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12 pages, 1599 KiB  
Article
CRISPR/Cas12a-Chemiluminescence Cascaded Bioassay for Amplification-Free and Sensitive Detection of Nucleic Acids
by Xiaotian Guan, Peizheng Wang, Yi Wang and Shuqing Sun
Biosensors 2025, 15(8), 479; https://doi.org/10.3390/bios15080479 - 24 Jul 2025
Viewed by 305
Abstract
The CRISPR/Cas system has attracted increasing attention in accurate nucleic acid detection. Herein, we reported a CRISPR/Cas12a-chemiluminescence cascaded bioassay (CCCB) for the amplification-free and sensitive detection of human papillomavirus type 16 (HPV-16) and parvovirus B19 (PB-19). A magnetic bead (MB)-linking single-stranded DNA (LssDNA)-alkaline [...] Read more.
The CRISPR/Cas system has attracted increasing attention in accurate nucleic acid detection. Herein, we reported a CRISPR/Cas12a-chemiluminescence cascaded bioassay (CCCB) for the amplification-free and sensitive detection of human papillomavirus type 16 (HPV-16) and parvovirus B19 (PB-19). A magnetic bead (MB)-linking single-stranded DNA (LssDNA)-alkaline phosphatase (ALP) complex was constructed as the core component of the bioassay. During the detection process, the single-stranded target DNA was captured and enriched by LssDNA and then activated the trans-cleavage activity of Cas12a. Due to the Cas12a-mediated cleavage of LssDNA, ALP was released from the MB, subsequently catalyzing the substrate to generate a chemiluminescence (CL) signal. Given the cascade combination of CRISPR/Cas12a with the CL technique, the limits of detection for HPV-16 and PB-19 DNA were determined as 0.14 pM and 0.37 pM, respectively, and the whole detection could be completed within 60 min. The practicality and reliability of the platform were validated through target-spiked clinical specimens, and the recovery rate was 93.4–103.5%. This dual-amplification strategy—operating without target pre-amplification—featured high specificity, low contamination risk, facile preparation, and robust stability. It provides a novel approach for sensitive nucleic acid detection, with the potential for rapid extension to the diagnosis of various infectious diseases. Full article
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23 pages, 3808 KiB  
Article
Cells of the Maternal–Fetal Interface May Contribute to Epidural-Related Maternal Fever After Administration of Ropivacaine: The Role of Phosphatases DUSP9 and PHLPP1
by Florian Horn, Verena Tretter, Victoria Kunihs, Peter Wohlrab, Bettina Trimmel, Kevin A. Janes, Tamara Djurkic, Meriem Mekiri, Martin Knöfler and Leila Saleh
Int. J. Mol. Sci. 2025, 26(12), 5520; https://doi.org/10.3390/ijms26125520 - 9 Jun 2025
Viewed by 374
Abstract
Epidural-related maternal fever (ERMF) occurs with significant incidence in women receiving local anesthetics such as ropivacaine via epidural catheter for pain relief during labor. The causal mechanism behind this phenomenon is still not fully resolved, but evidence suggests that these anesthetics cause sterile [...] Read more.
Epidural-related maternal fever (ERMF) occurs with significant incidence in women receiving local anesthetics such as ropivacaine via epidural catheter for pain relief during labor. The causal mechanism behind this phenomenon is still not fully resolved, but evidence suggests that these anesthetics cause sterile inflammation. In this observational study, we investigated a possible contributory role of the dual-specificity phosphatase-9 (DUSP9) controlling the activity of mitogen-activated protein kinases (MAPK), and also PH-domain and Leucine-rich repeat phosphatase (PHLPP) regulating AKT kinases. The data show that ropivacaine differentially affects the expression of these phosphatases in distinct cell types of the umbilical cord and placenta. The gene expression of DUSP9 was almost completely switched off in the presence of ropivacaine in HUVECs and extravillous trophoblasts for up to 6 h, while the expression of PHLPP1 was upregulated in HUVECs and syncytiotrophoblasts. Extravillous trophoblasts were identified as a source of pro-inflammatory mediators and regulatory miRNAs in response to ropivacaine. Placentae at term exhibited a distinct DUSP9 expression pattern, whether the patients belonged to the control group or received epidural analgesia with or without elevated body temperature. The observed data imply that ropivacaine induces complex effects on the MAPK and AKT pathways at the feto–maternal interface, which contribute to the ERMF phenomenon. Full article
(This article belongs to the Special Issue The Role of Phosphatases in Human Disease)
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10 pages, 401 KiB  
Article
Serum Markers of Bone Turnover and Bone Remodeling in Children with Noonan Syndrome: Genotype-Phenotype Correlation
by Mariangela Chiarito, Ilaria Farella, Crescenza Lattanzio, Rossella Vitale, Flavia Urbano, Pietro Guida, Laura Piacente, Paola Muggeo and Maria Felicia Faienza
Genes 2025, 16(6), 668; https://doi.org/10.3390/genes16060668 - 30 May 2025
Viewed by 908
Abstract
Noonan syndrome (NS) is a genetic disorder characterized by distinctive craniofacial and skeletal features, short stature, mild to moderate developmental impairment, and multisystem involvement, notably affecting the cardiovascular, musculoskeletal, and endocrine systems. Although abnormalities of the bone matrix, as well as osteopenia and [...] Read more.
