International Journal of Molecular Sciences

13 pages, 3150 KiB

Open AccessArticle

L-Arginine and Taurisolo^® Effects on Brain Hypoperfusion–Reperfusion Damage in Hypertensive Rats

by Dominga Lapi, Gian Carlo Tenore, Giuseppe Federighi, Martina Chiurazzi, Santo Nunziato, Maria S. Lonardo, Mariano Stornaiuolo, Antonio Colantuoni, Ettore Novellino and Rossana Scuri

Int. J. Mol. Sci. 2024, 25(19), 10868; https://doi.org/10.3390/ijms251910868 - 9 Oct 2024

Viewed by 510

Abstract

Acute and chronic hypertension causes cerebral vasculopathy, increasing the risk of ischemia and stroke. Our study aimed to compare the effects of arterial pressure reduction on the pial microvascular responses induced by hypoperfusion and reperfusion in spontaneously hypertensive Wistar rats, desamethasone-induced hypertensive Wistar [...] Read more.

Acute and chronic hypertension causes cerebral vasculopathy, increasing the risk of ischemia and stroke. Our study aimed to compare the effects of arterial pressure reduction on the pial microvascular responses induced by hypoperfusion and reperfusion in spontaneously hypertensive Wistar rats, desamethasone-induced hypertensive Wistar rats and age-matched normotensive Wistar rats fed for 3 months with a normal diet or normal diet supplemented with L-arginine or Taurisolo^® or L-arginine plus Taurisolo^®. At the end of treatments, the rats were submitted to bilateral occlusion of common carotid arteries for 30 min and reperfusion. The microvascular parameters investigated in vivo through a cranial window were: arteriolar diameter changes, permeability increase, leukocyte adhesion to venular walls and percentage of capillaries perfused. Hypoperfusion–reperfusion caused in all rats marked microvascular changes. L-arginine treatment was effective in reducing arterial blood pressure causing vasodilation but did not significantly reduce the damage induced by hypoperfusion–reperfusion. Taurisolo^® treatment was less effective in reducing blood pressure but prevented microvascular damage from hypoperfusion–reperfusion. L-arginine plus Taurisolo^® maintained blood pressure levels within the physiological range and protected the pial microcirculation from hypoperfusion–reperfusion-induced microvascular injuries. Therefore, the blood pressure reduction is not the only fundamental aspect to protect the cerebral circulation from hypoperfusion–reperfusion damage. Full article

(This article belongs to the Special Issue Hypertension: Mechanisms of Oxidative Stress and Antioxidant Regulation)

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15 pages, 9325 KiB

Open AccessArticle

Compound Heterozygous RYR1 Variants in a Patient with Severe Congenital Myopathy: Case Report and Comparison with Additional Cases of Recessive RYR1-Related Myopathy

by Sören Janßen, Leoni S. Erbe, Moritz Kneifel, Matthias Vorgerd, Kristina Döring, Krzysztof P. Lubieniecki, Joanna M. Lubieniecka, Wanda M. Gerding, Nicolas Casadei, Anne-Katrin Güttsches, Christoph Heyer, Thomas Lücke, Hoa Huu Phuc Nguyen, Cornelia Köhler and Sabine Hoffjan

Int. J. Mol. Sci. 2024, 25(19), 10867; https://doi.org/10.3390/ijms251910867 - 9 Oct 2024

Viewed by 486

Abstract

Pathogenic variants in the ryanodine receptor 1 (RYR1) gene are causative for a wide spectrum of muscular phenotypes, ranging from malignant hyperthermia over mild, non-progressive to severe congenital myopathy. Both autosomal dominant and recessive inheritance can occur, with the more severe [...] Read more.

Pathogenic variants in the ryanodine receptor 1 (RYR1) gene are causative for a wide spectrum of muscular phenotypes, ranging from malignant hyperthermia over mild, non-progressive to severe congenital myopathy. Both autosomal dominant and recessive inheritance can occur, with the more severe forms usually showing recessive inheritance. However, genotype–phenotype correlations are complicated due to the large size of the gene and heterogeneous phenotypes. We present a 6-year-old patient with severe congenital myopathy, carrying a heterozygous pathogenic RYR1 variant inherited from the healthy mother. Through whole genome sequencing we identified a second, deep intronic RYR1 variant that has recently been described in another patient with severe congenital myopathy and shown to affect splicing. Segregation analyses confirmed the variants to be compound heterozygous. We compared our patient’s phenotype to that of the patient from the literature as well as five additional patients with compound heterozygous RYR1 variants from our center. The main overlapping features comprised congenital onset, predominant muscular hypotonia, and normal creatine kinase (CK) levels, while overall clinical expression varied substantially. Interestingly, both patients carrying the new intronic splice variant showed a very severe disease course. More widespread use of genome sequencing will open the way for better genotype–phenotype correlations. Full article

(This article belongs to the Special Issue Molecular and Neuromuscular Mechanisms in Skeletal Muscle Aging)

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15 pages, 2976 KiB

Open AccessArticle

Maternal Obesity Alters Placental and Umbilical Cord Plasma Oxidative Stress, a Cross-Sectional Study

by Thanyawan Jantape, Kiattisak Kongwattanakul, Silvia M. Arribas, Pilar Rodríguez-Rodríguez, Metee Iampanichakul, Wannapa Settheetham-Ishida and Sophida Phuthong

Int. J. Mol. Sci. 2024, 25(19), 10866; https://doi.org/10.3390/ijms251910866 - 9 Oct 2024

Viewed by 564

Abstract

Maternal obesity has been shown to impair the oxidative status in the placenta and newborns, potentially leading to adverse pregnancy outcomes and long-term effects on the programming of offspring metabolic status. This study aimed to investigate the impact of maternal obesity on maternal [...] Read more.

Maternal obesity has been shown to impair the oxidative status in the placenta and newborns, potentially leading to adverse pregnancy outcomes and long-term effects on the programming of offspring metabolic status. This study aimed to investigate the impact of maternal obesity on maternal and umbilical cord plasma oxidative status, as well as placental oxidative adaptation. Maternal obesity (n = 20), defined as a pre-pregnancy BMI ≥ 25 kg/m², and maternal leanness (n = 20), defined as a pre-pregnancy BMI < 23 kg/m², were the group categories used in this study. Both groups were matched according to gestational age at delivery. Maternal blood, umbilical cord blood, and placental tissue were collected to assess nutritional content (cholesterol, triglyceride, and protein), oxidative stress markers (MDA and protein carbonyl), and antioxidant activity (SOD and catalase). Placental protein expression (SOD2, catalase, UCP2, and Nrf2) was evaluated using Western blot analysis. Catalase activity in maternal plasma significantly increased in the maternal obesity group (p = 0.0200), with a trend toward increased MDA and protein carbonyl levels. In umbilical cord plasma, triglyceride, protein carbonyl, and catalase activity were significantly elevated in the maternal obesity group compared with the lean controls (p = 0.0482, 0.0291, and 0.0347, respectively). Placental protein expression analysis revealed significantly decreased SOD2 (p = 0.0011) and catalase (p < 0.0001), along with Nrf2 downregulation (p < 0.0001). An increase in mitochondrial antioxidant UCP2 expression was observed (p = 0.0117). The neonatal protein carbonyl levels positively correlated with placental protein carbonyl (r = 0.7405, p < 0.0001) and negatively correlated with maternal catalase activity (r = −0.4332, p = 0.0052). This study thus provides evidence that maternal obesity is associated with placental and fetal oxidative stress, alongside a concurrent increase in placental antioxidant UCP2 expression. Full article

(This article belongs to the Special Issue Pathophysiological Research into and Treatment of Pregnancy Complications)

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25 pages, 2000 KiB

Open AccessReview

The Role of Adipokines between Genders in the Pathogenesis of Osteoarthritis

by Alessio Economou, Ilenia Mallia, Antonella Fioravanti, Stefano Gentileschi, Francesca Nacci, Silvia Bellando Randone, Gemma Lepri and Serena Guiducci

Int. J. Mol. Sci. 2024, 25(19), 10865; https://doi.org/10.3390/ijms251910865 - 9 Oct 2024

Viewed by 500

Abstract

Osteoarthritis (OA) is a chronic, progressive, degenerative joint disease characterized by joint pain, stiffness, and limited movement. It presents significant intra- and inter-individual variability—in particular, between genders. Recent research has increasingly focused on the role of adipokines—especially leptin, adiponectin, and resistin—in the development [...] Read more.

