Biomedicines

16 pages, 8537 KiB

Open AccessCase Report

Complex Full-Arch Treatment with Zygomatic Implants, Fully Digital Protocol with Scan Flag Intraoral Scanning, and 3D-Printed Temporary Reconstructions in a Periodontal Patient—A Case Report

by Adam Nowicki and Karolina Osypko

Biomedicines 2024, 12(11), 2617; https://doi.org/10.3390/biomedicines12112617 - 15 Nov 2024

Abstract

Background: The following case report presents the treatment of a patient with severe maxillary atrophy and failing residual dentition. The patient has been diagnosed with stage IV grade C periodontitis, making this case challenging from the very beginning. Methods: The treatment plan was [...] Read more.

Background: The following case report presents the treatment of a patient with severe maxillary atrophy and failing residual dentition. The patient has been diagnosed with stage IV grade C periodontitis, making this case challenging from the very beginning. Methods: The treatment plan was based on collecting and merging digital data: CBCT, a face scan, and an intraoral scan. Due to the advancement of the periodontal disease, the treatment was divided into three stages. The entire process was conducted in a digital manner, based on the concept of prosthetically driven implantology. Additionally, all prosthetic temporaries were planned via digital smile design. Stage I included extracting the residual dentition, placing four implants in the mandible, and the delivery of a 3D-printed upper removable denture. Stage II included placing two zygomatic implants, two anchored piriform rims, and one midline implant. Both arches were immediately loaded with the intraoral welding of abutments screwed to multiunit abutments and 3D-printed shells. Subsequently, in stage III, two milled ceramic superstructures combined with a titanium milled bar were delivered as a final screw-retained restoration with the application of scan flags (horizontal scan bodies) for intraoral scanning. Results: The aforementioned technologies can all be implemented and merged into one complex treatment plan combining high predictability, successful esthetics, and a reliable and accurate end result. Even though the concept of scan flags is relatively new, this case shows its potential and merit. Conclusions: This case represents the power of the digital approach as a helpful tool in the recreation of functional and esthetic smiles in compromised conditions in periodontal patients. Full article

(This article belongs to the Special Issue Periodontal Disease: From Pathophysiology to Novel Therapeutic Approaches)

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11 pages, 1160 KiB

Open AccessArticle

Risk Factors for Unplanned Emergency Department Visits in Patients with Nasopharyngeal Carcinoma During Radiotherapy

by Wei-Shan Chen, Chien-Lin Lee, Wei-Chih Chen, Ching-Nung Wu, Tai-Jan Chiu, Yao-Hsu Yang, Hao-Wei Lu, Sheng-Dean Luo and Yu-Ming Wang

Biomedicines 2024, 12(11), 2616; https://doi.org/10.3390/biomedicines12112616 - 15 Nov 2024

Abstract

Background/Objectives: Nasopharyngeal carcinoma (NPC) is commonly treated with radiotherapy (RT) or concurrent chemoradiotherapy (CCRT). However, unplanned emergency department (ED) visits during treatment can disrupt therapy and impact patient outcomes. This study aims to identify the risk factors associated with unplanned ED visits in [...] Read more.

Background/Objectives: Nasopharyngeal carcinoma (NPC) is commonly treated with radiotherapy (RT) or concurrent chemoradiotherapy (CCRT). However, unplanned emergency department (ED) visits during treatment can disrupt therapy and impact patient outcomes. This study aims to identify the risk factors associated with unplanned ED visits in patients with NPC receiving RT or CCRT. Methods: We retrospectively analyzed 2111 patients with NPC treated between 2001 and 2019 at Chang Gung Memorial Hospital. Patients were categorized based on whether they experienced an unplanned ED visit during or up to three months post-treatment. Demographic and clinical variables were compared using the Chi-squared test, and survival outcomes were assessed using Kaplan-Meier analysis. Results: Among the cohort, 573 patients (27.2%) experienced at least 1 unplanned ED visit. Risk factors for unplanned ED visits included older age (p < 0.001), hypertension (p < 0.001), higher Charlson Comorbidity Index (p = 0.001), and advanced clinical stage (T stage, p = 0.0046; N stage, p = 0.0034; M stage, p = 0.0008). No significant difference in ED visit rates was observed between RT alone and CCRT groups. Conclusions: Unplanned ED visits were common during NPC treatment, with risk factors primarily related to patient age, comorbidities, and disease stage. Identifying high-risk patients may enable interventions to reduce ED visits, improve survival outcomes, and alleviate healthcare costs. Full article

(This article belongs to the Special Issue Advances in Head and Neck Cancer)

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15 pages, 4108 KiB

Open AccessArticle

Humanin-G Ameliorates Hemorrhage-Induced Acute Lung Injury in Mice Through AMPKα1-Dependent and -Independent Mechanisms

by Allison M. Amman, Vivian Wolfe, Giovanna Piraino, Assem Ziady and Basilia Zingarelli

Biomedicines 2024, 12(11), 2615; https://doi.org/10.3390/biomedicines12112615 - 15 Nov 2024

Abstract

Background/Objectives: The severity of acute lung injury is significantly impacted by age and sex in patients with hemorrhagic shock. AMP-activated protein kinase (AMPK) is a crucial regulator of energy metabolism but its activity declines with aging. Humanin is a mitochondrial peptide that [...] Read more.

