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Int. J. Mol. Sci., Volume 26, Issue 5 (March-1 2025) – 590 articles

Cover Story (view full-size image): Macrophages are the immune system’s ultimate shapeshifters, constantly adapting to their environment. As the guardians of homeostasis, they orchestrate immune responses, clear pathogens, and promote tissue repair. Yet, their remarkable plasticity also makes them key players in disease, fueling chronic inflammation, autoimmune disorders, and cancer progression. This review delves into the intricate biology of macrophages, highlighting their polarization states, their roles in health and disease, and their potential as therapeutic targets. Understanding their functional plasticity opens new avenues for innovative treatments, leveraging their power to heal or, when misdirected, to harm. View this paper
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18 pages, 7554 KiB  
Article
OsRNE Encodes an RNase E/G-Type Endoribonuclease Required for Chloroplast Development and Seedling Growth in Rice
by Huimin Fang, Lili Song, Kangwei Liu, Yishu Gu, Yao Guo, Chao Zhang and Long Zhang
Int. J. Mol. Sci. 2025, 26(5), 2375; https://doi.org/10.3390/ijms26052375 - 6 Mar 2025
Viewed by 596
Abstract
Chloroplast biogenesis is a crucial biological process in plants. Endoribonuclease E (RNase E) functions in the RNA metabolism of chloroplast and plays a vital role for chloroplast development in Arabidopsis. However, despite sharing 44.7% of its amino acid sequence identity with Arabidopsis [...] Read more.
Chloroplast biogenesis is a crucial biological process in plants. Endoribonuclease E (RNase E) functions in the RNA metabolism of chloroplast and plays a vital role for chloroplast development in Arabidopsis. However, despite sharing 44.7% of its amino acid sequence identity with Arabidopsis RNase E, the biological function of rice OsRNE (Oryza sativa RNase E) remains unknown. Here, we identified a white leaf and lethal 1 (wll1) mutant that displayed white leaves and died at the seedling stage. The causal gene OsRNE was isolated by MutMap+ method. CRISPR/Cas9-mediated knockout of OsRNE resulted in white leaves and seedling lethality, confirming OsRNE as the causal gene for the wll1 phenotype. The albino phenotype of osrne mutant was associated with decreased chlorophyll content and abnormal thylakoid morphology in the chloroplast. The absence of OsRNE led to a significant reduction in the Rubisco large subunit (RbcL), and the 23S and 16S chloroplast rRNAs were nearly undetectable in the osrne mutant. OsRNE transcripts were highly expressed in green tissues, and the protein was localized to chloroplasts, indicating its essential role in photosynthetic organs. Furthermore, transcriptome analysis showed that most of the genes associated with photosynthesis and carbohydrate metabolism pathways in the osrne mutant were significantly down-regulated compared with those in WT. Chlorophyll- and other pigment-related genes were also differentially expressed in the osrne mutant. Our findings demonstrated that OsRNE plays an important role in chloroplast development and chlorophyll biosynthesis in rice. Full article
(This article belongs to the Special Issue Genetic Regulation of Plant Growth and Protection)
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16 pages, 6892 KiB  
Article
Reduced Expression of SATB2 in Colorectal Cancer and Its Association with Demographic and Clinicopathological Parameters
by Anna Ewa Kowalczyk, Agnieszka Śliwińska-Jewsiewicka, Bartłomiej Emil Kraziński, Aleksandra Piotrowska, Jędrzej Grzegrzółka, Janusz Godlewski, Piotr Dzięgiel and Zbigniew Kmieć
Int. J. Mol. Sci. 2025, 26(5), 2374; https://doi.org/10.3390/ijms26052374 - 6 Mar 2025
Viewed by 669
Abstract
Special AT-rich sequence-binding protein 2 (SATB2), as a nuclear matrix-associated protein and transcription factor engaged in chromatin remodeling and the regulation of gene expression, plays an important role in growth and development processes. SATB2 has been shown to have tissue-specific expression, also related [...] Read more.
Special AT-rich sequence-binding protein 2 (SATB2), as a nuclear matrix-associated protein and transcription factor engaged in chromatin remodeling and the regulation of gene expression, plays an important role in growth and development processes. SATB2 has been shown to have tissue-specific expression, also related to some cancers, including colorectal cancer (CRC). The aim of this study was to compare SATB2 gene expression in tumor and matched non-involved colorectal tissues obtained from CRC patients, and to investigate its association with clinicopathological and demographic parameters, as well as patients’ overall survival. SATB2 mRNA levels in the tested tissues were assessed by quantitative polymerase chain reaction, while SATB2 protein expression was determined by immunohistochemistry. We found that the average levels of both SATB2 mRNA and protein were significantly lower in tumor specimens than in matched non-involved colon tissues. Moreover, SATB2 immunoreactivity was associated with patients’ sex, tumor localization, and grade of differentiation. Lower immunoreactivity of SATB2 protein was noted in high-grade tumors, in women, and in tumors located in the cecum, ascending, and transverse colon. However, the results of the present study did not show an association between SATB2 expression levels and patients’ overall survival. Our findings indicate the involvement of impaired SATB2 expression, significantly reduced in high-grading tumors, in the pathogenesis of CRC, while its sex- and localization-specificity should be further elucidated. Full article
(This article belongs to the Special Issue Colorectal Cancers: An Update on Their Molecular Pathology and Therapy)
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19 pages, 4541 KiB  
Article
The Aldehyde Dehydrogenase Superfamily in Brassica napus L.: Genome-Wide Identification and Expression Analysis Under Low-Temperature Conditions
by Ting Jin, Chunhua Wu, Zhen Huang, Xingguo Zhang, Shimeng Li, Chao Ding and Weihua Long
Int. J. Mol. Sci. 2025, 26(5), 2373; https://doi.org/10.3390/ijms26052373 - 6 Mar 2025
Viewed by 650
Abstract
The Aldehyde Dehydrogenase (ALDH) superfamily comprises a group of NAD+ or NADP+-dependent enzymes that play essential roles in responding to abiotic stresses in plants. In Brassica napus L., however, the increasing frequency of extremely low temperatures during winter in recent [...] Read more.
The Aldehyde Dehydrogenase (ALDH) superfamily comprises a group of NAD+ or NADP+-dependent enzymes that play essential roles in responding to abiotic stresses in plants. In Brassica napus L., however, the increasing frequency of extremely low temperatures during winter in recent years has significantly affected both yield and quality. This study conducted a genome-wide screening of ALDH superfamily genes, analyzing their gene structures, evolutionary relationships, protein physicochemical properties, and expression patterns under low-temperature stress to explore the function of the ALDH superfamily gene in cold tolerance in Brassica napus L. A total of six BnALDH genes with significant differences in expression levels were verified utilizing quantitative real-time polymerase chain reaction (qRT-PCR), revealing that BnALDH11A2, BnALDH7B2, BnALDH3F5, BnALDH12A3, BnALDH2B6, and BnALDH7B3 all exhibited higher expression in cold-tolerant material 24W233 compared with cold-sensitive material 24W259. Additionally, a single nucleotide polymorphism (SNP) in the BnALDH11A2 promoter region shows differences between the cold-tolerant (24W233) and the cold-sensitive (24W259) Brassica napus varieties, and it may be associated with the cold tolerance of these two varieties. This comprehensive analysis offers valuable insights into the role of ALDH family genes in low-temperature stress adaptation in Brassica napus and offers genetic resources for the development of novel cold-tolerant cultivars. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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14 pages, 2158 KiB  
Article
Mechanisms of mepA Overexpression and Membrane Potential Reduction Leading to Ciprofloxacin Heteroresistance in a Staphylococcus aureus Isolate
by Mengyuan Li, Qianting Jian, Xinyi Ye, Mou Jing, Jia’en Wu, Zhihong Wu, Yali Ruan, Xiaoling Long, Rongmin Zhang, Hao Ren, Jian Sun, Yahong Liu, Xiaoping Liao and Xinlei Lian
Int. J. Mol. Sci. 2025, 26(5), 2372; https://doi.org/10.3390/ijms26052372 - 6 Mar 2025
Viewed by 673
Abstract
Heteroresistance has seriously affected the evaluation of antibiotic efficacy against pathogenic bacteria, causing misjudgment of antibiotics’ sensitivity in clinical therapy, leading to treatment failure, and posing a serious threat to current medical health. However, the mechanism of Staphylococcus aureus heteroresistance to ciprofloxacin remains [...] Read more.