Osteoarthritis (OA) is a chronic, progressive, degenerative joint disease characterized by joint pain, stiffness, and limited movement. It presents significant intra- and inter-individual variability—in particular, between genders. Recent research has increasingly focused on the role of adipokines—especially leptin, adiponectin, and resistin—in the development of OA. Adipokines, peptide hormones primarily secreted by adipose tissue, are involved in crucial physiological processes related to metabolism and immunity. They can also impact bone and cartilage turnover by interacting with joint cells such as osteoblasts, osteoclasts, chondrocytes, and mesenchymal stem cells, thereby linking inflammation with bone cartilage homeostasis. This review aims to elucidate the structure and functions of various adipokines, their serum and synovial levels, and their association with clinical presentation and radiographic progression in OA patients, with a focus on differences between sexes. A narrative literature review was conducted using three databases specifically analyzing sex differences. OA patients generally show elevated serum and synovial levels of leptin, chemerin, and visfatin, as well as high plasma levels of resistin and visfatin. In contrast, synovial levels of adiponectin and omentin are reduced in OA patients compared to healthy individuals, with an inverse relationship to disease severity, suggesting a potential protective role. Resistin and leptin were positively correlated with pain severity and radiographic progression, while adiponectin’s role in OA remains controversial. Regarding sex differences, male OA patients exhibited higher serum levels of leptin, chemerin, and omentin compared to healthy controls, with a positive correlation to the BMI and estrogen levels, potentially explaining the sexual dimorphism observed in this condition. Studies on visfatin and lipocalin did not reveal significant differences in synovial or serum levels between the sexes. The role of resistin remains controversial. Adipokines influence the joint microenvironment and contribute to the progression of osteoarthritis (OA). However, the precise biological mechanisms are not yet fully understood due to the complex interactions between the metabolic, mechanical, and immune systems. Further research is needed to clarify their roles in OA and to identify targeted therapies for managing this degenerative disease. Full article

(This article belongs to the Special Issue Osteoarthritis Biomarkers, Diagnosis and Treatments)

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9 pages, 1272 KiB

Open AccessCommunication

Solid-State Nanopore-Based Nanosystem for Registration of Enzymatic Activity of a Single Molecule of Cytochrome P450 BM3

by Yuri D. Ivanov, Angelina V. Vinogradova, Ekaterina D. Nevedrova, Alexander N. Ableev, Andrey F. Kozlov, Ivan D. Shumov, Vadim S. Ziborov, Oleg N. Afonin, Nikita V. Vaulin, Denis V. Lebedev, Anton S. Bukatin, Polina K. Afonicheva, Ivan S. Mukhin, Sergey A. Usanov and Alexander I. Archakov

Int. J. Mol. Sci. 2024, 25(19), 10864; https://doi.org/10.3390/ijms251910864 - 9 Oct 2024

Viewed by 420

Abstract

Experimental methods of single-molecule enzymology allow scientists to determine physicochemical properties of distinct single molecules of various enzymes and to perform direct monitoring of functioning of enzymes at different steps of their catalytic cycle. The approach based on the use of solid-state nanopores [...] Read more.

Experimental methods of single-molecule enzymology allow scientists to determine physicochemical properties of distinct single molecules of various enzymes and to perform direct monitoring of functioning of enzymes at different steps of their catalytic cycle. The approach based on the use of solid-state nanopores is a promising tool for studying the functioning of single-enzyme molecules. Herein, this approach is employed for monitoring the functioning of cytochrome P450 BM3, which represents a very convenient model of cytochrome P450-containing monooxygenase systems. A nanopore of ~5 nm in diameter has been formed in a 40 nm-thick silicon nitride chip by electron beam drilling (EBD), and a single molecule of the BM3 enzyme has been entrapped in the pore. The functioning of the enzyme molecule has been monitored by recording the time dependence of the ion current through the nanopore during the reaction of laurate hydroxylation. In our experiments, the enzyme molecule has been found to be active for 1500 s. The results of our research can be further used in the development of highly sensitive detectors for single-molecule studies in enzymology. Full article

(This article belongs to the Special Issue New Trends in Molecular Biosensors)

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15 pages, 3576 KiB

Open AccessArticle

High-Throughput Transcriptomics Identifies Chemoresistance-Associated Gene Expression Signatures in Human Angiosarcoma

by Glenys Mai Shia Khor, Sara Haghani, Tiffany Rui En Tan, Elizabeth Chun Yong Lee, Bavani Kannan, Boon Yee Lim, Jing Yi Lee, Zexi Guo, Tun Kiat Ko and Jason Yongsheng Chan

Int. J. Mol. Sci. 2024, 25(19), 10863; https://doi.org/10.3390/ijms251910863 - 9 Oct 2024

Viewed by 584

Abstract

Angiosarcomas, clinically aggressive cancers of endothelial origin, are a rare subtype of soft-tissue sarcomas characterized by resistance to chemotherapy and dismal prognosis. In this study, we aim to identify the transcriptomic biomarkers of chemoresistance in angiosarcoma. We examined 72 cases of Asian angiosarcomas, [...] Read more.

Angiosarcomas, clinically aggressive cancers of endothelial origin, are a rare subtype of soft-tissue sarcomas characterized by resistance to chemotherapy and dismal prognosis. In this study, we aim to identify the transcriptomic biomarkers of chemoresistance in angiosarcoma. We examined 72 cases of Asian angiosarcomas, including 35 cases treated with palliative chemotherapy, integrating information from NanoString gene expression profiling, whole transcriptome profiling (RNA-seq), immunohistochemistry, cell line assays, and clinicopathological data. In the chemoresistant cohort (defined as stable disease or progression), we observed the significant overexpression of genes, including SPP1 (log2foldchange 3.49, adj. p = 0.0112), CXCL13, CD48, and CLEC5A, accompanied by the significant enrichment of myeloid compartment and cytokine and chemokine signaling pathways, as well as neutrophils and macrophages. RNA-seq data revealed higher SPP1 expression (p = 0.0008) in tumor tissues over adjacent normal compartments. Immunohistochemistry showed a significant moderate positive correlation between SPP1 protein and gene expression (r = 0.7016; p < 0.00110), while higher SPP1 protein expression correlated with lower chemotherapeutic sensitivity in patient-derived angiosarcoma cell lines MOLAS and ISOHAS. In addition, SPP1 mRNA overexpression positively correlated with epithelioid histology (p = 0.007), higher tumor grade (p = 0.0023), non-head and neck location (p = 0.0576), and poorer overall survival outcomes (HR 1.84, 95% CI 1.07–3.18, p = 0.0288). There was no association with tumor mutational burden, tumor inflammation signature, the presence of human herpesvirus-7, ultraviolet exposure signature, and metastatic state at diagnosis. In conclusion, SPP1 overexpression may be a biomarker of chemoresistance and poor prognosis in angiosarcoma. Further investigation is needed to uncover the precise roles and underlying mechanisms of SPP1. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Tumor Microenvironment, Biomarker Discovery and Immune Resistance: 2nd Edition)

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13 pages, 3287 KiB

Open AccessArticle

Cleavage of DNA Substrate Containing Nucleotide Mismatch in the Complementary Region to sgRNA by Cas9 Endonuclease: Thermodynamic and Structural Features

by Svetlana V. Baranova, Polina V. Zhdanova, Anastasia D. Koveshnikova, Pavel E. Pestryakov, Ivan P. Vokhtantsev, Alexander A. Chernonosov and Vladimir V. Koval

Int. J. Mol. Sci. 2024, 25(19), 10862; https://doi.org/10.3390/ijms251910862 - 9 Oct 2024

Viewed by 524

Abstract

The non-ideal accuracy and insufficient selectivity of CRISPR/Cas9 systems is a serious problem for their use as a genome editing tool. It is important to select the target sequence correctly so that the CRISPR/Cas9 system does not cut similar sequences. This requires an [...] Read more.