Background/Objectives: The severity of acute lung injury is significantly impacted by age and sex in patients with hemorrhagic shock. AMP-activated protein kinase (AMPK) is a crucial regulator of energy metabolism but its activity declines with aging. Humanin is a mitochondrial peptide that exerts cytoprotective effects in response to oxidative stressors and is associated with longevity. Using a mouse model of hemorrhagic shock that mimics the clinical condition of adult patients, we investigated whether treatment with a humanin analog, humanin-G, mitigates lung injury and whether its mechanisms of action are dependent on the catalytic AMPKα1 subunit activation. Methods: Male and female AMPKα1 wild-type (WT) and knock-out (KO) mice (8–13 months old) were subjected to hemorrhagic shock by blood withdrawal, followed by resuscitation with shed blood and lactated Ringer’s solution. The mice were treated with PEGylated humanin-G or vehicle and euthanized 3 h post-resuscitation. Results: Sex- and genotype-related differences were observed after hemorrhagic shock as lung neutrophil infiltration was more pronounced in the male AMPKα1 WT mice than the female WT mice; also, the male AMPKα1 KO mice experienced a significant decline in mean arterial blood pressure when compared to the male WT mice after resuscitation. The scores of histological lung injury were similarly elevated in all the male and female AMPKα1 WT and KO mice when compared to the control mice. At molecular analysis, acute lung injury was associated with the downregulation of AMPKα1/α2 catalytic subunits in the WT mice, whereas an increased activation of the signal transducer and activator of transcription-3 (STAT3) was observed in all the vehicle-treated groups. The in vivo administration of humanin-G ameliorated histological lung damage in all the groups of animals and ameliorated mean arterial blood pressure in the male AMPKα1 KO mice. The in vivo administration of humanin-G lowered lung neutrophil infiltration in the male and female AMPKα1 WT mice only but not in the KO mice. The beneficial results of humanin-G correlated with the lung cytosolic and nuclear activation of AMPKα in the male and female AMPKα1 WT groups, whereas STAT3 activation was not modified. Conclusions: In adult age, hemorrhage-induced acute lung injury manifests with sex-dependent characteristics. Humanin-G has therapeutic potential and the AMPKα1subunit is an important requisite for its inhibitory effects on lung leucosequestration, but not for the amelioration of lung alveolar structure or the hemodynamic effects of the peptide. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapeutics in Hemorrhagic Shock)

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15 pages, 5714 KiB

Open AccessArticle

Metabolic, Microvascular, and Structural Predictors of Long-Term Functional Changes Evaluated by Multifocal Electroretinogram in Type 1 Diabetes

by Mariacristina Parravano, Serena Fragiotta, Eliana Costanzo, Fabiana Picconi, Paola Giorno, Daniele De Geronimo, Daniela Giannini, Monica Varano, Vincenzo Parisi and Lucia Ziccardi

Biomedicines 2024, 12(11), 2614; https://doi.org/10.3390/biomedicines12112614 - 15 Nov 2024

Abstract

Background: This study aimed to analyze the potential pathogenic connection between metabolic factors, photoreceptor cell rearrangements, retinal microvascular perfusion, and functional parameters through multifocal electroretinography (mfERG) in type 1 diabetes mellitus (DM1). Methods: This prospective observational cohort study enrolled DM1 patients (40.5 ± [...] Read more.

Background: This study aimed to analyze the potential pathogenic connection between metabolic factors, photoreceptor cell rearrangements, retinal microvascular perfusion, and functional parameters through multifocal electroretinography (mfERG) in type 1 diabetes mellitus (DM1). Methods: This prospective observational cohort study enrolled DM1 patients (40.5 ± 9.1 years) with mild nonproliferative diabetic retinopathy followed for 4 years. Patients were subjected to multimodal imaging, which included color fundus photography, optical coherence tomography (OCT), OCT angiography, adaptive optics (AO), and mfERG. OCTA slabs were analyzed using ImageJ software (software version 2.3.0/1.53f) to calculate perfusion density (PD) at both superficial (SCP) and deep (DCP) capillary plexuses, as well as flow deficit percentage (FD%) at the choriocapillaris (CC). To calculate cone metrics on AO at the parafovea, including cone density (CD), linear dispersion index (LDi), and heterogeneity packing index (Hpi%) in the parafovea, the images were post-processed using a MATLAB algorithm. The mfERG P1 implicit time (IT) and N1-P1 response amplitude density (RAD) from R1 (foveal area), R2 (parafoveal area), and the unified rings R1 + R2 were evaluated. Results: A total of 22 patients (22 eyes) were enrolled. No significant differences were noted in central mfERG amplitude and implicit time-averaged values (p > 0.05, all). The main factor influencing R1 IT was HbA1c, while R1 RAD was affected by Hpi and CC FD%. R1 + R2 IT was influenced by Hpi, LDi (p > 0.001, all), and modifications in the perfusion density in the SCP (p < 0.001) and DCP (p = 0.03) at the parafovea. In contrast, R1 + R2 RAD were associated with HbA1c (p = 0.02) and Hpi (p < 0.001). Conclusions: Microvascular changes and glucometabolic factors are key elements influencing the long-term morphofunctional alterations at the photoreceptor level in DM1. Full article