Heteroresistance has seriously affected the evaluation of antibiotic efficacy against pathogenic bacteria, causing misjudgment of antibiotics’ sensitivity in clinical therapy, leading to treatment failure, and posing a serious threat to current medical health. However, the mechanism of Staphylococcus aureus heteroresistance to ciprofloxacin remains unclear. In this study, heteroresistance to ciprofloxacin in S. aureus strain 529 was confirmed by antimicrobial susceptibility testing and population analysis profiling (PAP), with the resistance of subclonal 529_HR based on MIC being 8-fold that of the original bacteria. A 7-day serial MIC evaluation and growth curves demonstrate that their phenotype was stable, with 529_HR growing more slowly than 529, but reaching a plateau in a similar proportion. WGS analysis showed that there were 11 nonsynonymous mutations and one deletion gene between the two bacteria, but none of these SNPs were directly associated with ciprofloxacin resistance. Transcriptome data analysis showed that the expression of membrane potential related genes (qoxA, qoxB, qoxC, qoxD, mprF) was downregulated, and the expression of multidrug resistance efflux pump gene mepA was upregulated. The combination of ciprofloxacin and limonene restored the 529_HR MIC from 1 mg/L to 0.125 mg/L. Measurement of the membrane potential found that 529_HR had a lower potential, which may enable it to withstand the ciprofloxacin-induced decrease in membrane potential. In summary, we demonstrated that upregulation of mepA gene expression and a reduction in membrane potential are the main heteroresistance mechanisms of S. aureus to ciprofloxacin. Additionally, limonene may be a potentially effective agent to inhibit ciprofloxacin heteroresistance phenotypes. Full article
(This article belongs to the Section Molecular Microbiology)
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13 pages, 1510 KiB  
Article
The Role of Energy Homeostasis-Associated Gene Expression and Serum Adropin Levels in Patients with Familial Mediterranean Fever
by Durkadin Demir Eksi, Gulay Gulbol Duran, Muhammet Murat Celik, Yunus Emre Eksi and Ramazan Gunesacar
Int. J. Mol. Sci. 2025, 26(5), 2371; https://doi.org/10.3390/ijms26052371 - 6 Mar 2025
Viewed by 479
Abstract
Familial Mediterranean Fever (FMF) is a genetic autoinflammatory disease primarily affecting populations in the Mediterranean region. The pathogenesis of FMF and the roles of various molecules remain unclear. Adropin, a protein encoded by the Energy Homeostasis-Associated Gene (ENHO), is involved in [...] Read more.
Familial Mediterranean Fever (FMF) is a genetic autoinflammatory disease primarily affecting populations in the Mediterranean region. The pathogenesis of FMF and the roles of various molecules remain unclear. Adropin, a protein encoded by the Energy Homeostasis-Associated Gene (ENHO), is involved in energy metabolism and inflammation. This study aimed to explore the relationship between ENHO expression, Adropin levels, and FMF, examining their correlations with disease characteristics. This study included 30 patients clinically diagnosed with FMF and 35 healthy controls. The ENHO expression in peripheral blood mononuclear cells was assessed using a qRT-PCR, and the serum Adropin levels were measured via ELISA. The ENHO expression was significantly elevated in the FMF patients compared to the controls (p = 0.0007), while no significant differences were observed in the serum Adropin levels between the groups (p = 0.81). A correlation analysis revealed a negative association between the ENHO expression and age (r = −0.47, p = 0.009), whereas the serum Adropin levels were positively correlated with age, disease onset, and diagnostic delay (p < 0.05). No significant associations were found between the ENHO expression and Adropin levels or FMF clinical features. These findings suggest that increased ENHO expression may play a role in FMF pathophysiology, potentially as a compensatory mechanism. The correlation between Adropin levels and disease onset indicates a potential protective role. Further studies are needed to confirm these findings. Full article
(This article belongs to the Special Issue Human Hereditary Diseases: Advances in Molecular Genetics, Genomics and Therapeutic Strategies)
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13 pages, 2612 KiB  
Article
Novel Insights into the Therapeutic Effect of Amentoflavone Against Aeromonas hydrophila Infection by Blocking the Activity of Aerolysin
by Jing Dong, Shengping Li, Shun Zhou, Yongtao Liu, Qiuhong Yang, Ning Xu, Yibin Yang, Bo Cheng and Xiaohui Ai
Int. J. Mol. Sci. 2025, 26(5), 2370; https://doi.org/10.3390/ijms26052370 - 6 Mar 2025
Viewed by 495
Abstract
Aeromonas hydrophila (A. hydrophila) is an opportunistic and foodborne pathogen widely spread in the environments, particularly aquatic environments. Diseases caused by A. hydrophila in freshwater aquaculture result in huge economic losses every year. The increasing emergence of antibiotic resistance has limited [...] Read more.
Aeromonas hydrophila (A. hydrophila) is an opportunistic and foodborne pathogen widely spread in the environments, particularly aquatic environments. Diseases caused by A. hydrophila in freshwater aquaculture result in huge economic losses every year. The increasing emergence of antibiotic resistance has limited the application of antibiotics in aquaculture. Aerolysin (AerA), the main virulence factor produced by A. hydrophila, has been identified as a promising target for developing drugs controlling A. hydrophila infection. Here, we found that the natural compound amentoflavone (AMF) with the MIC of 512 μg/mL against A. hydrophila could dose-dependently reduce the hemolysis of AerA, ranging from 0.5 to 4 μg/mL. Molecular docking and dynamics simulation results predicted that AMF could directly bind to domain 3 of AerA via Pro333 and Trp375 residues. Then, the binding sites were confirmed by fluorescence quenching assays. The results of heptamer formation demonstrated that the binding of AMF could affect the formation of oligomers and result in the loss of pore-forming activity. Cell viability assay showed that AerA after treatment with AMF ranging from 0.5 to 4 μg/mL could significantly reduce AerA-mediated cytotoxicity. Moreover, experimental therapeutics results showed that channel catfish infected with A. hydrophila and then administered with 20 mg/kg AMF at intervals of 12 h for 3 days could increase the survival rate by 35% compared with the positive control after a 10-day observation. These findings provided a novel approach to developing anti-infective drugs and a promising candidate for controlling A. hydrophila infection in aquaculture. Full article
(This article belongs to the Special Issue Molecular Aspects of Bacterial Infection)
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17 pages, 4047 KiB  
Article
Development of a PLA Polymer-Based Liquid Filler for Next-Generation Aesthetics
by Ji Hyun Sung, Na Jeong Park, Jeong Eun Park, Hye Sung Yoon, Ji Hyeon Baek, Helen Cho and Ji Hoon Park
Int. J. Mol. Sci. 2025, 26(5), 2369; https://doi.org/10.3390/ijms26052369 - 6 Mar 2025
Viewed by 766
Abstract
In regard to both natural aging and photoaging caused by UV radiation, a decrease in skin collagen and elastin fibers results in the loss of soft tissue volume. Biodegradable polymer fillers have been used to overcome this problem, but the slow rate of [...] Read more.
In regard to both natural aging and photoaging caused by UV radiation, a decrease in skin collagen and elastin fibers results in the loss of soft tissue volume. Biodegradable polymer fillers have been used to overcome this problem, but the slow rate of reconstruction and particle agglomeration has limited this approach. The DMSB01 filler, which consists of poly d-l-lactic acid (PDLLA) with a methoxy polyethylene glycol (mPEG) initiator, was created to address this issue. In this study, we assessed the reconstruction and dispersion of the DMSB01 filler in vitro, as well as its effect on collagen expression in rats. DMSB01 showed rapid reconstruction and excellent dispersion stability; gelation occurred within 5 min at 37 °C and remained stable. In an animal model, DMSB01 induced M2 macrophages, Transforming growth factor beta (TGF-β) expression, and significantly increased collagens I and III. Collagen recovery and wrinkle improvement were confirmed by the aging and photoaging models, and hematoxylin and eosin (H&E) staining was used to demonstrate the safety and biodegradability of DMSB01. DMSB01 was effective in terms of inducing collagen production and improving skin aging, and shows promise as an innovative ingredient to overcome the limitations of existing fillers. Full article
(This article belongs to the Section Molecular Pharmacology)
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28 pages, 1169 KiB  
Review
The Potential of Selected Plants and Their Biologically Active Molecules in the Treatment of Depression and Anxiety Disorders
by Nicol Urbanska, Tolulope Joshua Ashaolu, Simona Mattova, Patrik Simko and Terezia Kiskova
Int. J. Mol. Sci. 2025, 26(5), 2368; https://doi.org/10.3390/ijms26052368 - 6 Mar 2025
Viewed by 964
Abstract
The incidence of anxiety and depression disorders is increasing worldwide. There is an increasing incidence of hard-to-treat depression with various aspects of origin. Almost 80% of people prefer to use natural remedies and supplements as their primary healthcare solution. Not surprisingly, around one-third [...] Read more.