The non-ideal accuracy and insufficient selectivity of CRISPR/Cas9 systems is a serious problem for their use as a genome editing tool. It is important to select the target sequence correctly so that the CRISPR/Cas9 system does not cut similar sequences. This requires an understanding of how and why mismatches in the target sequence can affect the efficiency of the Cas9/sgRNA complex. In this work, we studied the catalytic activity of the Cas9 enzyme to cleave DNA substrates containing nucleotide mismatch at different positions relative to the PAM in the “seed” sequence. We show that mismatches in the complementarity of the sgRNA/DNA duplex at different positions relative to the protospacer adjacent motif (PAM) sequence tend to decrease the cleavage efficiency and increase the half-maximal reaction time. However, for two mismatches at positions 11 and 20 relative to the PAM, an increase in cleavage efficiency was observed, both with and without an increase in half-reaction time. Thermodynamic parameters were obtained from molecular dynamics results, which showed that mismatches at positions 8, 11, and 20 relative to the PAM thermodynamically stabilize the formed complex, and a mismatch at position 2 of the PAM fragment exerts the greatest stabilization compared to the original DNA sequence. The weak correlation of the thermodynamic binding parameters of the components of the Cas9/sgRNA:dsDNA complex with the cleavage data of DNA substrates containing mismatches indicates that the efficiency of Cas9 operation is mainly affected by the conformational changes in Cas9 and the mutual arrangement of sgRNA and substrates. Full article

(This article belongs to the Special Issue Biomolecular Structures, Dynamics, and Functions)

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18 pages, 281 KiB

Open AccessReview

Immunotherapy for Treatment of Pleural Mesothelioma: Current and Emerging Therapeutic Strategies

by Lauren Chiec and Debora S. Bruno

Int. J. Mol. Sci. 2024, 25(19), 10861; https://doi.org/10.3390/ijms251910861 - 9 Oct 2024

Viewed by 790

Abstract

Pleural mesothelioma is a rare malignancy associated with asbestos exposure and very poor prognosis, with a 5-year overall survival of 12%. Outcomes may vary according to stage at time of diagnosis and histologic subtype. Most recently, clinical trials utilizing dual checkpoint inhibitor regimens [...] Read more.

Pleural mesothelioma is a rare malignancy associated with asbestos exposure and very poor prognosis, with a 5-year overall survival of 12%. Outcomes may vary according to stage at time of diagnosis and histologic subtype. Most recently, clinical trials utilizing dual checkpoint inhibitor regimens and chemotherapy in combination with immune oncologic agents have demonstrated impactful changes in outcomes. In this article, we review studies that have led to the successful implementation of immunotherapy in clinical practice for the treatment of this disease and highlight ongoing clinical trials exploring the use of different immunotherapy strategies for the treatment of pleural mesothelioma. We also discuss the challenges of immunotherapy-based approaches in the context of mesothelioma and future strategies currently being investigated to overcome them. Full article

(This article belongs to the Special Issue Immunotherapy-Based Combinations in Thoracic Malignancies)

21 pages, 306 KiB

Open AccessArticle

Analysis of ICAM-1 rs3093030, VCAM-1 rs3783605, and E-Selectin rs1805193 Polymorphisms in African Women Living with HIV and Preeclampsia

by Samukelisiwe Sibiya, Zinhle Pretty Mlambo, Mbuso Herald Mthembu, Nompumelelo P. Mkhwanazi and Thajasvarie Naicker

Int. J. Mol. Sci. 2024, 25(19), 10860; https://doi.org/10.3390/ijms251910860 - 9 Oct 2024

Viewed by 708

Abstract

Intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and E-selectin are cell adhesion molecules that play a significant role in inflammation and are implicated in the pathophysiology of preeclampsia development and HIV infection. More specifically, the immune expression of ICAM-1, VCAM-1, and E-selectin [...] Read more.

Intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and E-selectin are cell adhesion molecules that play a significant role in inflammation and are implicated in the pathophysiology of preeclampsia development and HIV infection. More specifically, the immune expression of ICAM-1, VCAM-1, and E-selectin within cyto- and syncytiotrophoblast cells are dysregulated in preeclampsia, indicating their role in defective placentation. This study investigates the associations of ICAM-1, VCAM-1, and E-selectin gene variants (rs3093030, rs3783605, and rs1805193, respectively) with preeclampsia comorbid with HIV infection in women of African ancestry. It also examines the susceptibility to preeclampsia development and the effect of highly active antiretroviral therapy (HAART). A total of 405 women were enrolled in this study. Out of these women, 204 were preeclamptic and 201 were normotensive. Clinical characteristics were maternal age, weight, blood pressure (systolic and diastolic), and gestational age. Whole blood was collected, DNA was extracted, and genotyping of the ICAM-1 (rs3093030 C>T), VCAM-1(rs3783605 A>G), and E-selectin (rs1805193 A>C) gene polymorphisms was performed. Comparisons were made using the Chi-squared test. Our results demonstrated that preeclamptic women exhibited a higher frequency of analyzed variants, in contrast to those with the duality of preeclampsia and HIV infection. Additionally, the C allele of the ICAM-1 (rs3093030 C>T) and G allele of the VCAM-1 (rs3783605 A>G) genes were found to have a greater role in the co-morbidity and may be considered as a risk factor for preeclampsia development in women of African ancestry. In contrast, the SNP of rs1805193 of the E-selectin gene indicated that A>C was only significantly associated with HIV infection and not with preeclampsia. These findings highlight a strong association of the rs3093030 SNP of the ICAM-1 gene and of the VCAM-1 rs3783605 gene with the development of preeclampsia, indicating their role in the defective trophoblast invasion of preeclampsia. Sub-group analysis further reveals an association of the AA genotype with late-onset preeclampsia, a less severe form of disease indicating differing genetic predispositions between early and late-onset forms. Full article

(This article belongs to the Special Issue Molecular Research on Vascular Disease: Current Status and Future Directions)

11 pages, 1825 KiB

Open AccessArticle

The Expression of miR-211-5p in Sentinel Lymph Node Metastases of Malignant Melanoma Is a Potential Marker for Poor Prognosis

by Rose Kathrin Caroline Moritz, Nicole Ebelt, Tina Rattay, Jovine Ehrenreich, Cord Sunderkötter and Dennis Gerloff

Int. J. Mol. Sci. 2024, 25(19), 10859; https://doi.org/10.3390/ijms251910859 - 9 Oct 2024

Viewed by 431

Abstract

Metastatic primary cutaneous melanoma is a frequently fatal disease despite recent therapeutic advances. Biomarkers to stratify patients’ prognosis are lacking. MicroRNAs (miRNAs) are small, non-coding RNAs. We aimed to determine the expression of miR-211-5p in primary tumors and metastases of malignant melanoma and [...] Read more.

Metastatic primary cutaneous melanoma is a frequently fatal disease despite recent therapeutic advances. Biomarkers to stratify patients’ prognosis are lacking. MicroRNAs (miRNAs) are small, non-coding RNAs. We aimed to determine the expression of miR-211-5p in primary tumors and metastases of malignant melanoma and its potential use as a prognostic biomarker. We performed in situ hybridization for miRNA-211-5p on 109 FFPE melanoma samples from 76 patients, including 31 paired primary tumor/metastasis samples. For validation, we performed in silico analyses of TCGA skin cutaneous melanoma (SKCM) cohort. High miR-211-5p expression was more frequent in primary tumors (70.8%) compared to metastases (39.3%). In metastases, it was associated with a significantly worse overall survival. Data from TCGA SKCM cohort confirmed that high miR-211-5p expression in melanoma metastases, but not primary tumors, is associated with worse overall survival. MiR-211-5p expression in metastases is associated with a shorter survival, emphasizing the potential of miR-211-5p as a risk predictor for a less favorable clinical outcome in metastatic disease. In situ hybridization could be implemented in a routine laboratory workflow and can be performed on diagnostic tissue. Full article

(This article belongs to the Special Issue Roles and Mechanisms of Non-coding RNAs in Human Health and Disease)

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16 pages, 4428 KiB

Open AccessArticle

Dengue Envelope Protein as a Cytotoxic Factor Inducing Hemorrhage and Endothelial Cell Death in Mice

by Te-Sheng Lien, Der-Shan Sun, Wen-Sheng Wu and Hsin-Hou Chang

Int. J. Mol. Sci. 2024, 25(19), 10858; https://doi.org/10.3390/ijms251910858 - 9 Oct 2024

Viewed by 561

Abstract

Dengue virus (DENV) infection, prevalent in tropical and subtropical regions, can progress to dengue hemorrhagic fever (DHF), which increases mortality during secondary infections. DHF is characterized by endothelial damage and vascular leakage. Despite its severity, no specific antiviral treatments exist, and the viral [...] Read more.