Noonan syndrome (NS) is a genetic disorder characterized by distinctive craniofacial and skeletal features, short stature, mild to moderate developmental impairment, and multisystem involvement, notably affecting the cardiovascular, musculoskeletal, and endocrine systems. Although abnormalities of the bone matrix, as well as osteopenia and osteoporosis, are well recognized in individuals with NS and other RASopathies, the specific impact of RAS/MAPK pathway dysregulation on bone health remains poorly understood. Objectives: The aim of this study was to evaluate bone turnover and bone remodeling markers in a cohort of children with NS, to gain further insights into the bone status of these patients. Methods: In this cross-sectional, case-control study, we analyzed 28 children (20 males) with a molecular diagnosis of NS and 35 healthy subjects (21 males), matched by age and sex. We assessed markers of bone metabolism and bone turnover (calcium, phosphate, PTH, 25(OH)-vitamin D, osteocalcin, procollagen I N-propeptide-P1NP, bone alkaline phosphatase-BALP, C-telopeptides of type I collagen-CTX) and bone remodeling (RANKL, OPG, and sclerostin). Bone mineralization was measured at the lumbar spine (L2–L4) using dual-energy X-ray absorptiometry (DEXA). Results: Serum CTX levels were significantly higher in NS patients compared to controls (1.8 ± 0.7 vs. 1.3 ± 0.5 ng/mL, p = 0.0004). RANKL levels were higher in NS patients, although the difference did not reach statistical significance. No significant differences were found for OPG, sclerostin, or other markers of bone metabolism between patients and controls. Conclusions: Children with NS exhibit increased bone resorption, as indicated by elevated CTX levels, suggesting a potential imbalance in bone remodeling processes. Further studies are warranted to better define the impact of RAS/MAPK pathway dysregulation on bone health in this population. Full article
(This article belongs to the Collection Genetics and Genomics of Rare Disorders)
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22 pages, 8463 KiB  
Article
Synergistic Impacts of Phosphorus Deficiency Coupled with Thermal and High-Light Stress on Physiological Profiles of Cultivated Saccharina japonica
by Jing Zhang, Xiaonan Wang, Xingyue Ren, Xu Gao and Jingyu Li
Plants 2025, 14(10), 1412; https://doi.org/10.3390/plants14101412 - 8 May 2025
Viewed by 680
Abstract
Global kelp farming is garnering growing attention for its contributions to fishery yields, environmental remediation, and carbon neutrality efforts. Kelp farming systems face escalating pressures from compounded climatic and environmental stressors. A severe outbreak disaster caused extensive kelp mortality and significant economic losses [...] Read more.
Global kelp farming is garnering growing attention for its contributions to fishery yields, environmental remediation, and carbon neutrality efforts. Kelp farming systems face escalating pressures from compounded climatic and environmental stressors. A severe outbreak disaster caused extensive kelp mortality and significant economic losses in Rongcheng, China, one of the world’s largest kelp farming areas. This study investigated the growth and physiological responses of Saccharina japonica to combined stressors involving three levels of N:P ratios (10:1 as a control; 100:1 and 500:1 to represent phosphorus deficiency stress) and two temperature/light regimes (12 °C, 90 μmol photons m−2 s−1 as a control, and 17 °C, 340 μmol photons m−2 s−1 to represent thermal and high-light stress). The results demonstrated that phosphorus deficiency significantly inhibited the relative growth rate of kelp (24% decrease), and the strongest growth inhibition in kelp was observed at the N:P ratio of 500:1 combined with thermal and high-light stress. The algal tissue was whitened due to its progressive disintegration under escalating stress, coupled with damage to its chloroplasts and nucleus ultrastructures. Phosphorus-deficiency-induced declines in photochemistry (27–56% decrease) and chlorophyll content (63% decrease) were paradoxically and transiently reversed by thermal and high-light stress, but this “false recovery” accelerated subsequent metabolic collapse (a 60–75% decrease in the growth rate and a loss of thallus integrity). Alkaline phosphatase was preferentially activated to cope with phosphorus deficiency combined with photothermal stress, while acid phosphatase was subsequently induced to provide auxiliary support. S. japonica suppressed its metabolism but upregulated its nucleotides under phosphorus deficiency; however, the energy/amino acid/coenzyme pathways were activated and a broad spectrum of metabolites were upregulated under combined stressors, indicating that S. japonica employs a dual adaptive strategy where phosphorus scarcity triggers metabolic conservation. Thermal/light stress can override phosphorus limitations by activating specific compensatory pathways. The findings of this study provide a foundation for the sustainable development of kelp farming under climate and environmental changes. Full article
(This article belongs to the Special Issue Marine Macrophytes Responses to Global Change)
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17 pages, 1216 KiB  
Article
Type 2 Diabetes Mellitus and Osteoporosis: Site-Specific Bone Mineral Density Variations and Metabolic Correlations in Postmenopausal Saudi Women
by Nogood Mashahi Alhowiti, Amal M. H. Mackawy, Wanian Mohammed Al Wanian, Mohammad Alshebremi, Khaled S. Allemailem and Hajed Obaid Abdullah Alharbi
Medicina 2025, 61(5), 789; https://doi.org/10.3390/medicina61050789 - 24 Apr 2025
Viewed by 1027
Abstract
Background and Objectives: Osteoporosis (OP) is a prevalent condition among postmenopausal women, with an estimated 40% of Saudi women affected. Concurrently, type 2 diabetes mellitus (T2DM) is highly prevalent in the Qassim region, affecting 45% of individuals aged 40 and older. Despite conflicting [...] Read more.