The incidence of anxiety and depression disorders is increasing worldwide. There is an increasing incidence of hard-to-treat depression with various aspects of origin. Almost 80% of people prefer to use natural remedies and supplements as their primary healthcare solution. Not surprisingly, around one-third of drugs were inspired by nature. Over the past three decades, the use of such remedies has increased significantly. Synthetic antidepressants may cause various negative side effects, whereas herbal medicines are favored because of their ability to relieve symptoms with minimal to no side effects and lower financial burden. This review provides an overview of herbs and biologically active compounds used to treat depression. Full article
(This article belongs to the Special Issue Depression: From Molecular Basis to Therapy—2nd Edition)
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17 pages, 6314 KiB  
Article
Polyethylene Glycol Loxenatide Accelerates Diabetic Wound Healing by Downregulating Systemic Inflammation and Improving Endothelial Progenitor Cell Functions
by Zerui Ding, Chunru Yang, Xiaojun Zhai, Yuqi Xia, Jieying Liu and Miao Yu
Int. J. Mol. Sci. 2025, 26(5), 2367; https://doi.org/10.3390/ijms26052367 - 6 Mar 2025
Viewed by 823
Abstract
Diabetes wound healing presents several significant challenges, which can complicate recovery and lead to severe consequences. Polyethylene glycol loxenatide (PEG-loxe), a long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA), shows cardiovascular benefits, yet its role in diabetic wound healing remains unclear. Diabetic mice received PEG-loxe [...] Read more.
Diabetes wound healing presents several significant challenges, which can complicate recovery and lead to severe consequences. Polyethylene glycol loxenatide (PEG-loxe), a long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA), shows cardiovascular benefits, yet its role in diabetic wound healing remains unclear. Diabetic mice received PEG-loxe (0.03 mg/kg/week, i.p.) for three months. Glucose metabolism was evaluated using the insulin tolerance test (ITT) and oral glucose tolerance test (OGTT). Wound closure rates and angiogenesis-related proteins were analyzed. Serum proteomics was performed using the Olink assay to evaluate systemic inflammation. In vitro, human endothelial progenitor cells (EPCs) were exposed to high glucose and palmitic acid, with or without PEG-loxe treatment. EPC tube formation and migratory capacity were evaluated using the tube formation assay and migration assay, respectively. Levels of nitric oxide (NO) and phosphorylated endothelial nitric oxide synthase (p-eNOS) were quantified. Mitochondrial reactive oxygen species (ROS) production and mitochondrial membrane potential were assessed using MitoSOX and JC-1 staining. Cellular respiratory function was analyzed via the Seahorse XF assay. Autophagy was evaluated by examining the expression of autophagy-related proteins and the colocalization of mitochondria with lysosomes. PEG-loxe improved glucose tolerance, accelerated wound closure, and upregulated the hypoxia-inducible factor-1α/vascular endothelial growth factor/stromal cell-derived factor-1 axis (HIF-1α/VEGF/SDF-1) in diabetic mice. Serum proteomics revealed reduced pro-inflammatory markers and elevated anti-inflammatory IL-5. In vitro, PEG-loxe restored EPC function by enhancing NO production, reducing mitochondrial ROS, improving cellular respiratory function, and restoring autophagic flux. These findings suggest that PEG-loxe offers therapeutic benefits for diabetic wound healing by downregulating systemic inflammation, enhancing angiogenesis, and improving mitochondrial quality control in EPCs, highlighting GLP-1RAs as potential therapies for diabetic vascular complications. Full article
(This article belongs to the Section Molecular Endocrinology and Metabolism)
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16 pages, 1454 KiB  
Review
Managing a Burning Face: Clinical Manifestations and Therapeutic Approaches for Neurogenic Rosacea
by Gabriel Aedo, Marco Chahuán, Elsa Gatica, Isabel Herrera, Luis Felipe Parada, Alvaro Seguel, Nigel P. Murray, Sócrates Aedo and Diego Aragón-Caqueo
Int. J. Mol. Sci. 2025, 26(5), 2366; https://doi.org/10.3390/ijms26052366 - 6 Mar 2025
Viewed by 1381
Abstract
Rosacea is a common chronic inflammatory condition primarily affecting middle-aged women. It presents with flushing, erythema, telangiectasia, papules, pustules, phymatous changes, and ocular involvement. Although typically grouped into four subtypes—erythematotelangiectatic, papulopustular, ocular, and phymatous—overlapping features often favor a phenotypic diagnostic approach. Neurogenic rosacea [...] Read more.
Rosacea is a common chronic inflammatory condition primarily affecting middle-aged women. It presents with flushing, erythema, telangiectasia, papules, pustules, phymatous changes, and ocular involvement. Although typically grouped into four subtypes—erythematotelangiectatic, papulopustular, ocular, and phymatous—overlapping features often favor a phenotypic diagnostic approach. Neurogenic rosacea (NR) has emerged as a distinct subgroup featuring distinguishing features such as peripheral facial erythema, severe burning and stinging sensations, and resistance to standard rosacea therapies. Recent insights into the pathophysiology of NR propose neural dysregulation as the main driver of the condition. Specifically, the activation of TRP channels at cutaneous sensory nerve endings in the dermis triggers the release of vasoactive peptides, driving neuroinflammation and resulting in burning and stinging. Additionally, there is a marked association with neuropsychiatric comorbidities, which would further mediate the pathogenesis of the condition. In line with this pathophysiological model, NR often fails to respond to conventional rosacea treatments. Instead, patients benefit more from antidepressants and neuroleptic agents that help modulate neuronal activity and alleviate symptoms. This review explores and summarizes the scientific evidence regarding the new insights on disease pathogenesis, clinical manifestations, and proposed treatments for NR. Full article
(This article belongs to the Special Issue Dermatology: Advances in Pathophysiology and Therapies (2nd Edition))
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15 pages, 4987 KiB  
Article
Dihydromyricetin Alleviated Acetaminophen-Induced Acute Kidney Injury via Nrf2-Dependent Anti-Oxidative and Anti-Inflammatory Effects
by Jianan Shi, Xiufang Peng, Junyi Huang, Mengyi Zhang and Yuqin Wang
Int. J. Mol. Sci. 2025, 26(5), 2365; https://doi.org/10.3390/ijms26052365 - 6 Mar 2025
Viewed by 576
Abstract
Acute kidney injury (AKI) is a common side effect of acetaminophen (APAP) overdose. Dihydromyricetin (DHM) is the most abundant flavonoid in rattan tea, which has a wide range of pharmacological effects. In the current study, APAP-induced AKI models were established both in vivo [...] Read more.
Acute kidney injury (AKI) is a common side effect of acetaminophen (APAP) overdose. Dihydromyricetin (DHM) is the most abundant flavonoid in rattan tea, which has a wide range of pharmacological effects. In the current study, APAP-induced AKI models were established both in vivo and in vitro. The results showed that DHM pretreatment remarkably alleviated APAP-induced AKI by promoting antioxidant capacity through the nuclear factor erythroid-related factor 2 (Nrf2) signaling pathway in vivo. In addition, DHM reduced ROS production and mitochondrial dysfunction, thereby alleviating APAP-induced cytotoxicity in HK-2 cells. The way in which DHM improved the antioxidant capacity of HK-2 cells was through promoting the activation of the Nrf2-mediated pathway and inhibiting the expression levels of inflammation-related proteins. Furthermore, Nrf2 siRNA partially canceled out the protective effect of DHM against the cytotoxicity caused by APAP in HK-2 cells. Altogether, the protective effect of DHM on APAP-induced nephrotoxicity was related to Nrf2-dependent antioxidant and anti-inflammatory effects. Full article
(This article belongs to the Section Molecular Pharmacology)
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18 pages, 6344 KiB  
Article
Spatio-Temporal Characterization of Cellular Senescence Hallmarks in Experimental Ischemic Stroke
by Júlia Baixauli-Martín, Maria Consuelo Burguete, Mikahela A. López-Morales, María Castelló-Ruiz, Alicia Aliena-Valero, Teresa Jover-Mengual, Dianoush Falahatgaroshibi, Germán Torregrosa and Juan B. Salom
Int. J. Mol. Sci. 2025, 26(5), 2364; https://doi.org/10.3390/ijms26052364 - 6 Mar 2025
Viewed by 607
Abstract
In recent years, evidence of the existence of cellular senescence in the central nervous system has accumulated. In ischemic stroke, cellular senescence has been suggested as an unidentified pathophysiological mechanism, prompting research into the neuroprotective potential of senolytic drugs. This study aims to [...] Read more.
