Biomedicines

12 pages, 11253 KiB

Open AccessArticle

Fluctuations in Medium Viscosity May Affect the Stability of the CAG Tract in the ATXN2 Gene

by Anna Dorohova, Oksana Lyasota, Stepan Dzhimak, Alexandr Svidlov, Olga Leontyeva and Mikhail Drobotenko

Biomedicines 2024, 12(10), 2396; https://doi.org/10.3390/biomedicines12102396 (registering DOI) - 19 Oct 2024

Abstract

Background: Trinucleotide repeats are the cause of many neurodegenerative diseases that are currently incurable. In this regard, the question of the causes of occurrence and methods of prevention or treatment of diseases caused by the expansion of repeats in the CAG tract of [...] Read more.

Background: Trinucleotide repeats are the cause of many neurodegenerative diseases that are currently incurable. In this regard, the question of the causes of occurrence and methods of prevention or treatment of diseases caused by the expansion of repeats in the CAG tract of the ATXN2 gene remains relevant. Previously, it was shown that the frequency of occurrence of additional OS (open states) zones increases with increasing length of the CAG tract, and the value inverse to the frequency correlates with the age of disease onset. Methods: In this work, the influence of the viscosity of the medium and the external torque on the stability of the CAG tract in the ATXN2 gene was studied using mathematical modeling methods. Results: It has been established that the probability of the appearance of additional OS zones of significant size increases with an increase in the CAG of the tract (k > 40 CAG repeats) for all viscosity values, however, at k ≤ 40, the change in viscosity does not significantly affect the probability of additional OS zones in the tract. Conclusions: It was found that under normal conditions (absence of pathology), viscosity does not have a reliable effect on the stability of the DNA molecule, but when pathology appears, an increase in viscosity contributes to an increase in DNA stability, and, accordingly, a decrease has a negative effect on the stabilization of the DNA molecule. In the zone of close to incomplete penetrance of the disease, viscosity does not have a reliable effect on the stability of the CAG tract. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: From Mechanisms to Therapeutic Approaches)

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10 pages, 2090 KiB

Open AccessArticle

The Clinical and Sonographic Features of Cervical Muscle Involvement in Patients with Frozen Shoulder: A Retrospective Study

by Alice Chu-Wen Tang, Shih-Ting Huang, Szu-Yuan Wu and Simon Fuk-Tan Tang

Biomedicines 2024, 12(10), 2395; https://doi.org/10.3390/biomedicines12102395 (registering DOI) - 19 Oct 2024

Abstract

Background/Objectives: Frozen shoulder is a common shoulder disorder that often places limitations on the range of motion of the shoulder. The disease may induce neck pain due to overuse of the neck muscle in an attempt to compensate for lack of shoulder [...] Read more.

Background/Objectives: Frozen shoulder is a common shoulder disorder that often places limitations on the range of motion of the shoulder. The disease may induce neck pain due to overuse of the neck muscle in an attempt to compensate for lack of shoulder movement. In clinical practice, swelling and inflammation of the scalene and levator scapulae may be detected via sonography in patients with frozen shoulder. The aim of this study was, therefore, to determine whether the involvement of the scalene complex or levator scapulae could compensate for the limited motion of the shoulder in patients with frozen shoulder. Methods: We retrospectively reviewed the medical records of 362 patients with unilateral frozen shoulder. These patients were divided into four groups depending on the involvement of the scalene complex or levator scapulae muscle. The range of motion of the shoulder—encompassing flexion, abduction, and external rotation—was measured with a goniometer. We also performed an ultrasound scan on each shoulder. The involvement of the scalene complex and levator scapulae muscle was also assessed via musculoskeletal ultrasound. Results: The range of motion of the shoulder in terms of flexion, abduction, external rotation, and total range of motion differed significantly between the four groups (p < 0.05). Patients in whom the scalene complex or levator scapulae muscle was involved demonstrated a significantly wider range of motion in different shoulder directions than patients without the involvement of those muscles (p < 0.05). Conclusions: A greater range of motion in the shoulder can be obtained through the activation of the scalene complex or levator scapulae muscle, which act to compensate for the lack of shoulder movement in patients with frozen shoulder. These two muscles showed thickening and hypoechoic changes upon sonography. Full article

(This article belongs to the Special Issue Bone Regeneration, Osteoclastogenesis, Osteoporosis and Osteoarthritis)

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21 pages, 18578 KiB

Open AccessArticle

ABCG2 Gene Expression in Non-Small Cell Lung Cancer

by Agnieszka Jeleń, Marta Żebrowska-Nawrocka, Mariusz Łochowski, Dagmara Szmajda-Krygier and Ewa Balcerczak

Biomedicines 2024, 12(10), 2394; https://doi.org/10.3390/biomedicines12102394 (registering DOI) - 19 Oct 2024

Abstract

Background/Objectives: ATP-binding cassette subfamily G member 2 [ABCG2/breast cancer resistance protein (BCRP)] contributes to mechanisms of multidrug resistance (MDR) and is a marker of side population (SP) cells in human cancers. The primary objective of this study was to investigate the impact of [...] Read more.