Dengue virus (DENV) infection, prevalent in tropical and subtropical regions, can progress to dengue hemorrhagic fever (DHF), which increases mortality during secondary infections. DHF is characterized by endothelial damage and vascular leakage. Despite its severity, no specific antiviral treatments exist, and the viral factors responsible for endothelial damage remain unclear. This study examines the role of the DENV envelope protein domain III (EIII) in inducing endothelial apoptosis using a mouse model. Additionally, we aim to explore whether cell death-inducing pathways could serve as drug targets to ameliorate EIII-induced endothelial injury and hemorrhage. In vitro experiments using human endothelial HMEC-1 cells demonstrated that both recombinant EIII (rEIII) and DENV markedly induced caspase-3-mediated endothelial cell death, an effect that was attenuated by co-treatment with chondroitin sulfate B (CSB), N-acetyl cysteine (NAC), and the caspase-3 inhibitor z-DEVD-FMK. In vivo, sequential injections of rEIII and anti-platelet immunoglobulin in mice, designed to mimic the clinical phase of DHF with peak viremia followed by an increase in DENV-induced Ig, including autoantibodies, revealed that these dual treatments markedly triggered caspase-3-dependent apoptosis in vascular endothelial cells at hemorrhage sites. Treatments with z-DEVD-FMK effectively reduced DHF-like symptoms such as thrombocytopenia, hemorrhage, inflammation, hypercoagulation, and endothelial damage. Additionally, CSB and NAC alleviated hemorrhagic symptoms in the mice. These results suggest that targeting EIII, reactive oxygen species, and caspase-3-mediated apoptosis could offer potential therapeutic strategies for addressing EIII-induced hemorrhagic pathogenesis. Full article

(This article belongs to the Special Issue Impact of Signaling Pathways on Endothelial Cells: From Homeostasis to Disease)

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12 pages, 2426 KiB

Open AccessArticle

Insights of Expression Profile of Chemokine Family in Inflammatory Bowel Diseases and Carcinogenesis

by Yinjie Zhang, Yue Jin, Yanjing Wang, Siyi Wang, Yuchen Niu, Buyong Ma and Jingjing Li

Int. J. Mol. Sci. 2024, 25(19), 10857; https://doi.org/10.3390/ijms251910857 - 9 Oct 2024

Viewed by 483

Abstract

Chemokines are integral components of the immune system and deeply involved in the pathogenesis and progression of inflammatory bowel disease (IBD) and colorectal cancer (CRC). Although a considerable amount of transcriptome data has been accumulated on these diseases, most of them are limited [...] Read more.

Chemokines are integral components of the immune system and deeply involved in the pathogenesis and progression of inflammatory bowel disease (IBD) and colorectal cancer (CRC). Although a considerable amount of transcriptome data has been accumulated on these diseases, most of them are limited to a specific stage of the disease. The purpose of this study is to visually demonstrate the dynamic changes in chemokines across various stages of bowel diseases by integrating relevant datasets. Integrating the existing datasets for IBD and CRC, we compare the expression changes of chemokines across different pathological stages. This study collected 11 clinical databases from various medical centers around the world. Patients: Data of patient tissue types were classified into IBD, colorectal adenoma, primary carcinoma, metastasis, and healthy control according to the publisher’s annotation. The expression changes in chemokines in various pathological stages are statistically analyzed. The chemokines were clustered by different expression patterns. The chemokine family was clustered into four distinct expression patterns, which correspond to varying expression changes in different stages of colitis and tumor development. Certain chemokines and receptors associated with inflammation and tumorigenesis have been identified. Furthermore, it was confirmed that the 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis model and the azoxymethane (AOM)/ dextran sulfate sodium (DSS)-induced colon cancer model shows stronger correlations with the clinical data in terms of chemokine expression levels. This study paints a panoramic picture of the expression profiles of chemokine families at multiple stages from IBD to advanced colon cancer, facilitating a comprehensive understanding of the regulation patterns of chemokines and guiding the direction of drug development. This study provides researchers with a clear atlas of chemokine expression in the pathological processes of inflammatory bowel disease and colon cancer. Full article

(This article belongs to the Special Issue Advanced Research on Immune Cells and Cytokines (2nd Edition))

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32 pages, 2441 KiB

Open AccessReview

A Review on Apple Pomace Bioactives for Natural Functional Food and Cosmetic Products with Therapeutic Health-Promoting Properties

by Maria Vandorou, Christos Plakidis, Ilektra Maria Tsompanidou, Theodora Adamantidi, Eirini A. Panagopoulou and Alexandros Tsoupras

Int. J. Mol. Sci. 2024, 25(19), 10856; https://doi.org/10.3390/ijms251910856 - 9 Oct 2024

Viewed by 817

Abstract

Apples are consumed lavishly worldwide, while demand is increasing for the management of the huge apple-waste amounts that lead to significant disposal costs and ecological issues. Additionally, apples represent fruits with several bioactive constituents, which are key factors in a healthy, balanced diet. [...] Read more.

Apples are consumed lavishly worldwide, while demand is increasing for the management of the huge apple-waste amounts that lead to significant disposal costs and ecological issues. Additionally, apples represent fruits with several bioactive constituents, which are key factors in a healthy, balanced diet. In the present study, an extensive review is presented regarding the bioactive compounds of an apple processing by-product, namely apple pomace, mentioning their significance as viable ingredients/substances in foods and cosmetics aiming at chronic disease prevention and health promotion. Apple pomace contains several constituents, such as polar lipids, phenolics, vitamins and dietary fibers, with potential antioxidant, anti-inflammatory, anti-thrombotic, anti-aging and skin-protecting properties, and thus, they may contribute to minimizing the risk of various health conditions. Additionally, the mechanisms of action of such functional bioactives from apple pomace exert health benefits that will be examined, while the potential synergistic effects will also be investigated. Moreover, we will present the methods and techniques needed for the utilization of apple pomace in the appropriate form, such as powder, extracts, essential oil and so on, and their several applications in the food and cosmeceutical industry sectors, which summarize that apple pomace represents an ideal alternative to synthetic bioactive compounds. Full article

(This article belongs to the Special Issue New Research on Bioactive Natural Products)

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19 pages, 6692 KiB

Open AccessArticle

Leonurine Inhibits Hepatic Lipid Synthesis to Ameliorate NAFLD via the ADRA1a/AMPK/SCD1 Axis

by Wen Fan, Maoxing Pan, Chuiyang Zheng, Haiyan Shen, Dajin Pi, Qingliang Song, Zheng Liang, Jianwei Zhen, Jinyue Pan, Lianghao Liu, Qinhe Yang and Yupei Zhang

Int. J. Mol. Sci. 2024, 25(19), 10855; https://doi.org/10.3390/ijms251910855 - 9 Oct 2024

Viewed by 529

Abstract

Leonurine is a natural product unique to the Lamiaceae plant Leonurus japonicus Houtt., and it has attracted attention due to its anti-oxidative stress, anti-apoptosis, anti-fibrosis, and metabolic regulation properties. Also, it plays an important role in the prevention and treatment of nonalcoholic [...] Read more.

Leonurine is a natural product unique to the Lamiaceae plant Leonurus japonicus Houtt., and it has attracted attention due to its anti-oxidative stress, anti-apoptosis, anti-fibrosis, and metabolic regulation properties. Also, it plays an important role in the prevention and treatment of nonalcoholic fatty liver disease (NAFLD) through a variety of biological mechanisms, but its mechanism of action remains to be elucidated. Therefore, this study aims to preliminarily explore the mechanisms of action of leonurine in NAFLD. Mice were randomly divided into four groups: the normal control (NC) group, the Model (M) group, the leonurine treatment (LH) group, and the fenofibrate treatment (FB) group. The NAFLD model was induced by a high-fat high-sugar diet (HFHSD) for 12 weeks, and liver pathological changes and biochemical indices were observed after 12 weeks. Transcriptomic analysis results indicated that leonurine intervention reversed the high-fat high-sugar diet-induced changes in lipid metabolism-related genes such as stearoyl-CoA desaturase 1 (Scd1), Spermine Synthase (Sms), AP-1 Transcription Factor Subunit (Fos), Oxysterol Binding Protein Like 5 (Osbpl5), and FK506 binding protein 5 (Fkbp5) in liver tissues. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis results suggest that leonurine may exert its lipid-lowering effects through the AMP-activated protein kinase (AMPK) signaling pathway. Liver lipidomic analysis showed that leonurine could alter the abundance of lipid molecules related to fatty acyl (FAs) and glycerophospholipids (GPs) such as TxB3, carnitine C12-OH, carnitine C18:1-OH, and LPC (20:3/0:0). Molecular biology experiments and molecular docking techniques verified that leonurine might improve hepatic lipid metabolism through the alpha-1A adrenergic receptor (ADRA1a)/AMPK/SCD1 axis. In summary, the present study explored the mechanism by which leonurine ameliorated NAFLD by inhibiting hepatic lipid synthesis via the ADRA1a/AMPK/SCD1 axis. Full article

(This article belongs to the Special Issue Natural Products as Multitarget Agents in Human Diseases)

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21 pages, 9715 KiB

Open AccessArticle

Chemokine Receptor N-Terminus Charge Dictates Reliance on Post-Translational Modifications for Effective Ligand Capture and Following Boosting by Defense Peptides

by Ting Xu, Anne Sophie Schou, Jarkko J. Lackman, Marina Barrio-Calvo, Lisa Verhallen, Christoffer Knak Goth, Benjamin Anderschou Holbech Jensen, Christopher T. Veldkamp, Brian F. Volkman, Francis C. Peterson and Gertrud Malene Hjortø

Int. J. Mol. Sci. 2024, 25(19), 10854; https://doi.org/10.3390/ijms251910854 - 9 Oct 2024

Viewed by 502

Abstract

The chemokine receptors CCR1 and CCR5 display overlapping expression patterns and ligand dependency. Here we find that ligand activation of CCR5, not CCR1, is dependent on N-terminal receptor O-glycosylation. Release from O-glycosylation dependency is obtained by increasing CCR5 N-terminus acidity to the level [...] Read more.