In recent years, evidence of the existence of cellular senescence in the central nervous system has accumulated. In ischemic stroke, cellular senescence has been suggested as an unidentified pathophysiological mechanism, prompting research into the neuroprotective potential of senolytic drugs. This study aims to provide spatio-temporal evidence of the existence of brain senescence following ischemic stroke and to elucidate the involved pathways and cell types. We focused on the most established markers of senescence: cell cycle arrest (p16, p21); lysosomal activity (senescence-associated β-galactosidase [SA-β-gal]); the senescence-associated secretory phenotype ([SASP]; Interleukin-6 [IL-6], Interleukin-1β [IL-1β], Tumor necrosis factor [TNF]); and DNA/nuclear damage (Checkpoint kinase 1 [Chk1], Checkpoint kinase 2 [Chk2], Lamin B1 [LB1]). Male Wistar rats underwent 60 min of transient middle cerebral artery occlusion, followed by 24 h and 3, 7, and 14 days of recovery. Our results show significant increases in p16 expression, particularly in neurons and microglia/macrophages; SA-β-gal accumulation in the infarcted tissue; significant increases in SASP markers as early as 24 h after reperfusion; and significant changes in Chk1, Chk2, and LB1 at 14 days. Overall, our findings lend support to the existence of senescence after ischemic stroke in neurons and microglia/macrophages. However, there is still room to gain further insight into the role of senescence in the pathophysiology of ischemic stroke and in the implementation of successful senolytic therapy. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Apoptosis and Senescence)
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17 pages, 8221 KiB  
Article
Revealing Lingonberry’s Neuroprotective Potential in Alzheimer’s Disease Through Network Pharmacology and Molecular Docking
by Juncheng Li, Mian Wang, Yi Wang, Xichen Peng, Guixiang Lv, Tianhu Zheng, Yahui Peng and Jihong Li
Int. J. Mol. Sci. 2025, 26(5), 2363; https://doi.org/10.3390/ijms26052363 - 6 Mar 2025
Viewed by 690
Abstract
Alzheimer’s disease is a progressive neurodegenerative disorder with limited treatment options. Lingonberry (Vaccinium vitis-idaea L.) has demonstrated neuroprotective and anti-inflammatory properties, yet the underlying mechanisms remain unclear. This study employed network pharmacology, molecular docking, and molecular dynamics simulations to explore the therapeutic [...] Read more.
Alzheimer’s disease is a progressive neurodegenerative disorder with limited treatment options. Lingonberry (Vaccinium vitis-idaea L.) has demonstrated neuroprotective and anti-inflammatory properties, yet the underlying mechanisms remain unclear. This study employed network pharmacology, molecular docking, and molecular dynamics simulations to explore the therapeutic potential in Alzheimer’s disease. Pathway analysis identified monoamine oxidase B as a key target involved in serotonergic synapse dysfunction related to Alzheimer’s disease. Molecular docking revealed that ferulic acid, a major bioactive compound in lingonberry, exhibits strong binding affinity to monoamine oxidase B. Further molecular dynamics simulations confirmed the stability of this interaction, highlighting the potential inhibitory effect of ferulic acid on monoamine oxidase B. These findings provide novel insights into the neuroprotective mechanisms of lingonberry and suggest its potential as a natural therapeutic intervention for Alzheimer’s disease. Full article
(This article belongs to the Section Molecular Informatics)
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14 pages, 952 KiB  
Article
Metabolomic Biomarkers in Bovine Embryo Culture Media and Their Relationship with the Developmental Potential of In Vitro-Produced Embryos
by Elina Tsopp, Kalle Kilk, Andres Gambini, Ants Kavak, Esta Nahkur, Anni Viljaste-Seera, Haldja Viinalass and Ülle Jaakma
Int. J. Mol. Sci. 2025, 26(5), 2362; https://doi.org/10.3390/ijms26052362 - 6 Mar 2025
Viewed by 614
Abstract
Recent studies have shown that the metabolome of single embryo culture media is linked to successful pregnancy. In this study, the analysis was expanded to compare the metabolomes of viable and non-viable early-stage embryos and to examine metabolomic markers associated with hatching in [...] Read more.
Recent studies have shown that the metabolome of single embryo culture media is linked to successful pregnancy. In this study, the analysis was expanded to compare the metabolomes of viable and non-viable early-stage embryos and to examine metabolomic markers associated with hatching in viable embryos. The authors hypothesized that the metabolomic profiles of high-quality early blastocysts differ from those of non-viable embryos that reach the blastocyst stage but undergo developmental arrest at later stages. The metabolic profile of 43 spent bovine embryo culture medium samples were analyzed using liquid chromatography–mass spectrometry, covering 189 metabolites, including 40 acylcarnitines, 42 amino acids/biogenic amines, 91 phospholipids, 15 sphingolipids, and the sum of hexoses. Embryos were produced from abattoir-derived oocytes, and the culture medium samples were derived from Grade 1 early blastocysts that progressed to hatching (VBL; n = 10), non-viable early blastocysts that developed to the blastocyst stage but failed to hatch (DBL; n = 12), Grade 1 hatched blastocysts (HBL; n = 16), and plain growth media for control (CM; n = 5). It was observed that methionine sulfoxide (Met-SO) and lysophosphatidylcholine (lysoPC) C24:0 concentrations were significantly lower in the culture media from viable blastocysts compared to those from non-viable blastocysts (p < 0.001). Additionally, blastocysts that resulted in successful hatching had significantly lower levels of phospholipid, arginine (Arg), and methionine-related metabolites that significantly differentiated the control and viable blastocyst culture media from the media containing non-viable embryos. Building on previous studies, there appears to be an overlap in metabolites released during hatching that are also associated with successful pregnancy. The identified biomarkers can aid in assessing an embryo’s developmental potential and enhance embryo selection for transfer or cryopreservation. Full article
(This article belongs to the Special Issue Molecular Research on Embryo Developmental Potential)
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24 pages, 11143 KiB  
Article
Differential Transcriptional Programs Reveal Modular Network Rearrangements Associated with Late-Onset Alzheimer’s Disease
by Alejandra Paulina Pérez-González, Guillermo de Anda-Jáuregui and Enrique Hernández-Lemus
Int. J. Mol. Sci. 2025, 26(5), 2361; https://doi.org/10.3390/ijms26052361 - 6 Mar 2025
Viewed by 691
Abstract
Alzheimer’s disease (AD) is a complex, genetically heterogeneous disorder. The diverse phenotypes associated with AD result from interactions between genetic and environmental factors, influencing multiple biological pathways throughout disease progression. Network-based approaches offer a way to assess phenotype-specific states. In this study, we [...] Read more.
Alzheimer’s disease (AD) is a complex, genetically heterogeneous disorder. The diverse phenotypes associated with AD result from interactions between genetic and environmental factors, influencing multiple biological pathways throughout disease progression. Network-based approaches offer a way to assess phenotype-specific states. In this study, we calculated key network metrics to characterize the network transcriptional structure and organization in LOAD, focusing on genes and pathways implicated in AD pathology within the dorsolateral prefrontal cortex (DLPFC). Our findings revealed disease-specific coexpression markers associated with diverse metabolic functions. Additionally, significant differences were observed at both the mesoscopic and local levels between AD and control networks, along with a restructuring of gene coexpression and biological functions into distinct transcriptional modules. These results show the molecular reorganization of the transcriptional program occurring in LOAD, highlighting specific adaptations that may contribute to or result from cellular responses to pathological stressors. Our findings may support the development of a unified model for the causal mechanisms of AD, suggesting that its diverse manifestations arise from multiple pathways working together to produce the disease’s complex clinical patho-phenotype. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Signaling Pathways in Alzheimer’s Disease)
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16 pages, 16494 KiB  
Article
Genome-Wide Analysis of the JAZ Gene Family in Potato and Functional Verification of StJAZ23 Under Drought Stress
by Zhuanfang Pu, Tianyuan Qin, Yihao Wang, Xiangdong Wang, Ningfan Shi, Panfeng Yao, Yuhui Liu, Jiangping Bai, Zhenzhen Bi and Chao Sun
Int. J. Mol. Sci. 2025, 26(5), 2360; https://doi.org/10.3390/ijms26052360 - 6 Mar 2025
Viewed by 554
Abstract
The JASMONATE-ZIM DOMAIN (JAZ) repressors are crucial proteins in the jasmonic acid signaling pathway that play a significant role in plant growth, development and response to abiotic stress (such as drought, heat, salinity, and low temperature). In this study, we identified 26 potato [...] Read more.