Background and Objectives: Osteoporosis (OP) is a prevalent condition among postmenopausal women, with an estimated 40% of Saudi women affected. Concurrently, type 2 diabetes mellitus (T2DM) is highly prevalent in the Qassim region, affecting 45% of individuals aged 40 and older. Despite conflicting evidence regarding the impact of T2DM on bone health, its role in OP development remains uncertain. Materials and Methods: This study investigates site-specific bone mineral density (BMD) variations and their metabolic correlations in postmenopausal Saudi women with T2DM. A cross-sectional study included 250 postmenopausal Saudi women, 100 without diabetes (Group 1) and 150 with diabetes (Group 2), matched for age, menopausal duration, and body mass index (BMI). BMD at the femoral neck (FN) and lumbar spine (LS) was assessed using dual-energy X-ray absorptiometry (DXA). Biochemical markers, including parathyroid hormone (PTH), alkaline phosphatase (ALP), estrogen, calcium, and HbA1c, were assessed. Statistical analyses, including chi-square tests, t-tests, ANOVA, Pearson correlation, and multivariate regression, evaluated BMD variations and biochemical associations. Results: Patients with diabetes exhibited significantly higher FN T-scores than those without diabetes (p = 0.001), while LS T-scores showed no significant difference. BMD distribution (normal, osteopenia, OP) did not differ between the groups (p > 0.05). FN T-scores correlated positively with parathyroid hormone (PTH) and alkaline phosphatase (ALP) levels, reduced estrogen, and prolonged menopause duration (p < 0.01) but were inversely associated with estrogen levels and menopause duration (p < 0.01). Conclusions: No significant association was found between HbA1c and BMD. Additionally, BMI demonstrated a protective effect on FN BMD. T2DM appears to influence bone metabolism without directly causing OP in postmenopausal women. Aging, menopause duration, metabolic markers (PTH, ALP, estrogen), and BMI play crucial roles in BMD variations, with a protective effect of BMI. These findings underscore the importance of site-specific BMD assessment and metabolic profiling in postmenopausal women with diabetes. Further longitudinal research is needed to elucidate the underlying mechanisms affecting bone health in postmenopausal women with diabetes. Full article
(This article belongs to the Section Endocrinology)
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15 pages, 3228 KiB  
Article
The Protective Role of DUSP4 in Retinal Pigment Epithelium Senescence and Degeneration
by Xiyuan Liu, Zhaoze Ni, Jing Zhang, Xiaoyan Lin, Chenxin Wu, Yuyang Wu, Lingqin Dong, Zongduan Zhang and Zai-Long Chi
Int. J. Mol. Sci. 2025, 26(8), 3735; https://doi.org/10.3390/ijms26083735 - 15 Apr 2025
Viewed by 681
Abstract
The retinal pigment epithelium (RPE) serves as a critical guardian of subretinal homeostasis, with its dysfunction implicated in major retinal pathologies, including age-related macular degeneration (AMD) and retinitis pigmentosa. While cellular senescence has emerged as a key driver of RPE degeneration, the molecular [...] Read more.