The chemokine receptors CCR1 and CCR5 display overlapping expression patterns and ligand dependency. Here we find that ligand activation of CCR5, not CCR1, is dependent on N-terminal receptor O-glycosylation. Release from O-glycosylation dependency is obtained by increasing CCR5 N-terminus acidity to the level of CCR1. Ligand activation of CCR5, not CCR1, drastically improves in the absence of glycosaminoglycans (GAGs). Ligand activity at both CCR1 and CCR5 is boosted by positively charged/basic peptides shown to interact with acidic chemokine receptor N-termini. We propose that receptors with an inherent low N-terminus acidity rely on post-translational modifications (PTMs) to efficiently compete with acidic entities in the local environment for ligand capture. Although crucial for initial ligand binding, strong electrostatic interactions between the ligand and the receptor N-terminus may counteract following insertion of the ligand into the receptor binding pocket and activation, a process that seems to be aided in the presence of basic peptides. Basic peptides bind to the naked CCR1 N-terminus, not the CCR5 N-terminus, explaining the loss of boosting of ligand-induced signaling via CCR5 in cells incapable of glycosylation. Full article

(This article belongs to the Special Issue Advances in Bioactive Molecules)

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19 pages, 742 KiB

Open AccessReview

Advances in Gouty Arthritis Management: Integration of Established Therapies, Emerging Treatments, and Lifestyle Interventions

by Ting-Kuo Yao, Ru-Ping Lee, Wen-Tien Wu, Ing-Ho Chen, Tzai-Chiu Yu and Kuang-Ting Yeh

Int. J. Mol. Sci. 2024, 25(19), 10853; https://doi.org/10.3390/ijms251910853 - 9 Oct 2024

Viewed by 692

Abstract

Gouty arthritis, a prevalent inflammatory condition characterized by the deposition of monosodium urate crystals within joints, often results in debilitating pain and inflammation. Conventional therapeutic approaches, including nonsteroidal anti-inflammatory drugs, corticosteroids, and urate-lowering agents such as allopurinol and febuxostat, often have limitations such [...] Read more.

Gouty arthritis, a prevalent inflammatory condition characterized by the deposition of monosodium urate crystals within joints, often results in debilitating pain and inflammation. Conventional therapeutic approaches, including nonsteroidal anti-inflammatory drugs, corticosteroids, and urate-lowering agents such as allopurinol and febuxostat, often have limitations such as adverse effects, drug interactions, and suboptimal patient compliance. This review presents a comprehensive overview of both established and emerging therapeutic strategies, developed between 2019 and 2024, for gouty arthritis; the review focuses on their mechanisms of action, efficacy, and safety profiles. Novel therapeutic approaches include pharmaceutical plant additives (e.g., Citrullus colocynthis, Atractylodes lancea), anti-inflammatory agents such as canakinumab and ozone therapy, and complementary therapies such as warm ginger compresses, Qingpeng ointment, and various lifestyle modifications. These strategies offer promising alternatives to conventional treatments by targeting uric acid metabolism, inflammatory pathways, and crystal formation, potentially reducing reliance on standard medications and minimizing adverse effects. Although therapies such as canakinumab have demonstrated significant efficacy in reducing gout flares, others such as polyphenol-rich foods offer favorable safety profiles. Further research, including large-scale clinical trials, is warranted to validate these findings and integrate these strategies into clinical practice to improve patient outcomes and quality of life. Full article

(This article belongs to the Special Issue Molecular Advances in Orthopedic Trauma and Therapy)

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15 pages, 1236 KiB

Open AccessReview

Genome-Scale Metabolic Models in Fungal Pathogens: Past, Present, and Future

by Angie Lorena Fonseca-Fernández, Andrés Fernando González Barrios and Adriana Marcela Celis Ramírez

Int. J. Mol. Sci. 2024, 25(19), 10852; https://doi.org/10.3390/ijms251910852 - 9 Oct 2024

Viewed by 603

Abstract

Fungi are diverse organisms with various characteristics and functions. Some play a role in recycling essential elements, such as nitrogen and carbon, while others are utilized in the food and drink production industry. Some others are known to cause diseases in various organisms, [...] Read more.

Fungi are diverse organisms with various characteristics and functions. Some play a role in recycling essential elements, such as nitrogen and carbon, while others are utilized in the food and drink production industry. Some others are known to cause diseases in various organisms, including humans. Fungal pathogens cause superficial, subcutaneous, and systemic infections. Consequently, many scientists have focused on studying the factors contributing to the development of human diseases. Therefore, multiple approaches have been assessed to examine the biology of these intriguing organisms. The genome-scale metabolic models (GEMs) have demonstrated many advantages to microbial metabolism studies and the ability to propose novel therapeutic alternatives. Despite significant advancements, much remains to be elucidated regarding the use of this tool for investigating fungal metabolism. This review aims to compile the data provided by the published GEMs of human fungal pathogens. It gives specific examples of the most significant contributions made by these models, examines the advantages and difficulties associated with using such models, and explores the novel approaches suggested to enhance and refine their development. Full article

(This article belongs to the Special Issue Yeast as a Model System to Study Human Diseases)

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12 pages, 3571 KiB

Open AccessArticle

Protective Potential of Cicerbita alpina Leaf Extract on Metabolic Disorders and Oxidative Stress in Model Animals

by Dimitrina Zheleva-Dimitrova, Alexandra Petrova, Yonko Savov, Reneta Gevrenova, Vessela Balabanova, Georgi Momekov and Rumyana Simeonova

Int. J. Mol. Sci. 2024, 25(19), 10851; https://doi.org/10.3390/ijms251910851 - 9 Oct 2024

Viewed by 418

Abstract

Metabolic disorders (MDs) include disease states such as diabetes mellitus, obesity, dyslipidemia, hyperuricemia, etc., affecting about 30% of the planet’s population. The purpose of the present study was to investigate the protective potential of Cicerbita alpina leaf extract (ECA) against chemically induced type [...] Read more.

Metabolic disorders (MDs) include disease states such as diabetes mellitus, obesity, dyslipidemia, hyperuricemia, etc., affecting about 30% of the planet’s population. The purpose of the present study was to investigate the protective potential of Cicerbita alpina leaf extract (ECA) against chemically induced type 2 diabetes in Wistar rats. Additionally, some biochemical parameters in the blood serum and liver, as well as histopathological investigation, were also performed. Quantitative analysis of the major compounds in the used extract was performed using ultrahigh-performance liquid chromatography-diode array detection (UHPLC-DAD) analyses using the external standard method. C. alpina extract revealed a beneficial effect on MDs, lowering blood sugar levels and MDA quantity in the liver, increasing the reduced glutathione level, and increasing antioxidant enzyme activity. Cichoric acid (CA) (91.93 mg/g dry extract (de) ± 4.64 mg/g de) was found to be the dominant compound in the extract, followed by caftaric (11.36 ± 2.10 mg/g de), and chlorogenic acid (CGA) (9.25 ± 0.05 mg/g de). In conclusion, C. alpina leaf extract (ECA) is rich in caffeoyltartaric and caffeoylquinic acids and provides beneficial effects on the diabetic animal model. Full article

(This article belongs to the Section Molecular Pharmacology)

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25 pages, 6515 KiB

Open AccessArticle

Modulation of the Arabidopsis Starch Metabolic Network by the Cytosolic Acetyl-CoA Pathway in the Context of the Diurnal Illumination Cycle

by Lei Wang, Carol M. Foster, Wieslawa I. Mentzen, Rezwan Tanvir, Yan Meng, Basil J. Nikolau, Eve Syrkin Wurtele and Ling Li

Int. J. Mol. Sci. 2024, 25(19), 10850; https://doi.org/10.3390/ijms251910850 - 9 Oct 2024

Viewed by 495

Abstract

The starch metabolic network was investigated in relation to other metabolic processes by examining a mutant with altered single-gene expression of ATP citrate lyase (ACL), an enzyme responsible for generating cytosolic acetyl-CoA pool from citrate. Previous research has shown that transgenic antisense plants [...] Read more.