The JASMONATE-ZIM DOMAIN (JAZ) repressors are crucial proteins in the jasmonic acid signaling pathway that play a significant role in plant growth, development and response to abiotic stress (such as drought, heat, salinity, and low temperature). In this study, we identified 26 potato JAZ genes and classified the corresponding predicted proteins into five subfamilies. All potato JAZ proteins exhibited the expected conserved TIFY (TIF[F/Y] XG) and JAZ domains. Additionally, we identified several stress-responsive cis-regulatory elements, notably ABRE and ARE in the promoters of the JAZ gene family. Whole transcriptome and gene family expression analysis identified StJAZ23 as a key gene responding to drought stress in the root tissues of the Atlantic (Atl) and Qingshu 9 (QS9) potato cultivars. The StJAZ23 gene was cloned, and subcellular localization analysis suggested that the StJAZ23 protein was mainly localized in the nucleus and cell membrane. This study confirmed that StJAZ23 plays a role in drought stress by analyzing several StJAZ23 overexpression (OE-3, OE-5, and OE-6) and RNA interference (RNAi-3, RNAi-6, and RNAi-13) transgenic potato lines. The OE lines displayed significantly increased StJAZ23 expression compared to wild-type (WT) plants, while RNAi lines exhibited significantly reduced expression. The total root length, root tip count, and root surface area were significantly enhanced in OE lines under drought stress, compared to WT plants, whereas RNAi lines showed significant reductions. StJAZ23 overexpression also increased the activities of SOD, POD, CAT, and root vigor under drought stress and JA and ABA hormone levels were also significantly increased in roots under drought stress. These results highlight the positive role of the StJAZ23 gene in enhancing potato resilience to drought stress. Full article
(This article belongs to the Special Issue Physiology and Molecular Biology of Plant Stress Tolerance: 2nd Edition)
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17 pages, 7296 KiB  
Article
Trichostatin A-Induced Epigenetic Modifications and Their Influence on the Development of Porcine Cloned Embryos Derived from Bone Marrow–Mesenchymal Stem Cells
by Seung-Chan Lee, Won-Jae Lee, Young-Bum Son, Yeung Bae Jin, Hyeon-Jeong Lee, Eunyeong Bok, Sangyeob Lee, Sang-Yun Lee, Chan-Hee Jo, Tae-Seok Kim, Chae-Yeon Hong, Seo-Yoon Kang, Gyu-Jin Rho, Yong-Ho Choe and Sung-Lim Lee
Int. J. Mol. Sci. 2025, 26(5), 2359; https://doi.org/10.3390/ijms26052359 - 6 Mar 2025
Viewed by 582
Abstract
Abnormal epigenetic reprogramming of nuclear-transferred (NT) embryos leads to the limited efficiency of producing cloned animals. Trichostatin A (TSA), a histone deacetylase inhibitor, improves NT embryo development, but its role in histone acetylation in porcine embryos cloned with mesenchymal stem cells (MSCs) is [...] Read more.
Abnormal epigenetic reprogramming of nuclear-transferred (NT) embryos leads to the limited efficiency of producing cloned animals. Trichostatin A (TSA), a histone deacetylase inhibitor, improves NT embryo development, but its role in histone acetylation in porcine embryos cloned with mesenchymal stem cells (MSCs) is not fully understood. This study aimed to compare the effects of TSA on embryo development, histone acetylation patterns, and key epigenetic-related genes between in vitro fertilization (IVF), NT-MSC, and 40 nM TSA-treated NT-MSC (T-NT-MSC). The results demonstrated an increase in the blastocyst rate from 13.7% to 32.5% in the T-NT-MSC, and the transcription levels of CDX2, NANOG, and IGF2R were significantly elevated in T-NT-MSC compared to NT-MSC. TSA treatment also led to increased fluorescence intensity of acH3K9 and acH3K18 during early embryo development but did not differ in acH4K12 levels. The expression of epigenetic-related genes (HDAC1, HDAC2, CBP, p300, DNMT3a, and DNMT1) in early pre-implantation embryos followed a pattern similar to IVF embryos. In conclusion, TSA treatment improves the in vitro development of porcine embryos cloned with MSCs by increasing histone acetylation, modifying chromatin structure, and enhancing the expression of key genes, resulting in profiles similar to those of IVF embryos. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Somatic Cell Cloning and Other Assisted Reproductive Technologies in Mammals)
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16 pages, 4918 KiB  
Article
Chitin Synthase Is Required for Cuticle Formation and Molting in the Chinese Mitten Crab Eriocheir sinensis
by Ting Zhang, Yuning Hu, Siyu Lu, Yanfei Deng, Huimin Zhang, Yanhua Zhao, Yawen Yu, Hongbin Huang, Jun Zhou and Xuguang Li
Int. J. Mol. Sci. 2025, 26(5), 2358; https://doi.org/10.3390/ijms26052358 - 6 Mar 2025
Viewed by 454
Abstract
Chitin synthase is an essential enzyme of the chitin synthesis pathway during molting. In this study, we identified and characterized a chitin synthase (EsCHS) gene in the Chinese mitten crab, Eriocheir sinensis. The spatio-temporal expression and functional role of EsCHS [...] Read more.
Chitin synthase is an essential enzyme of the chitin synthesis pathway during molting. In this study, we identified and characterized a chitin synthase (EsCHS) gene in the Chinese mitten crab, Eriocheir sinensis. The spatio-temporal expression and functional role of EsCHS were investigated. The open reading frame of EsCHS was 4725 bp long and encoded 1574 amino acid residues that contained the typical domain structure of the glycosyltransferase family 2. Phylogenetic analysis revealed that EsCHS belongs to the group I chitin synthase family. The expression of EsCHS was found in regenerative limbs, the cuticle and the intestines. During the molting cycle, EsCHS began to increase in the pre-molt stage and reached a significant peak in the post-molt stage. The knockdown of EsCHS resulted in the significant downregulation of chitin biosynthesis pathway genes, including TRE, HK, G6PI, PAGM and UAP. Moreover, the long-term RNAi of EsCHS resulted in thinning procuticles, abnormal molting and high mortality, suggesting that EsCHS is indispensable for the formation of chitin in the cuticle during molting. In conclusion, EsCHS is involved in the chitin biosynthesis pathway and plays an important role in molting in E. sinensis. These findings highlight the potential of incorporating EsCHS into selective breeding programs to optimize molting regulation and improve growth performance in crustacean aquaculture. Full article
(This article belongs to the Special Issue Recent Advances in Crustacean Aquaculture)
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21 pages, 1952 KiB  
Review
Efforts to Downsize Base Editors for Clinical Applications
by Beomjong Song
Int. J. Mol. Sci. 2025, 26(5), 2357; https://doi.org/10.3390/ijms26052357 - 6 Mar 2025
Viewed by 602
Abstract
Since the advent of the clustered regularly interspaced short palindromic repeats (CRISPR) system in the gene editing field, diverse CRISPR-based gene editing tools have been developed for treating genetic diseases. Of these, base editors (BEs) are promising because they can carry out precise [...] Read more.