The retinal pigment epithelium (RPE) serves as a critical guardian of subretinal homeostasis, with its dysfunction implicated in major retinal pathologies, including age-related macular degeneration (AMD) and retinitis pigmentosa. While cellular senescence has emerged as a key driver of RPE degeneration, the molecular mechanisms underlying this process remain incompletely defined. Emerging evidence implicates dual-specificity phosphatase 4 (DUSP4) in cellular stress responses through its antioxidant and anti-inflammatory capacities, yet its role in RPE pathophysiology remains unexplored. Our study reveals a compensatory increase in DUSP4 expression during AMD-associated RPE senescence. To functionally characterize this observation, we knocked down DUSP4 in the RPE of mice via subretinal injection of AAV-shDUSP4. In a sodium iodate-induced dry AMD model, mice with DUSP4 knockdown presented more severe visual impairment than control mice did. To further investigate the molecular mechanism, stable DUSP4-knockout cell lines were constructed via CRISPR/Cas9 technology. The high expression of senescence markers in the DUSP4-knockout cell lines was reversed by DUSP4 overexpression. Furthermore, DUSP4 coordinates the modulation of cell cycle, stress response, and pro-inflammatory signaling by inhibiting the p53, p38, and NF-kB pathways. These findings establish DUSP4 as a multi-functional regulator of RPE senescence. Our work not only elucidates a novel DUSP4-dependent mechanism in AMD pathogenesis but also highlights its therapeutic potential for preserving RPE function in AMD. Full article
(This article belongs to the Section Molecular Pharmacology)
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10 pages, 650 KiB  
Article
Could PTH/Ca Ratio Serve as a New Marker for Evaluating Bone Metabolism in Hemophilia Patients?
by Tuba Ersal, Fazıl Çağrı Hunutlu, Vildan Gürsoy, Ezel Elgün, Şeyma Yavuz, İpek Dal Akkuş, İlayda Baş, Vildan Özkocaman and Fahir Özkalemkaş
Diagnostics 2025, 15(5), 638; https://doi.org/10.3390/diagnostics15050638 - 6 Mar 2025
Viewed by 805
Abstract
Background/Objectives: Low bone mineral density (BMD) is common in hemophilia patients. Identifying high-risk patients for low BMD early is essential to prevent complications and reduce morbidity. The parathyroid hormone (PTH)/calcium (Ca) ratio is a cost-effective marker for predicting BMD, highlighting the need for [...] Read more.
Background/Objectives: Low bone mineral density (BMD) is common in hemophilia patients. Identifying high-risk patients for low BMD early is essential to prevent complications and reduce morbidity. The parathyroid hormone (PTH)/calcium (Ca) ratio is a cost-effective marker for predicting BMD, highlighting the need for routine screening and early intervention in this population. Hemophilia is a hereditary bleeding disorder caused by deficiencies in clotting factors VIII (hemophilia A) and IX (hemophilia B). Patients with hemophilia are at risk of low bone mineral density (BMD). This study aimed to evaluate the prevalence of low BMD, associated risk factors, and raise awareness regarding its significance in hemophilia patients. Methods: We retrospectively assessed bone metabolism in 62 hemophilia patients followed at our center. BMD was evaluated using dual-energy X-ray absorptiometry (DEXA). Additionally, serum levels of 25-OH-D3, alkaline phosphatase, PTH, Ca, phosphor, and creatinine were measured. The PTH/Ca, PTH/25-OH-D3, and Ca×25-OH-D3/PTH ratios were calculated. Results: The median age of the 62 patients with hemophilia included in the study (hemophilia A: 87.1%, hemophilia B: 12.9%) was 37 years (range: 21–66), and all were male. Of these patients, 67.7% (n = 42) had severe, 21% (n = 13) had moderate, and 11.3% (n = 7) had mild hemophilia. A total of 85.5% of patients were on factor prophylaxis, and 75.4% had a target joint. In laboratory analysis, the median 25-OH-D3 level was 13.4 µg/L and 75% patients had 25-OH-D3 deficiency. According to DEXA results, 62.9% had lower than normal BMD. When we divided the patients into normal and low BMD groups according to DEXA results, weight (p = 0.006), height (p = 0.024), factor levels (p = 0.004), PTH (p = 0.010), AST (p = 0.029), and PTH/Ca (p = 0.011) levels were statistically significantly different between the groups. The severity of the disease and the rate of receiving prophylaxis were higher in the group with low BMD (p = 0.015, p = 0.006, respectively). In multivariate analysis, PTH/Ca ratio and weight were found to be independent risk factors for BMD. A linear relationship was found between PTH/Ca ratio and BMD. The optimal cut-off value for PTH/Ca was 6.57, with a selectivity of 65% and specificity of 82%. When we divided the patients into groups according to the cut-off value of 6.57, we found that the probability of low BMD increased approximately 7-fold in the group with PTH/Ca > 6.57 (OR 7.045, 95% CI 1.485–33.42, p = 0.014). There was an inverse association between patient weight and low BMD (p = 0.043). Conclusions: Low BMD is a critical public health concern frequently observed in patients with hemophilia. The study highlights a high rate of low BMD and 25-OH-D3 deficiency in hemophilia patients, with the PTH/Ca ratio shown to be useful in predicting BMD. The PTH/Ca ratio is suggested as an accessible, cost-effective, and practical test for evaluating BMD in hemophilia patients. Full article
(This article belongs to the Special Issue Rare Diseases: Diagnosis and Management)
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15 pages, 2590 KiB  
Article
Mechanisms Underlying the Stimulation of DUSP10/MKP5 Expression in Chondrocytes by High Molecular Weight Hyaluronic Acid
by Wataru Ariyoshi, Jun Takeuchi, Sho Mitsugi, Ayaka Koga, Yoshie Nagai-Yoshioka and Ryota Yamasaki
Biomedicines 2025, 13(2), 376; https://doi.org/10.3390/biomedicines13020376 - 5 Feb 2025
Viewed by 875
Abstract
Background/Objectives: Previously, we reported that high molecular weight hyaluronic acid (HMW-HA) exerts chondroprotective effects by enhancing dual specificity protein phosphatase 10/mitogen-activated protein kinase (MAPK) phosphatase 5 (DUSP10/MKP5) expression and suppressing inflammatory cytokine-induced matrix metalloproteinase-13 (MMP13) expression in a human immortalized chondrocyte line [...] Read more.