The starch metabolic network was investigated in relation to other metabolic processes by examining a mutant with altered single-gene expression of ATP citrate lyase (ACL), an enzyme responsible for generating cytosolic acetyl-CoA pool from citrate. Previous research has shown that transgenic antisense plants with reduced ACL activity accumulate abnormally enlarged starch granules. In this study, we explored the underlying molecular mechanisms linking cytosolic acetyl-CoA generation and starch metabolism under short-day photoperiods. We performed transcriptome and quantification of starch accumulation in the leaves of wild-type and antisense seedlings with reduced ACL activity. The antisense-ACLA mutant accumulated more starch than the wild type under short-day conditions. Zymogram analyses were conducted to compare the activities of starch-metabolizing enzymes with transcriptomic changes in the seedling. Differential expression between wild-type and antisense-ACLA plants was detected in genes implicated in starch and acetyl-CoA metabolism, and cell wall metabolism. These analyses revealed a strong correlation between the transcript levels of genes responsible for starch synthesis and degradation, reflecting coordinated regulation at the transcriptomic level. Furthermore, our data provide novel insights into the regulatory links between cytosolic acetyl-CoA metabolism and starch metabolic pathways. Full article

(This article belongs to the Section Molecular Plant Sciences)

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17 pages, 6521 KiB

Open AccessArticle

DNA Methylation Negatively Regulates Gene Expression of Key Cytokines Secreted by BMMCs Recognizing FMDV-VLPs

by Mingzhu Li, Peng Ning, Ruoman Bai, Zhanyun Tian, Shujia Liu and Limin Li

Int. J. Mol. Sci. 2024, 25(19), 10849; https://doi.org/10.3390/ijms251910849 - 9 Oct 2024

Viewed by 555

Abstract

Virus-like particles (VLPs) have been studied and used as vaccines to control foot-and-mouth disease (FMD). Mast cells (MCs) express various pattern recognition receptors that recognize pathogens and secrete numerous cytokines to initiate and modulate immune responses. Our previous study showed that bone marrow-derived [...] Read more.

Virus-like particles (VLPs) have been studied and used as vaccines to control foot-and-mouth disease (FMD). Mast cells (MCs) express various pattern recognition receptors that recognize pathogens and secrete numerous cytokines to initiate and modulate immune responses. Our previous study showed that bone marrow-derived mast cells (BMMCs) can recognize foot-and-mouth disease virus-like particles (FMDV-VLPs) to differentially express various cytokines and that histone acetylation can regulate the cytokines secreted during BMMC recognition of FMDV-VLPs. To demonstrate the role of DNA methylation in this response process, BMMCs that recognize FMDV-VLPs were treated with azacytidine (5-AZA), an inhibitor of DNA methylation transferase. We prepared FMDV-VLPs as described previously and cultured the BMMCs. The transcription and expression of key cytokines and transcription factors were determined using real-time quantitative PCR (RT-qPCR) and Western blotting. Results showed that pre-treatment with AZA resulted in the increased transcription and expression of tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-13, and IL-10, while the changes in IL-13 transcription and IL-6 expression were irrelevant to mannose receptors (MRs). Furthermore, analysis of the transcription factors indicated that both the transcription and expression of nuclear factor-kappa B (NF-κB) increased significantly in the AZA pre-treated group, indicating that DNA methylation may also regulate NF-κB expression to modulate TNF-α, IL-13, and IL-6. However, pre-treatment with AZA did not alter the expression of microphthalmia-associated transcription factor (MITF) or GATA-2. All the data demonstrate that DNA methylation negatively regulates the transcription and expression of TNF-α, IL-13, IL-10, and IL-6 secreted by recognizing FMDV-VLPs. These results provide new ideas for the mast cell-based design of more effective vaccine adjuvants and targeted therapies in the future. Full article

(This article belongs to the Section Molecular Immunology)

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24 pages, 38571 KiB

Open AccessArticle

Signature Proteins in Small Extracellular Vesicles of Granulocytes and CD4⁺ T-Cell Subpopulations Identified by Comparative Proteomic Analysis

by Sara Vázquez-Mera, Pablo Miguéns-Suárez, Laura Martelo-Vidal, Sara Rivas-López, Lena Uller, Susana B. Bravo, Vicente Domínguez-Arca, Xavier Muñoz, Francisco J. González-Barcala, Juan J. Nieto Fontarigo and Francisco J. Salgado

Int. J. Mol. Sci. 2024, 25(19), 10848; https://doi.org/10.3390/ijms251910848 - 9 Oct 2024

Viewed by 697

Abstract

Several studies have described the proteomic profile of different immune cell types, but only a few have also analysed the content of their delivered small extracellular vesicles (sEVs). The aim of the present study was to compare the protein signature of sEVs delivered [...] Read more.

Several studies have described the proteomic profile of different immune cell types, but only a few have also analysed the content of their delivered small extracellular vesicles (sEVs). The aim of the present study was to compare the protein signature of sEVs delivered from granulocytes (i.e., neutrophils and eosinophils) and CD4⁺ T cells (i.e., TH1, TH2, and TH17) to identify potential biomarkers of the inflammatory profile in chronic inflammatory diseases. Qualitative (DDA) and quantitative (DIA-SWATH) analyses of in vitro-produced sEVs revealed proteome variations depending on the cell source. The main differences were found between granulocyte- and TH cell-derived sEVs, with a higher abundance of antimicrobial proteins (e.g., LCN2, LTF, MPO) in granulocyte-derived sEVs and an enrichment of ribosomal proteins (RPL and RPS proteins) in TH-derived sEVs. Additionally, we found differentially abundant proteins between neutrophil and eosinophil sEVs (e.g., ILF2, LTF, LCN2) and between sEVs from different TH subsets (e.g., ISG15, ITGA4, ITGB2, or NAMPT). A “proof-of-concept” assay was also performed, with TH2 biomarkers ITGA4 and ITGB2 displaying a differential abundance in sEVs from T2^high and T2^low asthma patients. Thus, our findings highlight the potential use of these sEVs as a source of biomarkers for diseases where the different immune cell subsets studied participate, particularly chronic inflammatory pathologies such as asthma or chronic obstructive pulmonary disease (COPD). Full article

(This article belongs to the Special Issue Role of Extracellular Vesicles in Immunology)

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19 pages, 4897 KiB

Open AccessArticle

Photodynamic Therapy against Colorectal Cancer Using Porphin-Loaded Arene Ruthenium Cages

by Suzan Ghaddar, Aline Pinon, Manuel Gallardo-Villagran, Jacquie Massoud, Catherine Ouk, Claire Carrion, Mona Diab-Assaf, Bruno Therrien and Bertrand Liagre

Int. J. Mol. Sci. 2024, 25(19), 10847; https://doi.org/10.3390/ijms251910847 - 9 Oct 2024

Viewed by 512

Abstract

Colorectal cancer (CRC) is the third most common cancer in the world, with an ongoing rising incidence. Despite secure advancements in CRC treatments, challenges such as side effects and therapy resistance remain to be addressed. Photodynamic therapy (PDT) emerges as a promising modality, [...] Read more.