Since the advent of the clustered regularly interspaced short palindromic repeats (CRISPR) system in the gene editing field, diverse CRISPR-based gene editing tools have been developed for treating genetic diseases. Of these, base editors (BEs) are promising because they can carry out precise gene editing at single-nucleotide resolution without inducing DNA double-strand breaks (DSBs), which pose significant risks of genomic instability. Despite their outstanding advantages, the clinical application of BEs remains challenging due to their large size, which limits their efficient delivery, particularly in adeno-associated virus (AAV)-based systems. To address this issue, various strategies have been explored to reduce the size of BEs. These approaches include truncating the nonessential domains and replacing the bulky components with smaller substitutes without compromising the editing efficiency. In this review, we highlight the importance of downsizing BEs for therapeutic applications and introduce recent advances in size-reduction strategies. Additionally, we introduce the ongoing efforts to overcome other limitations of BEs, providing insights into their potential for improving in vivo gene editing. Full article
(This article belongs to the Special Issue Advances, Pitfalls and Future Perspectives for CRISPR/Cas9 Mediated Genome Editing: 4th Edition)
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46 pages, 1183 KiB  
Review
Molecular Anatomy of Synaptic and Extrasynaptic Neurotransmission Between Nociceptive Primary Afferents and Spinal Dorsal Horn Neurons
by Miklós Antal
Int. J. Mol. Sci. 2025, 26(5), 2356; https://doi.org/10.3390/ijms26052356 - 6 Mar 2025
Viewed by 720
Abstract
Sensory signals generated by peripheral nociceptors are transmitted by peptidergic and nonpeptidergic nociceptive primary afferents to the superficial spinal dorsal horn, where their central axon terminals establish synaptic contacts with secondary sensory spinal neurons. In the case of suprathreshold activation, the axon terminals [...] Read more.
Sensory signals generated by peripheral nociceptors are transmitted by peptidergic and nonpeptidergic nociceptive primary afferents to the superficial spinal dorsal horn, where their central axon terminals establish synaptic contacts with secondary sensory spinal neurons. In the case of suprathreshold activation, the axon terminals release glutamate into the synaptic cleft and stimulate postsynaptic spinal neurons by activating glutamate receptors located on the postsynaptic membrane. When overexcitation is evoked by peripheral inflammation, neuropathy or pruritogens, peptidergic nociceptive axon terminals may corelease various neuropeptides, neurotrophins and endomorphin, together with glutamate. However, in contrast to glutamate, neuropeptides, neurotrophins and endomorphin are released extrasynaptically. They diffuse from the site of release and modulate the function of spinal neurons via volume transmission, activating specific extrasynaptic receptors. Thus, the released neuropeptides, neurotrophins and endomorphin may evoke excitation, disinhibition or inhibition in various spinal neuronal populations, and together with glutamate, induce overall overexcitation, called central sensitization. In addition, the synaptic and extrasynaptic release of neurotransmitters is subjected to strong retrograde control mediated by various retrogradely acting transmitters, messengers, and their presynaptic receptors. Moreover, the composition of this complex chemical apparatus is heavily dependent on the actual patterns of nociceptive primary afferent activation in the periphery. This review provides an overview of the complexity of this signaling apparatus, how nociceptive primary afferents can activate secondary sensory spinal neurons via synaptic and volume transmission in the superficial spinal dorsal horn, and how these events can be controlled by presynaptic mechanisms. Full article
(This article belongs to the Special Issue Editorial Board Members’ Collection Series: Pain)
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34 pages, 1582 KiB  
Review
Blood-Based DNA Methylation Biomarkers to Identify Risk and Progression of Cardiovascular Disease
by Tarryn Willmer, Lawrence Mabasa, Jyoti Sharma, Christo J. F. Muller and Rabia Johnson
Int. J. Mol. Sci. 2025, 26(5), 2355; https://doi.org/10.3390/ijms26052355 - 6 Mar 2025
Viewed by 719
Abstract
Non-communicable diseases (NCDs) are the leading cause of death worldwide, with cardiovascular disease (CVD) accounting for half of all NCD-related deaths. The biological onset of CVD may occur long before the development of clinical symptoms, hence the urgent need to understand the molecular [...] Read more.
Non-communicable diseases (NCDs) are the leading cause of death worldwide, with cardiovascular disease (CVD) accounting for half of all NCD-related deaths. The biological onset of CVD may occur long before the development of clinical symptoms, hence the urgent need to understand the molecular alterations underpinning CVD, which would facilitate intervention strategies to prevent or delay the onset of the disease. There is evidence to suggest that CVD develops through a complex interplay between genetic, lifestyle, and environmental factors. Epigenetic modifications, including DNA methylation, serve as proxies linking genetics and the environment to phenotypes and diseases. In the past decade, a growing list of studies has implicated DNA methylation in the early events of CVD pathogenesis. In this regard, screening for these epigenetic marks in asymptomatic individuals may assist in the early detection of CVD and serve to predict the response to therapeutic interventions. This review discusses the current literature on the relationship between blood-based DNA methylation alterations and CVD in humans. We highlight a set of differentially methylated genes that show promise as candidates for diagnostic and prognostic CVD biomarkers, which should be prioritized and replicated in future studies across additional populations. Finally, we discuss key limitations in DNA methylation studies, including genetic diversity, interpatient variability, cellular heterogeneity, study confounders, different methodological approaches used to isolate and measure DNA methylation, sample sizes, and cross-sectional study design. Full article
(This article belongs to the Special Issue Molecular Advances in Heart Disease: Genomics, Proteomics, and Bioinformatics of Heart Research)
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23 pages, 1115 KiB  
Review
Effectiveness of Extracellular Vesicle Application in Skin Aging Treatment and Regeneration: Do We Have Enough Evidence from Clinical Trials?
by Anna Domaszewska-Szostek, Marta Krzyżanowska, Agnieszka Polak and Monika Puzianowska-Kuźnicka
Int. J. Mol. Sci. 2025, 26(5), 2354; https://doi.org/10.3390/ijms26052354 - 6 Mar 2025
Viewed by 1323
Abstract
In recent years, there has been a dynamic development in therapies utilizing extracellular vesicles (EVs) including exosomes. Therefore, we have conducted an analysis of the scientific literature to verify the current state of knowledge about these therapies. A total of 12 clinical studies [...] Read more.
In recent years, there has been a dynamic development in therapies utilizing extracellular vesicles (EVs) including exosomes. Therefore, we have conducted an analysis of the scientific literature to verify the current state of knowledge about these therapies. A total of 12 clinical studies were analyzed, covering the use of EVs in treating skin aging, acne scars, alopecia, and wound healing. The results indicate that EVs and exosomes hold potential in regenerative skin therapies, offering innovative and non-invasive therapeutic approaches. At the same time, significant challenges related to the standardization of their production and the lack of large-scale randomized studies were identified. Thus, we also evaluated the investigated clinical trials in regard to the MISEV (Minimal Information for Studies of Extracellular Vesicles) criteria. This review provides a comprehensive overview of the contemporary applications of EVs in skin therapy and regenerative medicine, highlighting directions for further research. Full article
(This article belongs to the Special Issue Molecular Mechanisms for Skin Protection and Aging)
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19 pages, 2694 KiB  
Article
A Truncated Mutation of TP53 Promotes Chemoresistance in Tongue Squamous Cell Carcinoma
by Xiaoyun Du, Junheng Zheng, Xiangwan Lu and Yan Zhang
Int. J. Mol. Sci. 2025, 26(5), 2353; https://doi.org/10.3390/ijms26052353 - 6 Mar 2025
Viewed by 550
Abstract
Tongue squamous cell carcinoma (TSCC), a subtype of head and neck squamous cell carcinoma, is characterized by frequent chemoresistance. Genetic mutations commonly observed in TSCC play a critical role in malignant progression; thus, elucidating their functional significance is essential for developing effective treatment [...] Read more.