Background/Objectives: ATP-binding cassette subfamily G member 2 [ABCG2/breast cancer resistance protein (BCRP)] contributes to mechanisms of multidrug resistance (MDR) and is a marker of side population (SP) cells in human cancers. The primary objective of this study was to investigate the impact of ABCG2 gene expression on the non-small cell lung cancer (NSCLC) development, course of cancer disease, and patient prognosis using publicly available data. Obtained results were supplemented with assessment of ABCG2 expression in blood of NSCLC patients. Methods: The dataset of lung cancer was analyzed utilizing the TIMER 2.0, UALCAN, TNMplot, MEXPRESS, cBioPortal, MethSurv, KM Plotter, STRING, and ShinyGO 0.80 databases. Blood samples from 50 patients were assessed using the real-time PCR method. Results: The ABCG2 gene was expressed at a low level in NSCLC, and did not correlate with clinical aggressiveness of lung cancer. Higher ABCG2 expression improved overall survival, but only in LUAD. In addition, CpG sites located on the CpG island affecting the NSCLC patient’s prognosis were indicated. In the case of our own laboratory results, the study did not reveal any changes in the ABCG2 expression levels in blood collected from patients at different time points during the diagnostic–therapeutic procedure. In the in silico analysis, most ABCG2 protein interactors were associated with the development of drug resistance. Conclusions: ABCG2 appears to have a particularly significant impact on the survival of patients with lung cancer and on the effect of immunotherapy related to immune cell infiltration. Presented findings may support personalized medicine strategies based on bioinformatics findings. Full article

(This article belongs to the Special Issue Molecular Biomarkers of Tumors: Advancing Genetic Studies)

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14 pages, 2404 KiB

Open AccessArticle

Circulating Serum Micro-RNA as Non-Invasive Diagnostic Biomarkers of Endometriosis

by Antonella Ravaggi, Cosetta Bergamaschi, Chiara Galbiati, Laura Zanotti, Aline S. C. Fabricio, Massimo Gion, Elia Cappelletto, Antonette E. Leon, Massimo Gennarelli, Cesare Romagnolo, Giuseppe Ciravolo, Stefano Calza, Eliana Bignotti and Franco Odicino

Biomedicines 2024, 12(10), 2393; https://doi.org/10.3390/biomedicines12102393 (registering DOI) - 19 Oct 2024

Abstract

Background/Objectives: Endometriosis (END) is a painful gynecological condition. Clinical examination, imaging, and laparoscopy can provide a definitive diagnosis of END. Nonetheless, non-invasive biomarkers could help enhance and streamline the diagnostic process. Micro-RNAs (miRNAs), a family of small non-coding RNAs, could serve as useful [...] Read more.

Background/Objectives: Endometriosis (END) is a painful gynecological condition. Clinical examination, imaging, and laparoscopy can provide a definitive diagnosis of END. Nonetheless, non-invasive biomarkers could help enhance and streamline the diagnostic process. Micro-RNAs (miRNAs), a family of small non-coding RNAs, could serve as useful non-invasive biomarkers for END. The aim of this study was to perform serum miRNA profiling in a retrospective cohort of women to identify miRNAs that are differentially expressed in END compared to control patients. Methods: RNA was isolated from serum samples of 67 END patients and 60 control women. The expression profile of a 754-miRNA panel was studied with RT-qPCR performed on a QuantStudio 12K Flex with the TaqMan OpenArray miRNA panel. A Censored Regression Model was used for miRNA differential expression analysis. Several gene-enrichment algorithms were employed to identify pathways related to the target genes of differentially expressed miRNAs. Results: One hundred and thirty miRNAs were detected in at least 75% of samples from either the END or the control group. Sixteen miRNAs were significantly modulated between the END and control groups. Enrichment analysis identified targets significantly overrepresented in numerous pathways involved in biological processes related to END, including inflammation, angiogenesis, cellular invasion, cell-cycle/cell proliferation, and estrogen and progesterone hormonal signaling. Conclusions: Our study indicates that differentially expressed miRNAs between END patients and controls can be identified through liquid biopsy. Our findings also suggest a potential role for serum miRNAs in the pathophysiology of END, warranting further investigations for their use as non-invasive biomarkers. Full article