(This article belongs to the Special Issue Molecular Research and Recent Advances in Diabetic Retinopathy: Second Edition)

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21 pages, 1186 KiB

Open AccessSystematic Review

Neurobiological Changes Induced by Mindfulness and Meditation: A Systematic Review

by Andrea Calderone, Desirée Latella, Federica Impellizzeri, Paolo de Pasquale, Fausto Famà, Angelo Quartarone and Rocco Salvatore Calabrò

Biomedicines 2024, 12(11), 2613; https://doi.org/10.3390/biomedicines12112613 - 15 Nov 2024

Abstract

Background and Objectives: Meditation and mindfulness, rooted in ancient traditions, enhance mental well-being by cultivating awareness and emotional control. It has been shown to induce neuroplasticity, increase cortical thickness, reduce amygdala reactivity, and improve brain connectivity and neurotransmitter levels, leading to improved emotional [...] Read more.

Background and Objectives: Meditation and mindfulness, rooted in ancient traditions, enhance mental well-being by cultivating awareness and emotional control. It has been shown to induce neuroplasticity, increase cortical thickness, reduce amygdala reactivity, and improve brain connectivity and neurotransmitter levels, leading to improved emotional regulation, cognitive function, and stress resilience. This systematic review will synthesize research on neurobiological changes associated with mindfulness and meditation practices. Materials and Methods: Studies were identified from an online search of PubMed, Web of Science, Cochrane Library, and Embase databases without any search time range. This review has been registered on Open OSF (n) GV2JY. Results: Mindfulness-Based Stress Reduction (MBSR) enhances brain regions related to emotional processing and sensory perception, improves psychological outcomes like anxiety and depression, and exhibits unique mechanisms of pain reduction compared to placebo. Conclusions: This review highlights that mindfulness, particularly through MBSR, improves emotional regulation and brain structure, reduces anxiety, and enhances stress resilience. Future research should focus on diverse populations and naturalistic settings to better understand and optimize these benefits. Full article

(This article belongs to the Section Neurobiology and Clinical Neuroscience)

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3 pages, 170 KiB

Open AccessEditorial

Trends in 3D Printing Processes for Biomedical Field: Opportunities and Challenges: An Editorial Retrospective

by M. R. Mozafari

Biomedicines 2024, 12(11), 2612; https://doi.org/10.3390/biomedicines12112612 - 15 Nov 2024

Abstract

On 8 August 1984, Chuck Hull (Charles W [...] Full article

(This article belongs to the Special Issue Trends in 3D Printing Processes for Biomedical Field: Opportunities and Challenges)

14 pages, 1570 KiB

Open AccessReview

The Notable Role of Telomere Length Maintenance in Complex Diseases

by Jiahui Lv, Xinmiao Zhao, Linjie Zhao, Chengjun Gong, Wanjie Zheng, Li Guo, Jun Wang and Tingming Liang

Biomedicines 2024, 12(11), 2611; https://doi.org/10.3390/biomedicines12112611 - 15 Nov 2024

Abstract

Telomere length function serves as a critical biomarker for biological aging and overall health. Its maintenance is linked to cancer, neurodegenerative conditions, and reproductive health. This review mainly examines genetic variations and environmental influences on telomere dynamics, highlighting key regulatory genes and mechanisms. [...] Read more.

Telomere length function serves as a critical biomarker for biological aging and overall health. Its maintenance is linked to cancer, neurodegenerative conditions, and reproductive health. This review mainly examines genetic variations and environmental influences on telomere dynamics, highlighting key regulatory genes and mechanisms. Advances in telomere measurement methodologies are also reviewed, underscoring the importance of precise telomere assessment for disease prevention and treatment. Telomerase activation offers potential for cellular lifespan extension and anti-aging effects, whereas its inhibition emerges as a promising therapeutic approach for cancer. Regulatory mechanisms of tumor suppressor genes on telomerase activity are analyzed, with a comprehensive overview of the current state and future potential of telomerase inhibitors. In addition, the association between telomeres and neurodegenerative diseases is discussed, detailing how telomere attrition heightens disease risk and outlining multiple pathways by which telomerase protects neurons from damage and apoptosis. Full article

(This article belongs to the Special Issue Telomere Biology in Human Health, Aging and Diseases)

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2 pages, 931 KiB

Open AccessCorrection

Correction: Sharma et al. Modulation of Renal Injury by Variable Expression of Myo-Inositol Oxygenase (MIOX) via Perturbation in Metabolic Sensors. Biomedicines 2020, 8, 217

by Isha Sharma, Fei Deng and Yashpal S. Kanwar

Biomedicines 2024, 12(11), 2610; https://doi.org/10.3390/biomedicines12112610 - 15 Nov 2024

Abstract

In the original publication [...] Full article

(This article belongs to the Special Issue Regenerative Medicine in Diabetes)