Colorectal cancer (CRC) is the third most common cancer in the world, with an ongoing rising incidence. Despite secure advancements in CRC treatments, challenges such as side effects and therapy resistance remain to be addressed. Photodynamic therapy (PDT) emerges as a promising modality, clinically used in treating different diseases, including cancer. Among the main challenges with current photosensitizers (PS), hydrophobicity and low selective uptake by the tumor remain prominent. Thus, developing an optimal design for PS to improve their solubility and enhance their selective accumulation in cancer cells is crucial for enhancing the efficacy of PDT. Targeted photoactivation triggers the production of reactive oxygen species (ROS), which promote oxidative stress within cancer cells and ultimately lead to their death. Ruthenium (Ru)-based compounds, known for their selective toxicity towards cancer cells, hold potential as anticancer agents. In this study, we investigated the effect of two distinct arene-Ru assemblies, which lodge porphin PS in their inner cavity, and tested them as PDT agents on the HCT116 and HT-29 human CRC cell lines. The cellular internalization of the porphin-loaded assemblies was confirmed by fluorescence microscopy. Additionally, significant photocytotoxicity was observed in both cell lines after photoactivation of the porphin in the cage systems, inducing apoptosis through caspase activation and cell cycle progression disruptions. These findings suggest that arene-Ru assemblies lodging porphin PS are potent candidates for PDT of CRC. Full article

(This article belongs to the Special Issue New Molecular Aspects of Colorectal Cancer)

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21 pages, 4908 KiB

Open AccessCase Report

PLP1-Targeting Antisense Oligonucleotides Improve FOXG1 Syndrome Mice

by Daniel C. S. Tan, Seonghee Jung, Yuanyuan Deng, Nicolle Morey, Gabriella Chan, Andre Bongers, Yazi D. Ke, Lars M. Ittner and Fabien Delerue

Int. J. Mol. Sci. 2024, 25(19), 10846; https://doi.org/10.3390/ijms251910846 - 9 Oct 2024

Viewed by 464

Abstract

FOXG1 syndrome is a rare neurodevelopmental disorder of the telencephalon, for which there is no cure. Underlying heterozygous pathogenic variants in the Forkhead Box G1 (FOXG1) gene with resulting impaired or loss of FOXG1 function lead to severe neurological impairments. Here, [...] Read more.

FOXG1 syndrome is a rare neurodevelopmental disorder of the telencephalon, for which there is no cure. Underlying heterozygous pathogenic variants in the Forkhead Box G1 (FOXG1) gene with resulting impaired or loss of FOXG1 function lead to severe neurological impairments. Here, we report a patient with a de novo pathogenic single nucleotide deletion c.946del (p.Leu316Cysfs*10) of the FOXG1 gene that causes a premature protein truncation. To study this variant in vivo, we generated and characterized Foxg1 c946del mice that recapitulate hallmarks of the human disorder. Accordingly, heterozygous Foxg1 c946del mice display neurological symptoms with aberrant neuronal networks and increased seizure susceptibility. Gene expression profiling identified increased oligodendrocyte- and myelination-related gene clusters. Specifically, we showed that expression of the c946del mutant and of other pathogenic FOXG1 variants correlated with overexpression of proteolipid protein 1 (Plp1), a gene linked to white matter disorders. Postnatal administration of Plp1-targeting antisense oligonucleotides (ASOs) in Foxg1 c946del mice improved neurological deficits. Our data suggest Plp1 as a new target for therapeutic strategies mitigating disease phenotypes in FOXG1 syndrome patients. Full article

(This article belongs to the Special Issue Application of Genomics in Complex Disorders: Focus on Pharmacogenomics Informed Theraputics)

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14 pages, 1495 KiB

Open AccessArticle

B-Cell Maturation Antigen (BCMA) as a Biomarker and Potential Treatment Target in Systemic Lupus Erythematosus

by Jonas Martin, Qingyu Cheng, Sarah A. Laurent, Franziska S. Thaler, Anne Elisabeth Beenken, Edgar Meinl, Gerhard Krönke, Falk Hiepe and Tobias Alexander

Int. J. Mol. Sci. 2024, 25(19), 10845; https://doi.org/10.3390/ijms251910845 - 9 Oct 2024

Viewed by 641

Abstract

The BAFF-APRIL system is crucial for the pathogenesis of systemic lupus erythematosus (SLE) by promoting B cell survival, differentiation and the maintenance of humoral autoimmunity. Here, we investigated the relationship of BCMA expression on B cell subsets with its ligands BAFF and APRIL, [...] Read more.

The BAFF-APRIL system is crucial for the pathogenesis of systemic lupus erythematosus (SLE) by promoting B cell survival, differentiation and the maintenance of humoral autoimmunity. Here, we investigated the relationship of BCMA expression on B cell subsets with its ligands BAFF and APRIL, together with soluble BCMA, and with clinical and serologic variables in a cohort of 100 SLE patients (86 under conventional and 14 under belimumab therapy) and 30 healthy controls (HCs) using multicolor flow cytometry and ELISA. We found that BCMA expression in SLE patients was significantly increased on all B cell subsets compared to HCs, with all examined components of the BAFF-APRIL system being upregulated. BCMA expression was significantly increased on switched and unswitched memory B cells compared to naïve B cells, both in HCs and SLE. BCMA expression on B cells correlated with plasmablast frequencies, serum anti-dsDNA antibodies and complement consumption, while soluble BCMA correlated with plasmablast frequency, highlighting its potential as a clinical biomarker. Belimumab treatment significantly reduced BCMA expression on most B cell subsets and soluble TACI and contributed to the inhibition of almost the entire BAFF-APRIL system and restoration of B cell homeostasis. These results provide insights into the complex dysregulation of the BAFF-APRIL system in SLE and highlight the therapeutic potential of targeting its components, particularly BCMA, in addition to its use as a biomarker for disease activity. Full article

(This article belongs to the Special Issue Immunopathogenesis and Novel Therapeutics Strategies of Systemic Lupus Erythematosus 2.0)

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10 pages, 1586 KiB

Open AccessCase Report

A Rare Case of TP63-Associated Lymphopenia Revealed by Newborn Screening Using TREC

by Andrey Marakhonov, Elena Serebryakova, Anna Mukhina, Anastasia Vechkasova, Nikolai Prokhorov, Irina Efimova, Natalia Balinova, Anastasia Lobenskaya, Tatyana Vasilyeva, Victoria Zabnenkova, Oxana Ryzhkova, Yulia Rodina, Dmitry Pershin, Nadezhda Soloveva, Anna Fomenko, Djamila Saydaeva, Aset Ibisheva, Taisiya Irbaieva, Alexander Koroteev, Rena Zinchenko, Sergey Voronin, Anna Shcherbina and Sergey Kutsev Show full author list Hide full author list

Int. J. Mol. Sci. 2024, 25(19), 10844; https://doi.org/10.3390/ijms251910844 - 9 Oct 2024

Viewed by 369

Abstract

The expanded newborn screening (NBS) program in the Russian Federation was initiated in 2023, among which severe combined immunodeficiency (SCID) is screened using TREC/KREC assays. Here, we report a rare case of a TP63-associated disease identified through this NBS program. Dried blood [...] Read more.

The expanded newborn screening (NBS) program in the Russian Federation was initiated in 2023, among which severe combined immunodeficiency (SCID) is screened using TREC/KREC assays. Here, we report a rare case of a TP63-associated disease identified through this NBS program. Dried blood spots from newborns were initially screened for TREC/KREC levels, and those with values below the cut-off underwent confirmatory testing and further genetic analysis, including whole-exome sequencing (WES). A male newborn was identified with significantly reduced TREC values, indicative of T cell lymphopenia. Genetic analysis revealed a heterozygous NM_003722.5:c.1027C>T variant in TP63, leading to the p.(Arg343Trp) substitution within the DNA binding domain. This mutation has been previously associated with Ectrodactyly–Ectodermal Dysplasia–Cleft lip/palate syndrome (EEC) syndrome and shown to reduce the transactivation activity of TP63 in a dominant-negative manner. This case represents one of the few instances of immune system involvement in a patient with a TP63 mutation, highlighting the need for further investigation into the immunological aspects of TP63-associated disorders. Our findings suggest that comprehensive immunological evaluation should be considered for patients with TP63 mutations to better understand and manage potential immune dysfunctions. Full article

(This article belongs to the Special Issue Genetic Studies of Immune-Related Diseases)

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14 pages, 599 KiB

Open AccessReview

Molecular Targets for the Diagnosis and Treatment of Pancreatic Cancer

by Robert G. Pergolizzi and Steven T. Brower

Int. J. Mol. Sci. 2024, 25(19), 10843; https://doi.org/10.3390/ijms251910843 - 9 Oct 2024

Viewed by 957

Abstract

Pancreatic cancer is one of the most aggressive and lethal forms of cancer, with a five-year survival rate of less than 10%. Despite advances in treatment modalities, the prognosis for pancreatic cancer patients remains poor, highlighting the urgent need for innovative approaches for [...] Read more.