Background/Objectives: Previously, we reported that high molecular weight hyaluronic acid (HMW-HA) exerts chondroprotective effects by enhancing dual specificity protein phosphatase 10/mitogen-activated protein kinase (MAPK) phosphatase 5 (DUSP10/MKP5) expression and suppressing inflammatory cytokine-induced matrix metalloproteinase-13 (MMP13) expression in a human immortalized chondrocyte line (C28/I2 cells) via inhibition of MAPKs. The aim of this study was to elucidate the molecular mechanisms underlying the enhancement of DUSP10/MKP5 expression by HMW-HA in C28/I2 cells. Methods: C28/I2 cells were treated with HMW-HA, and the activation of intracellular signaling molecules was determined using Western blot analysis. The expression levels of mRNAs and microRNAs (miRNAs) were evaluated through real-time quantitative reverse transcription PCR analysis. Results: HMW-HA treatment induced Akt phosphorylation via interaction with CD44, and pretreatment with specific inhibitors of phosphatidylinositol-3 kinase/protein kinase B (PI3K/Akt) signaling attenuated the HMW-HA-induced expression of DUSP10/MKP5. HMW-HA suppressed the expression of miR-92a, miR-181a, and miR-181d. Loss-of-function and gain-of-function analyses of these miRNAs indicate that miR-92a, miR-181a, and miR-181d negatively regulate DUSP10/MKP5 expression. Moreover, HMW-HA-induced Akt phosphorylation was partially suppressed by miR-181a and miR-181d mimics. Finally, we found that HMW-HA activates RhoA-associated protein kinase (ROK) signaling, which contributes to Akt phosphorylation. Conclusions: These findings suggest that the induction of DUSP10/MKP5 expression by HMW-HA binding to CD44, leading to MMP13 suppression, involves multiple regulatory mechanisms, including PI3K/Akt and RhoA-activated ROK signaling, in addition to miRNA-mediated regulation. Elucidating these detailed molecular mechanisms may reveal novel biological activities that contribute to the therapeutic efficacy of HMW-HA against osteoarthritis. Full article
(This article belongs to the Section Cell Biology and Pathology)
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17 pages, 6313 KiB  
Article
Could CH3-M6P Be a Potential Dual-Functioning Candidate for Bone Regeneration?
by Fidan Huseynova, Cătălina Ionescu, Frederic Cuisinier, Irada Huseynova, Alamdar Mammadov and Véronique Barragan-Montero
Biomedicines 2024, 12(12), 2697; https://doi.org/10.3390/biomedicines12122697 - 26 Nov 2024
Cited by 1 | Viewed by 1148
Abstract
Background: CI-RM6P has different binding sites with affinities for both M6P and IGF2, plays a role in the regulation of the TGF-β and IGF pathways that is important for controlling cell growth and differentiation. We hypothesize that previously synthesised derivative of M6P [...] Read more.