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6 pages, 2733 KiB

Open AccessCorrection

Correction: Chen et al. Heteronemin Suppresses Lymphangiogenesis Through ARF-1 and MMP-9/VE-Cadherin/Vimentin. Biomedicines 2021, 9, 1109

by Hsien-Lin Chen, Yu-Chieh Su, Huang-Chi Chen, Jui-Hsin Su, Chang-Yi Wu, Shih-Wei Wang, In-Pin Lin, Chung-Yi Chen and Chien-Hsing Lee

Biomedicines 2024, 12(11), 2609; https://doi.org/10.3390/biomedicines12112609 - 15 Nov 2024

Abstract

Error in Affiliation [...] Full article

(This article belongs to the Special Issue Biomedicine from the Sea)

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13 pages, 3002 KiB

Open AccessArticle

Alterations in the Levels of Urinary Exosomal MicroRNA-183-5p and MicroRNA-125a-5p in Individuals with Type 2 Diabetes Mellitus

by Yixuan Fang, Shiyi Sun, Jing Wu, Guanjian Liu, Qinqin Wu and Xingwu Ran

Biomedicines 2024, 12(11), 2608; https://doi.org/10.3390/biomedicines12112608 - 14 Nov 2024

Abstract

Background: Type 2 diabetes mellitus (T2DM) is a metabolic disorder, and urinary exosomal microRNAs (miRNAs) were utilized as potential disease prediction or diagnostic biomarkers in numerous studies. This study investigated the differential expression of urinary exosomal miRNAs between non-diabetes mellitus (NDM) individuals and [...] Read more.

Background: Type 2 diabetes mellitus (T2DM) is a metabolic disorder, and urinary exosomal microRNAs (miRNAs) were utilized as potential disease prediction or diagnostic biomarkers in numerous studies. This study investigated the differential expression of urinary exosomal miRNAs between non-diabetes mellitus (NDM) individuals and those with T2DM. Aim: To elucidate the association between urinary exosomal miRNAs and T2DM. Methods: We recruited patients diagnosed with T2DM and NDM individuals in West China Hospital, Sichuan University, from November 2023 to February 2024. Subsequently, we performed sequencing of urinary exosomal microRNAs in both groups. The obtained sequencing results were further validated using RT-qPCR in both the training set and the validation set. Additionally, we conducted logistic regression analysis and Spearman correlation analysis on miRNAs with significant differential expression, as well as analysis of their biological functions. Results: A total of 118 urine samples were collected, 59 from individuals diagnosed with T2DM and 59 from NDM. There were differentially expressed miR-183-5p (p = 0.034) and miR-125a-5p (p = 0.008) between the two groups. Furthermore, multivariate regression analysis demonstrated that higher miR-125a-5p levels were negatively associated with the risk of T2DM (p = 0.044; OR: 0.046; 95% CI: 0.002, 0.922). Bioinformatics analysis indicated that the target genes of miR-183-5p were predominantly involved in insulin signaling and glucose transport processes, while those target genes of miR-125a-5p primarily mediated autophagy. Conclusions: miR-183-5p and miR-125a-5p might be involved in the pathogenesis of T2DM, while higher urinary exosomal miR-125a-5p was negatively associated with the risk of T2DM. Full article

(This article belongs to the Section Endocrinology and Metabolism Research)

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15 pages, 2164 KiB

Open AccessArticle

Rhabdomyolysis After Prolonged Tourniquet Application Is Associated with Reversible Acute Kidney Injury (AKI) in Rats

by Thomas J. Walters, Luciana N. Torres, Kathy L. Ryan, Robert V. Hainline, Stephanie M. Lipiec, Ijeoma E. Obi, Jennifer Ybarra, Casey E. Niland and Lusha Xiang

Biomedicines 2024, 12(11), 2607; https://doi.org/10.3390/biomedicines12112607 - 14 Nov 2024

Abstract

Extremity trauma, including ischemia (e.g., prolonged tourniquet application or crush), is common among battlefield injuries. Injured muscle releases toxins leading to rhabdomyolysis and, potentially, acute kidney injury (AKI). The goal of this study was to characterize sequelae of ischemic extremity injury over 72 [...] Read more.

Extremity trauma, including ischemia (e.g., prolonged tourniquet application or crush), is common among battlefield injuries. Injured muscle releases toxins leading to rhabdomyolysis and, potentially, acute kidney injury (AKI). The goal of this study was to characterize sequelae of ischemic extremity injury over 72 h, focusing on time courses of rhabdomyolysis and AKI. Male Sprague Dawley rats were placed into two groups. Ischemic injury was produced in anesthetized rats using bilateral tourniquets (TK; n = 10) for 5 h; control (CON; n = 9) rats were treated identically without TK application. Indicators of rhabdomyolysis and renal function were measured in conscious rats 1 day preinjury (baseline, BL) and then at 1.5, 24, 48, and 72 h post-TK release. Prolonged TK application produced necrosis in both muscle and bone marrow but not in kidney. The wet/dry weights indicated edema in injured limbs at 72 h (4.1 (0.5) (TK) vs. 2.9 (0.1) (CON); p < 0.001). TK rats exhibited a 100-fold increase in creatine kinase activity compared to CON at 1.5 h (20,040 (7265) U/L vs. 195 (86) U/L (mean (SD); p < 0.0001). TK decreased the mean glomerular filtration rate (GFR; p < 0.001) at 1.5 h, but these values recovered by 24 h in concert with elevated urinary flow and alkalinization. Prolonged ischemic extremity injury therefore produced severe rhabdomyolysis without irreversible renal damage. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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10 pages, 4416 KiB