Tongue squamous cell carcinoma (TSCC), a subtype of head and neck squamous cell carcinoma, is characterized by frequent chemoresistance. Genetic mutations commonly observed in TSCC play a critical role in malignant progression; thus, elucidating their functional significance is essential for developing effective treatment strategies. To more accurately investigate the relationship between mutations and chemoresistance, we established low-passage TSCC cells, CTSC-1, obtained from a chemoresistant patient, and CTSC-2, from a treatment-naïve patient. Sanger sequencing revealed a specific TP53 mutation (Q331*) in CTSC-1, leading to the loss of the tetramerization and C-terminal regulatory domains. Notably, CTSC-1 cells harboring TP53-Q331* and CTSC-2 cells with TP53 knockout that have been engineered to ectopically express TP53-Q331* exhibit enhanced chemoresistance and increased cancer stem cell-like properties. Mechanistically, TP53-Q331* upregulates the expression of inhibitor of DNA binding 2 (ID2), which is crucial for maintaining the stemness of TSCC cells. Subsequently, ID2 activates the expression of nucleotide excision repair (NER) pathway-related genes ERCC4 and ERCC8, thereby enhancing the chemoresistance in TSCC. In conclusion, our study demonstrates that the TP53-Q331* mutation enhances TSCC chemoresistance through an ID2-mediated NER pathway, providing a potential prognostic marker and therapeutic target for TSCC chemotherapy resistance. Full article
(This article belongs to the Section Molecular Biology)
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21 pages, 9752 KiB  
Article
Enhancing the Quality of Indoor-Grown Basil Microgreens with Low-Dose UV-B or UV-C Light Supplementation
by Ernest Skowron, Magdalena Trojak, Ilona Pacak, Paulina Węzigowska and Julia Szymkiewicz
Int. J. Mol. Sci. 2025, 26(5), 2352; https://doi.org/10.3390/ijms26052352 - 6 Mar 2025
Viewed by 434
Abstract
Controlled-environment crop production often weakens plants’ defense mechanisms, reducing the accumulation of protective phytochemicals essential to human health. Our previous studies demonstrated that short-term supplementation of low-dose ultraviolet (UV) light to the red–green–blue (RGB) spectrum effectively boosts secondary metabolite (SM) synthesis and antioxidant [...] Read more.
Controlled-environment crop production often weakens plants’ defense mechanisms, reducing the accumulation of protective phytochemicals essential to human health. Our previous studies demonstrated that short-term supplementation of low-dose ultraviolet (UV) light to the red–green–blue (RGB) spectrum effectively boosts secondary metabolite (SM) synthesis and antioxidant capacity in lettuce. This study explored whether similar effects occur in basil cultivars by supplementing the RGB spectrum with ultraviolet B (UV-B, 311 nm) or ultraviolet C (UV-C, 254 nm) light shortly before harvest. Molecular analyses focused on UV-induced polyphenol synthesis, particularly chalcone synthase (CHS) level, and UV light perception via the UVR8 receptor. The impact of high-energy UV radiation on the photosynthetic apparatus (PA) was also monitored. The results showed that UV-B supplementation did not harm the PA, while UV-C significantly impaired photosynthesis and restricted plant growth and biomass accumulation. In green-leaf (Sweet Large, SL) basil, UV-B enhanced total antioxidant capacity (TAC), increasing polyphenolic secondary metabolites and ascorbic acid (AsA) levels. UV-C also stimulated phenolic compound accumulation in SL basil but had no positive effects in the purple-leaf (Dark Opal, DO) cultivar. Interestingly, while the UV-B treatment promoted UVR8 monomerization in both cultivars, the enhanced CHS level and concomitant SM synthesis were noted only for SL basil. In addition, UV-C also induced CHS activity and SM synthesis in SL basil but clearly in a UVR8-independeted manner. These findings underscore the potential of UV light supplementation for enhancing plant functional properties, highlighting species- and cultivar-specific effects without compromising photosynthetic performance. Full article
(This article belongs to the Special Issue Molecular and Metabolic Regulation of Plant Secondary Metabolism)
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22 pages, 8904 KiB  
Article
Callus Culture System from Lonicera japonica Thunb Anthers: Light Quality Effects on Callus Quality Evaluation
by Jiali Cheng, Fengxia Guo, Wei Liang, Hongyan Wang, Yuan Chen and Pengbin Dong
Int. J. Mol. Sci. 2025, 26(5), 2351; https://doi.org/10.3390/ijms26052351 - 6 Mar 2025
Viewed by 385
Abstract
Lonicera japonica Thunb has significant edible and medicinal value, possessing heat clearing, detoxification, antibacterial, and blood pressure reduction properties. Currently, its quality is constrained by factors such as climate, environment, flowering period, and germplasm degradation. The strategy of using bioreactors and abiotic inducers [...] Read more.
Lonicera japonica Thunb has significant edible and medicinal value, possessing heat clearing, detoxification, antibacterial, and blood pressure reduction properties. Currently, its quality is constrained by factors such as climate, environment, flowering period, and germplasm degradation. The strategy of using bioreactors and abiotic inducers to produce bioactive metabolites has not yet been implemented. This study reports, for the first time, the induction of an embryogenic callus from L. japonica anthers, the identification of tissue morphological structures, and the effects of light induction on the callus morphology, metabolite accumulation, and antioxidant activity. The results showed that the MS medium, supplemented with 1.0 mg·L−1 6-BA, 1.5 mg·L−1 NAA, 1.5 mg·L−1 2,4-D, and 0.2 mg·L−1 KT, induced 89% embryogenic callus formation. Uniform callus lines were obtained using 2.0 mg·L−1 6-BA, 0.5 mg·L−1 NAA, and 0.2 mg·L−1 KT in each subcultivation. Embryogenic cells were observed to have closely arranged spherical protruding granules on their surface, along with visible nuclei and numerous starch grains. After 15 days of blue light induction, active metabolites and antioxidant activities peaked. This experimental system not only provides support for germplasm innovation but also indicates that abiotic inducers can be utilized as a means to achieve higher yields of metabolic products. Full article
(This article belongs to the Section Molecular Plant Sciences)
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22 pages, 5118 KiB  
Article
Panduratin A from Boesenbergia rotunda Effectively Inhibits EGFR/STAT3/Akt Signaling Pathways, Inducing Apoptosis in NSCLC Cells with Wild-Type and T790M Mutations in EGFR
by Wanna Eiamart, Piyanuch Wonganan, Sarin Tadtong and Weerasak Samee
Int. J. Mol. Sci. 2025, 26(5), 2350; https://doi.org/10.3390/ijms26052350 - 6 Mar 2025
Cited by 1 | Viewed by 609
Abstract
Non-small cell lung cancer (NSCLC) is a challenging disease, with the epidermal growth factor receptor (EGFR) being a key target for new, effective treatments crucial for the signaling pathways regulating cancer cell survival. Targeting EGFR-mediated signaling offers promising strategies to improve NSCLC therapies, [...] Read more.
Non-small cell lung cancer (NSCLC) is a challenging disease, with the epidermal growth factor receptor (EGFR) being a key target for new, effective treatments crucial for the signaling pathways regulating cancer cell survival. Targeting EGFR-mediated signaling offers promising strategies to improve NSCLC therapies, particularly in overcoming resistance in EGFR-mutant lung cancer. In this study, we investigated the anticancer effects of panduratin A, a naturally occurring flavonoid from Boesenbergia rotunda, on human NSCLC cell lines expressing both wild-type EGFR (A549) and mutant EGFR (H1975) using in vitro experiments and molecular docking approaches. Cytotoxicity screening revealed that panduratin A exhibits potent effects on both A549 (IC50 of 6.03 ± 0.21 µg/mL) and H1975 (IC50 of 5.58 ± 0.15 µg/mL) cell lines while demonstrating low toxicity to normal MRC5 lung cells (12.96 ± 0.36 µg/mL). Furthermore, western blotting and flow cytometric analyses indicated that panduratin A induces apoptosis by inhibiting p-EGFR and its downstream effectors, p-STAT3 and p-Akt, in lung cancer cells. Additionally, the docking study showed lower binding energy between panduratin A and the target proteins, comparable to that of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs). The ADMET prediction also highlighted panduratin A’s exceptional drug-like properties. This study concludes that panduratin A shows significant promise as an anti-lung cancer candidate for NSCLC, offering an economical and effective strategy. Full article
(This article belongs to the Special Issue Anticancer Activity of Natural Products and Related Compounds)
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13 pages, 4344 KiB  
Article
Heterogeneity of the Immunological and Pathogenic Profiles in Patients Hospitalize Early Versus Late During an Acute Vital Illness as Shown in Native SARS-CoV-2 Infection
by Krzysztof Laudanski, Ahmed Sayed Ahmed, Mohamed A. Mahmoud, Mohamed Antar and Hossam Gad
Int. J. Mol. Sci. 2025, 26(5), 2349; https://doi.org/10.3390/ijms26052349 - 6 Mar 2025
Viewed by 543
Abstract
The immune system’s response to an invading pathogen is the critical determinant in recovery from illness. Here, we hypothesize that the immune response will swiftly follow classical activation and a resolution trajectory in patients with the rapid evolution of symptoms if challenged by [...] Read more.