Background: CI-RM6P has different binding sites with affinities for both M6P and IGF2, plays a role in the regulation of the TGF-β and IGF pathways that is important for controlling cell growth and differentiation. We hypothesize that previously synthesised derivative of M6P could be an alternative candidate for bone tissue regeneration in terms of higher binding affinity, stability in human serum, low cost and temporal delivery. Methods: CH3-M6P is synthesised based on previously described protocol; mesenchymal origin of isolated DPSCs was assessed by flow cytometry and AR staining prior to alkaline phosphatase (ALP) activity test, qPCR to evaluate differentiation specific marker expression, immunofluoresence, and SEM/EDS to evaluate organic and inorganic matrix formation; and rat aortic ring model to evaluate angiogenic effect of molecule. Results: CH3-M6P upregulated ALP activity, the expression of the ALP, Col1, RunX2, Mef2C, TGFβ1, TGFβ1R, TGFβ2, and Smad3 genes under osteogenic conditions. The results of immunofluorescence and SEM/EDS studies did not show enhancing effect on matrix formation. As we observed, the induction effect of CH3-M6P on the expression of angiogenic genes such as SMAD3 and TGFβ1R, even under osteogenic conditions, within the scope of research, we checked the angiogenic effect of the molecule and compared it to VEGF, showing that the CH3-M6P is really angiogenic. Conclusions: Our findings provide an important clue for the further exploration of the molecule, which can be necessary to enhance the capability of the commonly used osteomedium, possibly leading to the development of bone-forming drugs and has the potential to be a dual-functioning molecule for bone tissue engineering. Full article
(This article belongs to the Special Issue Angiogenesis)
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13 pages, 9121 KiB  
Article
PTEN Deficiency Induced by Extracellular Vesicle miRNAs from Clonorchis sinensis Potentiates Cholangiocarcinoma Development by Inhibiting Ferroptosis
by Lijia Wen, Meng Li and Jigang Yin
Int. J. Mol. Sci. 2024, 25(19), 10350; https://doi.org/10.3390/ijms251910350 - 26 Sep 2024
Viewed by 1647
Abstract
The human phosphatase and tensin homolog (PTEN) is a tumor suppressor. A slight deficiency in PTEN might cause cancer susceptibility and progression. Infection by the liver fluke Clonorchis sinensis could lead to persistent loss of PTEN in cholangiocarcinoma. However, the mechanism of PTEN [...] Read more.
The human phosphatase and tensin homolog (PTEN) is a tumor suppressor. A slight deficiency in PTEN might cause cancer susceptibility and progression. Infection by the liver fluke Clonorchis sinensis could lead to persistent loss of PTEN in cholangiocarcinoma. However, the mechanism of PTEN loss and its malignant effect on cholangiocarcinoma have not yet been elucidated. Extracellular vesicles secreted by Clonorchis sinensis (CS-EVs) are rich in microRNAs (miRNAs) and can mediate communication between hosts and parasites. Herein, we delved into the miRNAs present in CS-EVs, specifically those that potentially target PTEN and modulate the progression of cholangiocarcinoma via ferroptosis mechanisms. CS-EVs were extracted by differential ultra-centrifugation for high-throughput sequencing of miRNA. Lentiviral vectors were used to construct stably transfected cell lines. Erastin was used to construct ferroptosis induction models. Finally, 36 miRNAs were identified from CS-EVs. Among them, csi-miR-96-5p inhibited PTEN expression according to the predictions and dual luciferase assay. The CCK-8 assay, xenograft tumor assays and transwell assay showed that csi-miR-96-5p overexpression and PTEN knockout significantly increased the proliferation and migration of cholangiocarcinoma cells and co-transfection of PTEN significantly reversed the effect. In the presence of erastin, the cell proliferation and migration ability of the negative transfection control group were significantly impaired, although they did not significantly change with transfection of csi-miR-96-5p and PTEN knockout, indicating that they obtained ferroptosis resistance. Mechanistically, csi-miR-96-5p and PTEN knockout significantly inhibited ferroptosis through a decrease in ferrous ion (Fe2+) and malondialdehyde (MDA), and an increase in glutathione reductase (GSH), Solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4). In conclusion, loss of PTEN promoted the progression of cholangiocarcinoma via the ferroptosis pathway and csi-miR-96-5p delivered by CS-EVs may mediate this process. Full article
(This article belongs to the Special Issue The Molecular Basis of Extracellular Vesicles in Health and Diseases)
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20 pages, 3010 KiB  
Article
Salmonella Detection in Food Using a HEK-hTLR5 Reporter Cell-Based Sensor
by Esma Eser, Victoria A. Felton, Rishi Drolia and Arun K. Bhunia
Biosensors 2024, 14(9), 444; https://doi.org/10.3390/bios14090444 - 18 Sep 2024
Viewed by 2970
Abstract
The development of a rapid, sensitive, specific method for detecting foodborne pathogens is paramount for supplying safe food to enhance public health safety. Despite the significant improvement in pathogen detection methods, key issues are still associated with rapid methods, such as distinguishing living [...] Read more.