Open AccessBrief Report

Identification of Contactin-1 as a Potential Biomarker and Therapeutic Target in Neuroblastoma

by Christa N. Grant, Carson A. Wills, Xiaoming Liu, Longgui Chen, Zhenqiu Liu and Hong-Gang Wang

Biomedicines 2024, 12(11), 2606; https://doi.org/10.3390/biomedicines12112606 - 14 Nov 2024

Abstract

Background: Neuroblastoma is a common pediatric solid tumor with poor outcomes in high-risk patients. The identification of new therapeutic biomarkers is critical for the treatment of disease. Methods: An analysis of large publicly available datasets of tumor gene expression was performed. In vivo [...] Read more.

Background: Neuroblastoma is a common pediatric solid tumor with poor outcomes in high-risk patients. The identification of new therapeutic biomarkers is critical for the treatment of disease. Methods: An analysis of large publicly available datasets of tumor gene expression was performed. In vivo studies were performed to elucidate the role of contactin-1 (CNTN1) in tumor progression. Results: Expression of the glycoprotein CNTN1 is elevated in neuroblastoma compared to other tumor types. CNTN1 expression is higher in stage 1 and non-MYCN-amplified tumors, compared to more aggressive stage 4 and MYCN-amplified tumors. Moreover, high CNTN1 expression is associated with increased overall survival in neuroblastoma patients. In vivo studies demonstrate reduced metastasis in mice xenografted with CNTN1 knockout tumors compared to wildtype. Conclusions: The results of this study suggest that CNTN1 is a potential biomarker and therapeutic target in neuroblastoma. Further investigation of CNTN1 could have significant clinical implications for improving neuroblastoma treatment. Full article

(This article belongs to the Section Cell Biology and Pathology)

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11 pages, 590 KiB

Open AccessArticle

Osteopontin and Clinical Outcomes in Hemodialysis Patients

by Claudia Torino, Federico Carbone, Patrizia Pizzini, Sabrina Mezzatesta, Graziella D’Arrigo, Mercedes Gori, Luca Liberale, Margherita Moriero, Cristina Michelauz, Federica Frè, Simone Isoppo, Aurora Gavoci, Federica La Rosa, Alessandro Scuricini, Amedeo Tirandi, Davide Ramoni, Francesca Mallamaci, Giovanni Tripepi, Fabrizio Montecucco and Carmine Zoccali

Biomedicines 2024, 12(11), 2605; https://doi.org/10.3390/biomedicines12112605 - 14 Nov 2024

Abstract

Background/Objectives: Chronic kidney disease (CKD) and end-stage kidney disease (ESKD) are significant public health issues, with cardiovascular morbidity and mortality being the leading causes of death in hemodialysis patients. Osteopontin (OPN), a multifunctional glycoprotein, has emerged as a potential biomarker for vascular disease [...] Read more.

Background/Objectives: Chronic kidney disease (CKD) and end-stage kidney disease (ESKD) are significant public health issues, with cardiovascular morbidity and mortality being the leading causes of death in hemodialysis patients. Osteopontin (OPN), a multifunctional glycoprotein, has emerged as a potential biomarker for vascular disease in CKD due to its role in inflammation, tissue remodeling, and calcification. Methods: This cohort study included 1124 hemodialysis patients from the PROGREDIRE study, a registry involving 35 dialysis units in Southern Italy. Serum osteopontin levels were measured using enzyme-linked immunosorbent assay (ELISA). The primary endpoints were all-cause and cardiovascular mortality. Multivariate Cox regression analyses were performed to assess the association between osteopontin levels and mortality, adjusting for traditional risk factors, biomarkers of inflammation, nutritional status, and ESKD-related factors. Results: During a mean follow-up of 2.8 years, 478 patients died, 271 from cardiovascular causes. Independent correlates of osteopontin included alkaline phosphatase and parathyroid hormone. Elevated osteopontin levels were significantly associated with increased all-cause mortality (HR 1.19, 95% CI 1.09–1.31, p < 0.001) and cardiovascular mortality (HR 1.22, 95% CI 1.08–1.38, p = 0.001) after adjusting for confounders. Conclusions: Elevated osteopontin levels are associated with increased all-cause and cardiovascular mortality in hemodialysis patients. These findings implicate osteopontin in the high risk for death and cardiovascular disease in the hemodialysis population. Intervention studies are needed to definitively test this hypothesis. Full article

(This article belongs to the Special Issue Emerging Trends in Kidney Disease)

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11 pages, 2151 KiB

Open AccessArticle

mTOR Inhibitors Modulate the Biological Nature of TGF-β2-Treated or -Untreated Human Trabecular Meshwork Cells in Different Manners

by Megumi Watanabe, Tatsuya Sato, Toshiyuki Yano, Megumi Higashide, Toshifumi Ogawa, Nami Nishikiori, Masato Furuhashi and Hiroshi Ohguro

Biomedicines 2024, 12(11), 2604; https://doi.org/10.3390/biomedicines12112604 - 14 Nov 2024

Abstract

Background/Objectives: Mammalian target of rapamycin (mTOR) inhibition may have been suggested to have a beneficial effect on the glaucomatous human trabecular meshwork (HTM). To study the effects of the mTOR inhibitors rapamycin (Rapa) and Torin1 on the glaucomatous HTM, transforming growth factor-β2 (TGF-β2)-treated [...] Read more.