Pancreatic cancer is one of the most aggressive and lethal forms of cancer, with a five-year survival rate of less than 10%. Despite advances in treatment modalities, the prognosis for pancreatic cancer patients remains poor, highlighting the urgent need for innovative approaches for early diagnosis and targeted therapies. In recent years, there has been significant progress in understanding the molecular mechanisms underlying pancreatic cancer development and progression. This paper reviews the current knowledge of molecular targets for the diagnosis and treatment of pancreatic cancer. Full article

(This article belongs to the Special Issue Advances in the Molecular Diagnosis and Treatment of Pancreatic Cancer)

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12 pages, 3062 KiB

Open AccessArticle

The Complexity of the Influence of Growth Substances, Heavy Metals, and Their Combination on the Volume Dynamics of Vacuoles Isolated from Red Beet (Beta vulgaris L.) Taproot Cells

by Waldemar Karcz and Zbigniew Burdach

Int. J. Mol. Sci. 2024, 25(19), 10842; https://doi.org/10.3390/ijms251910842 - 9 Oct 2024

Viewed by 318

Abstract

The plant vacuole is a very dynamic organelle that can occupy more than 90% of the cell volume and is essential to plant cell growth and development, the processes in which auxin (indole-3-acetic acid, IAA) is a central player. It was found that [...] Read more.

The plant vacuole is a very dynamic organelle that can occupy more than 90% of the cell volume and is essential to plant cell growth and development, the processes in which auxin (indole-3-acetic acid, IAA) is a central player. It was found that when IAA or FC (fusicoccin) was present in the control medium of vacuoles isolated from red beet taproots at a final concentration of 1 µM, it increased their volume to a level that was 26% or 36% higher than that observed in the control medium without growth regulators, respectively. In the presence of IAA and FC, the time after which most vacuoles ruptured was about 10 min longer for IAA than for FC. However, when cadmium (Cd) or lead (Pb) was present in the control medium at a final concentration of 100 µM, it increased the volume of the vacuoles by about 26% or 80% compared to the control, respectively. The time after which the vacuoles ruptured was similar for both metals. The combined effect of IAA and Pb on the volume of the vacuoles was comparable with that observed in the presence of Pb only, while for FC combined with Pb, it was additive. The use of IAA or FC together with Cd caused in both cases a decrease in the vacuole volumes by about 50%. The data presented in this study are discussed, taking into account the structure and function of the vacuolar membrane (tonoplast) and their changes in the presence of growth substances, heavy metals, and their combination. Full article

(This article belongs to the Section Molecular Plant Sciences)

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7 pages, 1194 KiB

Open AccessCase Report

Challenging Diagnosis of a Patient with Two Novel Variants in the SYNE1 Gene

by Anna Kuchina, Aysylu Murtazina, Artem Borovikov, Dmitrii Subbotin, Sergey Bardakov, Maria Akhkiamova, Aleksandra Nikolaeva, Olga Shchagina and Sergey Kutsev

Int. J. Mol. Sci. 2024, 25(19), 10841; https://doi.org/10.3390/ijms251910841 - 9 Oct 2024

Viewed by 349

Abstract

We report a case of SYNE1-associated autosomal recessive spinocerebellar ataxia (SCAR8) presenting with a complex multisystemic phenotype, including highly elevated creatine kinase levels and lower-leg muscle atrophy. In addition to identifying two novel pathogenic variants in the SYNE1 gene, whole-exome sequencing revealed [...] Read more.

We report a case of SYNE1-associated autosomal recessive spinocerebellar ataxia (SCAR8) presenting with a complex multisystemic phenotype, including highly elevated creatine kinase levels and lower-leg muscle atrophy. In addition to identifying two novel pathogenic variants in the SYNE1 gene, whole-exome sequencing revealed three variants of uncertain significance in the DYSF gene. Electromyography and muscle magnetic resonance imaging indicated a neurogenic pattern of muscle involvement. These findings, along with the segregation analysis of the variants, allowed us to exclude DYSF-associated muscular dystrophy; however, we cannot entirely rule out the possibility that the DYSF gene variants may act as modifiers of the patient’s phenotype. Full article

(This article belongs to the Special Issue Genetic Variants in Neurological and Psychiatric Diseases)

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23 pages, 4136 KiB

Open AccessArticle

3,8-Disubstituted Pyrazolo[1,5-a]quinazoline as GABA_A Receptor Modulators: Synthesis, Electrophysiological Assays, and Molecular Modelling Studies

by Letizia Crocetti, Gabriella Guerrini, Fabrizio Melani, Maria Paola Mascia and Maria Paola Giovannoni

Int. J. Mol. Sci. 2024, 25(19), 10840; https://doi.org/10.3390/ijms251910840 - 9 Oct 2024

Viewed by 378

Abstract

As a continuation of our study in the field of GABA_A receptor modulators, we report the design and synthesis of new pyrazolo[1,5-a]quinazoline (PQ) bearing at the 8-position an oxygen or nitrogen function. All the final compounds and some intermediates, showing the three [...] Read more.

As a continuation of our study in the field of GABA_A receptor modulators, we report the design and synthesis of new pyrazolo[1,5-a]quinazoline (PQ) bearing at the 8-position an oxygen or nitrogen function. All the final compounds and some intermediates, showing the three different forms of the pyrazolo[1,5-a]quinazoline scaffold (5-oxo-4,5-dihydro, -4,5-dihydro, and heteroaromatic form), have been screened with an electrophysiological technique on recombinant GABA_AR (α1β2γ2-GABA_AR), expressed in Xenopus laevis oocytes, by evaluating the variation in produced chlorine current, and permitting us to identify some interesting compounds (6d, 8a, 8b, and 14) on which further functional assays were performed. Molecular modelling studies (docking, minimization of complex ligand–receptor, and MD model) and a statistical analysis by a Hierarchical Cluster Analysis (HCA) have collocated these ligands in the class corresponding to their pharmacological profile. The HCA results are coherent with the model we recently published (Proximity Frequencies), identifying the residues γThr142 and αHis102 as discriminant for the agonist and antagonist profile. Full article

(This article belongs to the Special Issue Ion Channels as Therapeutic Target: Drug Design and Pharmacological Investigation 2.0)

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Open AccessArticle

Pleiotrophin Activates cMet- and mTORC1-Dependent Protein Synthesis through PTPRZ1—The Role of α_νβ₃ Integrin

by Eleni Mourkogianni, Katerina Karavasili, Athanasios Xanthopoulos, Michaela-Karina Enake, Lydia Menounou and Evangelia Papadimitriou

Int. J. Mol. Sci. 2024, 25(19), 10839; https://doi.org/10.3390/ijms251910839 - 9 Oct 2024

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Abstract

Pleiotrophin (PTN) is a secreted factor that regulates endothelial cell migration through protein tyrosine phosphatase receptor zeta 1 (PTPRZ1) and α_vβ₃ integrin. Genetic deletion of Ptprz1 results in enhanced endothelial cell proliferation and migration, due to the decreased expression of [...] Read more.

Pleiotrophin (PTN) is a secreted factor that regulates endothelial cell migration through protein tyrosine phosphatase receptor zeta 1 (PTPRZ1) and α_vβ₃ integrin. Genetic deletion of Ptprz1 results in enhanced endothelial cell proliferation and migration, due to the decreased expression of β₃ integrin and the subsequent, enhanced cMet phosphorylation. In the present study, we investigated the effect of PTN and PTPRZ1 on activating the mTORC1 kinase and protein synthesis and identified part of the implicated signaling pathway in endothelial cells. PTN or genetic deletion of Ptprz1 activates protein synthesis in a mTORC1-dependent manner, as shown by the enhanced phosphorylation of the mTORC1-downstream targets ribosomal protein S6 kinase 1 (SK61) and 4E-binding protein 1 (4EBP1) and the upregulation of HIF-1α. The cMet tyrosine kinase inhibitor crizotinib abolishes the stimulatory effects of PTN or PTPRZ1 deletion on mTORC1 activation and protein synthesis, suggesting that mTORC1 activation is downstream of cMet. The mTORC1 inhibitor rapamycin abolishes the stimulatory effect of PTN or PTPRZ1 deletion on endothelial cell migration, suggesting that mTORC1 is involved in the PTN/PTPRZ1-dependent cell migration. The α_vβ₃ integrin blocking antibody LM609 and the peptide PTN_112–136, both known to bind to α_νβ₃ and inhibit PTN-induced endothelial cell migration, increase cMet phosphorylation and activate mTORC1, suggesting that cMet and mTORC1 activation are required but are not sufficient to stimulate cell migration. Overall, our data highlight novel aspects of the signaling pathway downstream of the PTN/PTPRZ1 axis that regulates endothelial cell functions. Full article

(This article belongs to the Special Issue Kinase Inhibitors and Kinase-Targeted Cancer Therapies)

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Int. J. Mol. Sci., Volume 25, Issue 19 (October-1 2024) – 637 articles

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