The development of a rapid, sensitive, specific method for detecting foodborne pathogens is paramount for supplying safe food to enhance public health safety. Despite the significant improvement in pathogen detection methods, key issues are still associated with rapid methods, such as distinguishing living cells from dead, the pathogenic potential or health risk of the analyte at the time of consumption, the detection limit, and the sample-to-result. Mammalian cell-based assays analyze pathogens’ interaction with host cells and are responsive only to live pathogens or active toxins. In this study, a human embryonic kidney (HEK293) cell line expressing Toll-Like Receptor 5 (TLR-5) and chromogenic reporter system (HEK dual hTLR5) was used for the detection of viable Salmonella in a 96-well tissue culture plate. This cell line responds to low concentrations of TLR5 agonist flagellin. Stimulation of TLR5 ligand activates nuclear factor-kB (NF-κB)—linked alkaline phosphatase (AP-1) signaling cascade inducing the production of secreted embryonic alkaline phosphatase (SEAP). With the addition of a ρ-nitrophenyl phosphate as a substrate, a colored end product representing a positive signal is quantified. The assay’s specificity was validated with the top 20 Salmonella enterica serovars and 19 non-Salmonella spp. The performance of the assay was also validated with spiked food samples. The total detection time (sample-to-result), including shortened pre-enrichment (4 h) and selective enrichment (4 h) steps with artificially inoculated outbreak-implicated food samples (chicken, peanut kernel, peanut butter, black pepper, mayonnaise, and peach), was 15 h when inoculated at 1–100 CFU/25 g sample. These results show the potential of HEK-DualTM hTLR5 cell-based functional biosensors for the rapid screening of Salmonella. Full article
(This article belongs to the Special Issue Advancements in Biosensors for Foodborne Pathogens Detection)
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17 pages, 2310 KiB  
Article
The Strong Activation of p53 Tumor Suppressor Drives the Synthesis of the Enigmatic Isoform of DUSP13 Protein
by Małgorzata Krześniak, Barbara Łasut-Szyszka, Agnieszka Będzińska, Agnieszka Gdowicz-Kłosok and Marek Rusin
Biomedicines 2024, 12(7), 1449; https://doi.org/10.3390/biomedicines12071449 - 28 Jun 2024
Viewed by 1491
Abstract
The p53 tumor suppressor protein activates various sets of genes depending on its covalent modifications, which are controlled by the nature and intensity of cellular stress. We observed that actinomycin D and nutlin-3a (A + N) collaborate in inducing activating phosphorylation of p53. [...] Read more.
The p53 tumor suppressor protein activates various sets of genes depending on its covalent modifications, which are controlled by the nature and intensity of cellular stress. We observed that actinomycin D and nutlin-3a (A + N) collaborate in inducing activating phosphorylation of p53. Our recent transcriptomic data demonstrated that these substances strongly synergize in the upregulation of DUSP13, a gene with an unusual pattern of expression, coding for obscure phosphatase having two isoforms, one expressed in the testes and the other in skeletal muscles. In cancer cells exposed to A + N, DUSP13 is expressed from an alternative promoter in the intron, resulting in the expression of an isoform named TMDP-L1. Luciferase reporter tests demonstrated that this promoter is activated by both endogenous and ectopically expressed p53. We demonstrated for the first time that mRNA expressed from this promoter actually produces the protein, which can be detected with Western blotting, in all examined cancer cell lines with wild-type p53 exposed to A + N. In some cell lines, it is also induced by clinically relevant camptothecin, by nutlin-3a acting alone, or by a combination of actinomycin D and other antagonists of p53-MDM2 interaction—idasanutlin or RG7112. This isoform, fused with green fluorescent protein, localizes in the perinuclear region of cells. Full article
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24 pages, 2336 KiB  
Review
Natural Product-Derived Compounds Targeting Keratinocytes and Molecular Pathways in Psoriasis Therapeutics
by Yu Geon Lee, Younjung Jung, Hyo-Kyoung Choi, Jae-In Lee, Tae-Gyu Lim and Jangho Lee
Int. J. Mol. Sci. 2024, 25(11), 6068; https://doi.org/10.3390/ijms25116068 - 31 May 2024
Cited by 8 | Viewed by 3102
Abstract
Psoriasis is a chronic autoimmune inflammatory skin disorder that affects approximately 2–3% of the global population due to significant genetic predisposition. It is characterized by an uncontrolled growth and differentiation of keratinocytes, leading to the formation of scaly erythematous plaques. Psoriasis extends beyond [...] Read more.
Psoriasis is a chronic autoimmune inflammatory skin disorder that affects approximately 2–3% of the global population due to significant genetic predisposition. It is characterized by an uncontrolled growth and differentiation of keratinocytes, leading to the formation of scaly erythematous plaques. Psoriasis extends beyond dermatological manifestations to impact joints and nails and is often associated with systemic disorders. Although traditional treatments provide relief, their use is limited by potential side effects and the chronic nature of the disease. This review aims to discuss the therapeutic potential of keratinocyte-targeting natural products in psoriasis and highlight their efficacy and safety in comparison with conventional treatments. This review comprehensively examines psoriasis pathogenesis within keratinocytes and the various related signaling pathways (such as JAK-STAT and NF-κB) and cytokines. It presents molecular targets such as high-mobility group box-1 (HMGB1), dual-specificity phosphatase-1 (DUSP1), and the aryl hydrocarbon receptor (AhR) for treating psoriasis. It evaluates the ability of natural compounds such as luteolin, piperine, and glycyrrhizin to modulate psoriasis-related pathways. Finally, it offers insights into alternative and sustainable treatment options with fewer side effects. Full article
(This article belongs to the Special Issue Natural Products as Multitarget Agents in Human Diseases)
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17 pages, 2365 KiB  
Review
Protein Tyrosine Phosphatase PRL-3: A Key Player in Cancer Signaling
by Haidong Liu, Xiao Li, Yin Shi, Zu Ye and Xiangdong Cheng
Biomolecules 2024, 14(3), 342; https://doi.org/10.3390/biom14030342 - 12 Mar 2024
Cited by 4 | Viewed by 3319
Abstract
Protein phosphatases are primarily responsible for dephosphorylation modification within signal transduction pathways. Phosphatase of regenerating liver-3 (PRL-3) is a dual-specific phosphatase implicated in cancer pathogenesis. Understanding PRL-3’s intricate functions and developing targeted therapies is crucial for advancing cancer treatment. This review highlights its [...] Read more.