Background/Objectives: Mammalian target of rapamycin (mTOR) inhibition may have been suggested to have a beneficial effect on the glaucomatous human trabecular meshwork (HTM). To study the effects of the mTOR inhibitors rapamycin (Rapa) and Torin1 on the glaucomatous HTM, transforming growth factor-β2 (TGF-β2)-treated two-dimensionally (2D) and three-dimensionally (3D) cultured HTM cells were used. Methods: We evaluated (1) the levels of autophagy via Western blot analysis using a specific antibody against microtubule-associated protein 1 light chain 3 (LC3), (2) barrier capacity based on transepithelial electrical resistance (TEER) and fluorescein isothiocyanate (FITC) permeability (2D), (3) cellular metabolic functions (2D), (4) the size and stiffness of spheroids, and (5) the mRNA expression of ECM proteins. Results: TGF-β2-induced inhibition of autophagy was significantly inhibited by Rapa and Torin1. Rapa and Torin1 substantially decreased barrier capacity in both TGF-β2-untreated and TGF-β2-treated HTM cells. Cellular metabolic analysis indicated that Rapa, but not Torin1, substantially enhanced both mitochondrial and glycolytic functions of TGF-β2-untreated HTM cells. In the physical properties of spheroids, TGF-β2 resulted in the formation of down-sized and stiffened spheroids. mTOR inhibitors decreased the size but not the stiffness of TGF-β2-untreated spheroids and significantly reduced the TGF-β2-related increase in the stiffness but not the size of spheroids. The diverse effects of mTOR inhibitors on TGF-β2-untreated and TGF-β2-treated spheroids were also observed in the mRNA expression of extracellular matrix proteins. Conclusions: The results taken together suggest that mTOR inhibitors significantly influence the biological aspects of both a single layer and multiple layers of the TGF-β2-treated HTM and untreated HTM. Full article

(This article belongs to the Section Cell Biology and Pathology)

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27 pages, 2212 KiB

Open AccessArticle

C11orf58 (Hero20) Gene Polymorphism: Contribution to Ischemic Stroke Risk and Interactions with Other Heat-Resistant Obscure Chaperones

by Irina Shilenok, Ksenia Kobzeva, Vladislav Soldatov, Alexey Deykin and Olga Bushueva

Biomedicines 2024, 12(11), 2603; https://doi.org/10.3390/biomedicines12112603 - 14 Nov 2024

Abstract

Background: Recently identified Hero proteins, which possess chaperone-like functions, are promising candidates for research into atherosclerosis-related diseases, including ischemic stroke (IS). Methods: 2204 Russian subjects (917 IS patients and 1287 controls) were genotyped for fifteen common SNPs in Hero20 gene C11orf58 [...] Read more.

Background: Recently identified Hero proteins, which possess chaperone-like functions, are promising candidates for research into atherosclerosis-related diseases, including ischemic stroke (IS). Methods: 2204 Russian subjects (917 IS patients and 1287 controls) were genotyped for fifteen common SNPs in Hero20 gene C11orf58 using probe-based PCR and the MassArray-4 system. Results: Six C11orf58 SNPs were significantly associated with an increased risk of IS in the overall group (OG) and significantly modified by smoking (SMK) and low fruit/vegetable intake (LFVI): rs10766342 (effect allele (EA) A; P(_OG = 0.02; _SMK = 0.009; _LFVI = 0.04)), rs11024032 (EA T; P(_OG = 0.01; _SMK = 0.01; _LFVI = 0.036)), rs11826990 (EA G; P(_OG = 0.007; _SMK = 0.004; _LFVI = 0.03)), rs3203295 (EA C; P(_OG = 0.016; _SMK = 0.01; _LFVI = 0.04)), rs10832676 (EA G; P(_OG = 0.006; _SMK = 0.002; _LFVI = 0.01)), rs4757429 (EA T; P(_OG = 0.02; _SMK = 0.04; _LFVI = 0.04)). The top ten intergenic interactions of Hero genes (two-, three-, and four-locus models) involved exclusively polymorphic loci of C11orf58 and C19orf53 and were characterized by synergic and additive (independent) effects between SNPs. Conclusions: Thus, C11orf58 gene polymorphism represents a major risk factor for IS. Bioinformatic analysis showed the involvement of C11orf58 SNPs in molecular mechanisms of IS mediated by their role in the regulation of redox homeostasis, inflammation, vascular remodeling, apoptosis, vasculogenesis, neurogenesis, lipid metabolism, proteostasis, hypoxia, cell signaling, and stress response. In terms of intergenic interactions, C11orf58 interacts most closely with C19orf53. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of CVD: Focus on Atherosclerosis (Volume II))

