinc and chloride-coordinating residues, hinting at impaired communication pathways. Overall, our findings show that hACE2 polymorphisms affect S BA.4/5 RBD stability and modulate spike RBD–hACE2 interactions, potentially influencing SARS-CoV-2 infectivity—key insights for vaccine and therapeutic development. Full article
(This article belongs to the Section Biochemistry)
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16 pages, 1841 KiB  
Article
AgNP-Containing Niosomes Functionalized with Fucoidan Potentiated the Intracellular Killing of Mycobacterium abscessus in Macrophages
by Nereyda Niño-Martínez, Kayla Audreyartha, Kaitlyn Cheung, Sol Melchor Parra, Gabriel Martínez-Castañón and Horacio Bach
Int. J. Mol. Sci. 2025, 26(3), 1366; https://doi.org/10.3390/ijms26031366 - 6 Feb 2025
Viewed by 368
Abstract
Intracellular pathogens represent a challenge for therapy because the antibiotics used need to diffuse into the cytoplasm to target the pathogens. The situation is more complicated in the mycobacteria family because members of this family infect and multiply within macrophages, the cells responsible [...] Read more.
Intracellular pathogens represent a challenge for therapy because the antibiotics used need to diffuse into the cytoplasm to target the pathogens. The situation is more complicated in the mycobacteria family because members of this family infect and multiply within macrophages, the cells responsible for clearing microorganisms in the body. In addition, mycobacteria members are enclosed inside pathogen-containing vesicles or phagosomes. The treatments of these pathogens are aggravated when these pathogens acquire resistance to antibiotic molecules. As a result, new antimicrobial alternatives are needed. Niosomes are vesicles composed of cholesterol and nonionic surfactants that can be used for antibiotic encapsulation and delivery. The current study developed a systematic formulation of niosomes to determine the best option for niosome functionalizing for precise delivery to the intracellular pathogen Mycobacterium abscessus. Silver nanoparticles (AgNPs) were synthesized using gallic acid as an antibacterial agent. Then, niosomes were prepared and characterized, following the encapsulation of AgNPs functionalized with a single-chain antibody screened against the cell wall glycopeptidolipid of Mycobacterium abscessus. For a precise delivery of the cargo into macrophages, the niosomes were also functionalized with the polysaccharide fucoidan, taken specifically by the scavenger receptor class A expressed on the surface of macrophages. Results of the study showed a steady decrease in the intracellular pathogen load after 48 h post-infection. In conclusion, this system could be developed into a platform to target other types of intracellular pathogens and as an option for antimicrobial therapy. Full article
(This article belongs to the Special Issue Advances in Antimicrobial Nanomaterials 2.0)
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14 pages, 7571 KiB  
Article
Sterol Regulatory Element-Binding Protein Sre1 Mediates the Development and Pathogenicity of the Grey Mould Fungus Botrytis cinerea
by Ye Yuan, Shengnan Cao, Jiao Sun, Jie Hou, Mingzhe Zhang, Qingming Qin and Guihua Li
Int. J. Mol. Sci. 2025, 26(3), 1365; https://doi.org/10.3390/ijms26031365 - 6 Feb 2025
Viewed by 452
Abstract
The grey mould fungus Botrytis cinerea is a dangerous plant pathogen responsible for substantial agricultural losses worldwide. The pathogenic mechanisms still have many unclear aspects, and numerous new pathogenic genes remain to be identified. Here, we show that the sterol regulatory element-binding protein [...] Read more.
The grey mould fungus Botrytis cinerea is a dangerous plant pathogen responsible for substantial agricultural losses worldwide. The pathogenic mechanisms still have many unclear aspects, and numerous new pathogenic genes remain to be identified. Here, we show that the sterol regulatory element-binding protein Sre1 plays an important role in the development and pathogenicity of B. cinerea. We identified a homologue of gene SRE1 in the B. cinerea genome and utilized a reverse genetics approach to create the knockout mutant Δsre1. Our results demonstrate that SRE1 is essential for conidiation, as Δsre1 produced only 3% of the conidia compared to the wild-type strain. Conversely, Δsre1 exhibited increased sclerotium production, indicating a negative regulatory role of SRE1 in sclerotium formation. Furthermore, ergosterol biosynthesis was significantly reduced in the Δsre1 mutant, correlating with increased sensitivity to low-oxygen conditions. Pathogenicity assays revealed that Δsre1 had significantly reduced virulence, although it maintained normal infection cushion formation and penetration capabilities. Additionally, SRE1 was found to be crucial for hypoxia adaptation, as Δsre1 showed abnormal germination and reduced growth under low-oxygen conditions. These findings suggest that SRE1 mediates the development and pathogenicity of B. cinerea by regulating lipid homeostasis and facilitating adaptation to host tissue environments. Full article
(This article belongs to the Special Issue Plant Responses to Biotic and Abiotic Stresses)
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