Protein phosphatases are primarily responsible for dephosphorylation modification within signal transduction pathways. Phosphatase of regenerating liver-3 (PRL-3) is a dual-specific phosphatase implicated in cancer pathogenesis. Understanding PRL-3’s intricate functions and developing targeted therapies is crucial for advancing cancer treatment. This review highlights its regulatory mechanisms, expression patterns, and multifaceted roles in cancer progression. PRL-3’s involvement in proliferation, migration, invasion, metastasis, angiogenesis, and drug resistance is discussed. Regulatory mechanisms encompass transcriptional control, alternative splicing, and post-translational modifications. PRL-3 exhibits selective expressions in specific cancer types, making it a potential target for therapy. Despite advances in small molecule inhibitors, further research is needed for clinical application. PRL-3-zumab, a humanized antibody, shows promise in preclinical studies and clinical trials. Our review summarizes the current understanding of the cancer-related cellular function of PRL-3, its prognostic value, and the research progress of therapeutic inhibitors. Full article
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22 pages, 4060 KiB  
Article
Proteomic Signaling of Dual-Specificity Phosphatase 4 (DUSP4) in Alzheimer’s Disease
by Erming Wang, Allen L. Pan, Pritha Bagchi, Srikant Rangaraju, Nicholas T. Seyfried, Michelle E. Ehrlich, Stephen R. Salton and Bin Zhang
Biomolecules 2024, 14(1), 66; https://doi.org/10.3390/biom14010066 - 3 Jan 2024
Viewed by 3229
Abstract
DUSP4 is a member of the DUSP (dual-specificity phosphatase) subfamily that is selective to the mitogen-activated protein kinases (MAPK) and has been implicated in a range of biological processes and functions in Alzheimer’s disease (AD). In this study, we utilized the stereotactic delivery [...] Read more.
DUSP4 is a member of the DUSP (dual-specificity phosphatase) subfamily that is selective to the mitogen-activated protein kinases (MAPK) and has been implicated in a range of biological processes and functions in Alzheimer’s disease (AD). In this study, we utilized the stereotactic delivery of adeno-associated virus (AAV)-DUSP4 to overexpress DUSP4 in the dorsal hippocampus of 5xFAD and wildtype (WT) mice, then used mass spectrometry (MS)-based proteomics along with the label-free quantification to profile the proteome and phosphoproteome in the hippocampus. We identified protein expression and phosphorylation patterns modulated in 5xFAD mice and examined the sex-specific impact of DUSP4 overexpression on the 5xFAD proteome/phosphoproteome. In 5xFAD mice, a substantial number of proteins were up- or down-regulated in both male and female mice in comparison to age and sex-matched WT mice, many of which are involved in AD-related biological processes, such as activated immune response or suppressed synaptic activities. Many proteins in pathways, such as immune response were found to be suppressed in response to DUSP4 overexpression in male 5xFAD mice. In contrast, such a shift was absent in female mice. For the phosphoproteome, we detected an array of phosphorylation sites regulated in 5xFAD compared to WT and modulated via DUSP4 overexpression in each sex. Interestingly, 5xFAD- and DUSP4-associated phosphorylation changes occurred in opposite directions. Strikingly, both the 5xFAD- and DUSP4-associated phosphorylation changes were found to be mostly in neurons and play key roles in neuronal processes and synaptic functions. Site-centric pathway analysis revealed that both the 5xFAD- and DUSP4-associated phosphorylation sites were enriched for a number of kinase sets in females but only a limited number of sets of kinases in male mice. Taken together, our results suggest that male and female 5xFAD mice responded to DUSP4 overexpression via shared and sex-specific molecular mechanisms, which might underly similar reductions in amyloid pathology in both sexes while learning deficits were reduced in only females with DUSP4 overexpression. Finally, we validated our findings with the sex-specific AD-associated proteomes in human cohorts and further developed DUSP4-centric proteomic network models and signaling maps for each sex. Full article
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