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10 pages, 2767 KiB

Open AccessArticle

Uricase-Expressing Engineered Macrophages Alleviate Murine Hyperuricemia

by Yu-Zhong Feng, Hao Cheng, Guo-Qing Xiong, Jia-Zhen Cui, Zhi-Li Chen, Yuan-Yuan Lu, Zhi-Xin Meng, Chen Zhu, Hao-Long Dong, Xiang-Hua Xiong, Gang Liu, Qing-Yang Wang and Hui-Peng Chen

Biomedicines 2024, 12(11), 2602; https://doi.org/10.3390/biomedicines12112602 - 14 Nov 2024

Abstract

Background: Uricase, or urate oxidase (Uox) is a key enzyme in uric acid (UA) metabolism and has been applied in clinical treatment of human hyperuricemia (HUA). However, the current clinically applied uricases, despite their potent urate-lowering capacity, tend to form anti-drug antibodies [...] Read more.

Background: Uricase, or urate oxidase (Uox) is a key enzyme in uric acid (UA) metabolism and has been applied in clinical treatment of human hyperuricemia (HUA). However, the current clinically applied uricases, despite their potent urate-lowering capacity, tend to form anti-drug antibodies because of their immunogenicity, leading to increased risk of anaphylaxis, faster drug clearance and reduced or even complete loss of therapeutic effect, limiting their clinical application. In this study, we constructed engineered macrophages that stably expressed uricase, which might serve as a promising alternative to the direct injection of uricases. Materials and Methods: Engineered macrophages RAW264.7 cells were injected intravenously to treat hyperuricemic KM mice. Serum uric acid and bio-indicators for renal and hepatic functions were detected by an automatic biochemical analyzer; inflammatory cytokines were determined by ELISA; the livers and kidneys of the mice were sectioned for histological examination. Results: The uricase-expressing macrophages reduced UA levels from 300 ± 1.5 μmol/L to 101 ± 8.3 μmol/L in vitro. And in an HUA mouse model established by gavage with yeast extract, intravenous injection of the engineered macrophages could reduce the serum uric acid (sUA) of mice to normal level on the 14th day of modeling, with a decrease of 48.6%, and the urate-lowering effect was comparable to that of the first-line clinical drug allopurinol. In terms of safety, engineered macrophages did not cause liver or kidney dysfunction in mice, nor did they induce systemic immune response. Conclusions: Using macrophages as a chassis to deliver uricase might be a new, safe and effective strategy for the treatment and control of hyperuricemia. Full article

(This article belongs to the Section Cell Biology and Pathology)

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22 pages, 5579 KiB

Open AccessArticle

Adipocyte-Mediated Electrophysiological Remodeling of PKP-2 Mutant Human Pluripotent Stem Cell-Derived Cardiomyocytes

by Justin Morrissette-McAlmon, Christianne J. Chua, Alexander Arking, Stanley Chun Ming Wu, Roald Teuben, Elaine Zhelan Chen, Leslie Tung and Kenneth R. Boheler

Biomedicines 2024, 12(11), 2601; https://doi.org/10.3390/biomedicines12112601 - 14 Nov 2024

Abstract

Background: Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder responsible for nearly a quarter of sports-related sudden cardiac deaths. ACM cases caused by mutations in desmosome proteins lead to right ventricular enlargement, the loss of cardiomyocytes, and fibrofatty tissue replacement, disrupting electrical and mechanical [...] Read more.

Background: Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder responsible for nearly a quarter of sports-related sudden cardiac deaths. ACM cases caused by mutations in desmosome proteins lead to right ventricular enlargement, the loss of cardiomyocytes, and fibrofatty tissue replacement, disrupting electrical and mechanical stability. It is currently unknown how paracrine factors secreted by infiltrating fatty tissues affect ACM cardiomyocyte electrophysiology. Methods: A normal and a PKP2 mutant (c.971_972InsT) ACM hiPSC line were cultivated and differentiated into cardiomyocytes (CMs). Adipocytes were differentiated from human adipose stem cells, and adipocyte conditioned medium (AdCM) was collected. Optical mapping and phenotypic analyses were conducted on human iPSC-cardiomyocytes (hiPSC-CMs) cultured in cardiac maintenance medium (CMM) and either with AdCM or specific cytokines. Results: Significant differences were observed in voltage parameters such as the action potential duration (APD₈₀, APD₃₀), conduction velocity (CV), and CV heterogeneity. When cultured in AdCM relative to CMM, the APD₈₀ increased and the CV decreased significantly in both groups; however, the magnitudes of changes often differed significantly between 1 and 7 days of cultivation. Cytokine exposure (IL-6, IL-8, MCP-1, CFD) affected the APD and CV in both the normal and PKP2 mutant hiPSC-CMs, with opposite effects. NF-kB signaling was also found to differ between the normal and PKP2 mutant hiPSC-CMs in response to AdCM and IL-6. Conclusions: Our study shows that hiPSC-CMs from normal and mPKP2 ACM lines exhibit distinct molecular and functional responses to paracrine factors, with differences in RNA expression and electrophysiology. These different responses to paracrine factors may contribute to arrhythmogenic propensity. Full article

(This article belongs to the Special Issue Advanced Research in Arrhythmogenic Cardiomyopathy)