The immune system’s response to an invading pathogen is the critical determinant in recovery from illness. Here, we hypothesize that the immune response will swiftly follow classical activation and a resolution trajectory in patients with the rapid evolution of symptoms if challenged by a viral pathogen for the first time. Alternatively, a dysregulated response will be signified by a protracted clinical trajectory. Consequently, we enrolled 106 patients during the first wave of COVID-19 and collected their blood within 24 h, 48 h, 7 days, and over 28 days from symptoms onset. The pathogenic burden was measured via serum levels of the S-spike protein and specific immunoglobulin titers against the S and N proteins of SARS-CoV-2. The nonspecific immunological response was gauged using interleukin 6, leukocytosis, and C-reactive protein. Coagulation status was assessed. Several serum biomarkers were used as surrogates of clinical outcomes. We identified four clusters depending on the onset of symptoms (immediate [A], 6 days [B], 12 days [C], and over 21 days [D]). High variability in the S-spike protein in cluster A was present. The corresponding immunoglobulin titer was random. Only procalcitonin differentiated clusters in terms of markers of nonspecific inflammation. Coagulation markers were not significantly different between clusters. Serum surrogates on cardiomyopathy and neuronal pathology exhibited significant variability. Implementation of ECMO or noninvasive ventilation was more prominent in cluster C and D. Interestingly, SOFA or APACHE II scores were not different between nominal (A and B) versus dysregulated clusters (C and D). Full article
(This article belongs to the Section Molecular Immunology)
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15 pages, 7332 KiB  
Article
Functional Characterization of PeVLN4 Involved in Regulating Pollen Tube Growth from Passion Fruit
by Hanbing Yang, Xiuqing Wei, Lifeng Wang, Ping Zheng, Junzhang Li, Yutong Zou, Lulu Wang, Xinyuan Feng, Jiahui Xu, Yuan Qin and Yuhui Zhuang
Int. J. Mol. Sci. 2025, 26(5), 2348; https://doi.org/10.3390/ijms26052348 - 6 Mar 2025
Viewed by 434
Abstract
Passion fruit (Passiflora edulis), mainly distributed in tropical and subtropical regions, is popular for its unique flavor and health benefits. The actin cytoskeleton plays a crucial role in plant growth and development, and villin is a key regulator of actin dynamics. [...] Read more.
Passion fruit (Passiflora edulis), mainly distributed in tropical and subtropical regions, is popular for its unique flavor and health benefits. The actin cytoskeleton plays a crucial role in plant growth and development, and villin is a key regulator of actin dynamics. However, the mechanism underlying the actin filament regulation of reproductive development in passion fruit remains poorly understood. Here, we characterized a villin isovariant in passion fruit, Passiflora edulis VLN4 (PeVLN4), highly and preferentially expressed in pollen. Subcellular localization analysis showed that PeVLN4 decorated distinct filamentous structures in pollen tubes. We next introduced PeVLN4 into Arabidopsis villin mutants to explore its functions on the growing pollen tubes. PeVLN4 rescued defects in the elongation of villin mutant pollen tubes. Pollen tubes expressing PeVLN4 were revealed to be less sensitive to latrunculin B, and PeVLN4 partially rescued defects in the actin filament organization of villin mutant pollen tubes. Additionally, biochemical assays revealed that PeVLN4 bundles actin filaments in vitro. Thus, PeVLN4 is an important regulator of F-actin stability and is required for normal pollen tube growth in passion fruit. This study provides a new insight into the function of the actin regulator villin involved in the reproduction development of passion fruit. Full article
(This article belongs to the Special Issue Molecular Advances in Plant Reproductive Development)
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19 pages, 5458 KiB  
Article
Differentially Expressed Genes in Rat Brain Regions with Different Degrees of Ischemic Damage
by Ivan B. Filippenkov, Yana Yu. Shpetko, Vasily V. Stavchansky, Alina E. Denisova, Vadim V. Yuzhakov, Natalia K. Fomina, Leonid V. Gubsky, Svetlana A. Limborska and Lyudmila V. Dergunova
Int. J. Mol. Sci. 2025, 26(5), 2347; https://doi.org/10.3390/ijms26052347 - 6 Mar 2025
Viewed by 588
Abstract
Ischemic stroke is a multifactorial disease that leads to brain tissue damage and severe neurological deficit. Transient middle cerebral artery occlusion (tMCAO) models are actively used for the molecular, genetic study of stroke. Previously, using high-throughput RNA sequencing (RNA-Seq), we revealed 3774 differentially [...] Read more.
Ischemic stroke is a multifactorial disease that leads to brain tissue damage and severe neurological deficit. Transient middle cerebral artery occlusion (tMCAO) models are actively used for the molecular, genetic study of stroke. Previously, using high-throughput RNA sequencing (RNA-Seq), we revealed 3774 differentially expressed genes (DEGs) in the penumbra-associated region of the frontal cortex (FC) of rats 24 h after applying the tMCAO model. Here, we studied the gene expression pattern in the striatum that contained an ischemic focus. Striatum samples were obtained from the same rats from which we previously obtained FC samples. Therefore, we compared DEG profiles between two rat brain tissues 24 h after tMCAO. Tissues were selected based on magnetic resonance imaging (MRI) and histological examination (HE) data. As a result, 4409 DEGs were identified 24 h after tMCAO in striatum. Among them, 2609 DEGs were overlapped in the striatum and FC, whereas more than one thousand DEGs were specific for each studied tissue. Furthermore, 54 DEGs exhibited opposite changes at the mRNA level in the two brain tissues after tMCAO. Thus, the spatial regulation of the ischemic process in the ipsilateral hemisphere of rat brain at the transcriptome level was revealed. We believe that the targeted adjustment of the genome responses identified can be the key for the induction of regeneration processes in brain cells after stroke. Full article
(This article belongs to the Special Issue New Insights of Biomarkers in Neurodegenerative Diseases)
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16 pages, 2427 KiB  
Article
Genetic Diversity Assessment and Core Germplasm Screening of Blackcurrant (Ribes nigrum) in China via Expressed Sequence Tag–Simple Sequence Repeat Markers
by Xinyu Sun, Qiang Fu, Dong Qin, Jinyu Xiong, Xin Quan, Hao Guo, Jiahan Tang, Junwei Huo and Chenqiao Zhu
Int. J. Mol. Sci. 2025, 26(5), 2346; https://doi.org/10.3390/ijms26052346 - 6 Mar 2025
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Abstract
Blackcurrant (Ribes nigrum L.) has high nutritional value for human health due to its abundant vitamin C, flavonoids, and organic acids. However, its breeding and genetic research have been severely hindered by the lack of scientific tools such as molecular markers. Here, [...] Read more.
Blackcurrant (Ribes nigrum L.) has high nutritional value for human health due to its abundant vitamin C, flavonoids, and organic acids. However, its breeding and genetic research have been severely hindered by the lack of scientific tools such as molecular markers. Here, we identified 14,258 EST-SSR loci from 9531 CDS sequences with lengths greater than 1 kb, which comprised 6211 mononucleotide repeats, 4277 dinucleotide repeats, and 2469 trinucleotide repeats. We then randomly selected 228 EST-SSR loci for PCR amplification and gel electrophoresis imaging in the Ribes collection of Northeast Agricultural University (95 blackcurrant cultivars and 12 other Ribes accessions). As a result, 31 pairs of markers produced clear and reproducible bands of the expected size. Based on the 107 Ribes accessions, the allele number (Na), information index (I), observed heterozygosity (Ho), expected heterozygosity (He), and polymorphic information content (PIC) of the 31 markers were 2–5, 0.23–1.32, 0.07–0.71, 0.11–0.68, and 0.14–0.67, respectively. For the blackcurrant gene pool, neighbor-joining and population structure analysis revealed three clusters, which did not align well with their geographical origins. Based on the results, two sets with 21 and 19 blackcurrant cultivars were identified by Power Core (PC) and Core Hunter (CH) programs. The integrated core germplasm (IC) set with 27 cultivars derived from the PC and CH sets harbored abundant genetic diversity, where the allele retention rate accounted for 98.9% of the blackcurrant gene pool. The SSR markers, data, and core germplasms presented in this study lay a solid foundation for the phylogenetic study, molecular breeding, and conservation genetics of Ribes, especially Ribes nigrum. Full article
(This article belongs to the Special Issue Advances in Breeding, Genetics, and Genomics of Fruit Crops)
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