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16 pages, 2244 KiB

Open AccessArticle

Rituximab Administration to Treat Nephrotic Syndrome in Children: 2-Year Follow-Up

by Dmytro Ivanov, Lutz T. Weber, Elena Levtchenko, Liudmyla Vakulenko, Mariia Ivanova, Iryna Zavalna, Yelizaveta Lagodych and Ninel Boiko

Biomedicines 2024, 12(11), 2600; https://doi.org/10.3390/biomedicines12112600 - 13 Nov 2024

Abstract

Background: Steroid-sensitive nephrotic syndrome (SSNS) and steroid-resistant nephrotic syndrome (SRNS) significantly affect children’s quality of life. There are frequent relapses in SSNS and progression in SRNS. IPNA guidelines suggest that monoclonal antibodies like rituximab (RTX) are promising treatments. Objective: This study aims to [...] Read more.

Background: Steroid-sensitive nephrotic syndrome (SSNS) and steroid-resistant nephrotic syndrome (SRNS) significantly affect children’s quality of life. There are frequent relapses in SSNS and progression in SRNS. IPNA guidelines suggest that monoclonal antibodies like rituximab (RTX) are promising treatments. Objective: This study aims to evaluate the long-term efficacy and safety of rituximab administration in children with SSNS, encompassing FRNS and SDNS, and SRNS over a two-year follow-up period, facilitating individualized management. Methods: We conducted an open-label, multicenter, randomized, and patient-oriented study (RICHNESS), involving children aged 3–18 with SRNS (18) and SSNS (11) undergoing 2 years continuous RTX therapy. The primary outcome was complete/partial remission (CR/PR), as defined by IPNA/KDIGO guidelines, at 6, 12, 18, and 24 months on RTX; secondary outcomes included adverse events. Key endpoints included the estimated glomerular filtration rate (eGFR), the albumin-to-creatinine ratio (ACR), CD20 levels, IgG levels, and the incidence of infections. Kidney biopsies were performed in 94% of SRNS patients. RTX was administered every 6–9 months, depending on CD20 levels, IgG levels, and the presence of infections. The eGFR and ACR were assessed every 6 months. Results: Some 31 children were selected for RTX treatment. Overall, 2 experienced severe allergic reactions, leading to their exclusion from the final analysis of 29 children. In the SSNS group, all children achieved and maintained complete remission within 2 years. Remission rates in the SRNS group ranged from 39% (RR 0.78; 95% CI: 16.4–61.4%, NNT 9) at the 6th month to 72% (RR 1.44; 95% CI: 51.5–92.9%) over the 2-year follow-up period due to continuous RTX therapy. The median duration of RTX use was 26.1 months, with a median cumulative dose of 1820 mg/m². Adverse reactions and complications were presented by mild infusion-related reactions in 3 children (10.3%), severe allergic reactions in 2 children (6.2%), hypogammaglobulinemia in 7 children (24%), infections in 3 children (10.3%), severe destructive pneumonia in 1 child, recurrent respiratory infections in 2 children, and neutropenia in 1 child (3.44%). Conclusions: RTX was tolerated well, and proved highly effective as a steroid-sparing agent, offering potential in terms of stopping relapses and minimizing steroid-related side effects. It also demonstrated efficacy in slowing progression in SRNS, indicating potential for use in ACR reduction and renal function restoration, but requires careful use given potential severe allergic reactions and infectious complications. Further studies should focus on long-term cost-effectiveness and deferred side effects. Full article

(This article belongs to the Section Cell Biology and Pathology)

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14 pages, 1015 KiB

Open AccessReview

Connexins and Aging-Associated Respiratory Disorders: The Role in Intercellular Communications

by Tatiana Zubareva, Ekaterina Mironova, Anna Panfilova, Yulia Krylova, Gianluigi Mazzoccoli, Maria Greta Pia Marasco, Igor Kvetnoy and Peter Yablonsky

Biomedicines 2024, 12(11), 2599; https://doi.org/10.3390/biomedicines12112599 - 13 Nov 2024

Abstract

This article reviews the contemporary understanding of the functional role of connexins in intercellular communications, their involvement in maintaining cellular and tissue homeostasis, and in aging-associated respiratory disease pathogenesis. Connexins are discussed as potential therapeutic targets. The review particularly focuses on the involvement [...] Read more.

This article reviews the contemporary understanding of the functional role of connexins in intercellular communications, their involvement in maintaining cellular and tissue homeostasis, and in aging-associated respiratory disease pathogenesis. Connexins are discussed as potential therapeutic targets. The review particularly focuses on the involvement of gap junction connexins and hemichannels in the transfer of calcium ions, metabolite molecules, ATP, and mitochondria through the cell membrane. Various disorders in the regulation of intercellular communication can heavily contribute to the pathogenesis of multiple diseases, including respiratory system diseases. A deeper understanding of molecular mechanisms underlying the activities of various connexins in gap junction channels will enable the prospective development of therapeutic approaches by either inhibiting or stimulating the activities of a certain connexin, while considering its critical functions in intercellular communications on the whole. Full article

(This article belongs to the Special Issue Cellular Senescence in Age-Related Diseases: Pathophysiology and Therapeutic Approaches)

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