(This article belongs to the Special Issue Advanced Research in Endometriosis 4.0)

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13 pages, 2388 KiB

Open AccessArticle

Effects of Far-Infrared Rays Emitted from Loess Bio-Balls on Lymphatic Circulation and Reduction of Inflammatory Fluids

by Yong Il Shin, Min Seok Kim, Yeong Ae Yang, Gye Rok Jeon, Jae Ho Kim, Yeon Jin Choi, Woo Cheol Choi and Jae Hyung Kim

Biomedicines 2024, 12(10), 2392; https://doi.org/10.3390/biomedicines12102392 (registering DOI) - 19 Oct 2024

Abstract

Background: FIR therapy is used in various medical settings to treat diseases associated with inflammation and edema. Unlike conventional FIR lamp therapy, this study investigated how body fluids change depending on the intensity and duration of FIR irradiation to the whole body. [...] Read more.

Background: FIR therapy is used in various medical settings to treat diseases associated with inflammation and edema. Unlike conventional FIR lamp therapy, this study investigated how body fluids change depending on the intensity and duration of FIR irradiation to the whole body. Method: Subjects in group A (n = 27) were exposed to FIR emitted from a loess bio-ball mat set at 40 °C for 30 min, and subjects in group B (n = 27) were exposed to FIR emitted from a loess bio-ball mat set at 30 °C for 7 h during sleep. Changes in bioimpedance parameters and fluid-related values were measured using a body fluid analyzer before and after exposure to FIR. Results: Changes in bioimpedance parameters associated with inflammatory fluids were quantitatively confirmed. In group A, there was a minimal change in fluid-related measurements. However, significant changes in bioimpedance parameters associated with inflammatory fluids were observed in group B exposure to FIR for 7 h during sleep. Conclusions: FIR emitted from loess bio-balls activates biological tissues and lymphatic circulation, gradually reducing the levels of inflammatory fluids over time. Full article

(This article belongs to the Section Biomedical Engineering and Materials)

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12 pages, 647 KiB

Open AccessArticle

Hyperosmotic Stress Induces the Expression of Organic Osmolyte Transporters in Porcine Intestinal Cells and Betaine Exerts a Protective Effect on the Barrier Function

by Elena De Angelis, Paolo Borghetti, Benedetta Passeri, Valeria Cavalli, Luca Ferrari, Melania Andrani, Paolo Martelli and Roberta Saleri

Biomedicines 2024, 12(10), 2391; https://doi.org/10.3390/biomedicines12102391 (registering DOI) - 18 Oct 2024

Viewed by 210

Abstract

Background/objectives: The porcine intestinal epithelium plays a fundamental role as a defence interface against pathogens. Its alteration can cause severe inflammatory conditions and diseases. Hyperosmotic stress under physiological conditions and upon pathogen challenge can cause malabsorption. Different cell types counteract the osmolarity increase [...] Read more.

Background/objectives: The porcine intestinal epithelium plays a fundamental role as a defence interface against pathogens. Its alteration can cause severe inflammatory conditions and diseases. Hyperosmotic stress under physiological conditions and upon pathogen challenge can cause malabsorption. Different cell types counteract the osmolarity increase by accumulating organic osmolytes such as betaine, taurine, and myo-inositol through specific transporters. Betaine is known for protecting cells from hyperosmotic stress and has positive effects when fed to pigs. The aim of this study is to demonstrate the modulation of osmolyte transporters gene expression in IPEC-J2 during osmolarity changes and assess the effects of betaine. Methods: IPEC-J2 were seeded in transwells, where differentiate as a polarized monolayer. Epithelial cell integrity (TEER), oxidative stress (NO) and gene expression of osmolyte transporters, tight junction proteins (TJp) and pro-inflammatory cytokines were evaluated. Results: Cells treated with NaCl hyperosmolar medium (500 mOsm/L) showed a TEER decrease at 3 h and detachment within 24 h, associated with an osmolyte transporters reduction. IPEC-J2 treated with mannitol hyperosmolar medium (500 mOsm/L) upregulated taurine (TauT), myo-inositol (SMIT) and betaine (BGT1) transporters expression. A decrease in TJp expression was associated with a TEER decrease and an increase in TNFα, IL6, and IL8. Betaine could attenuate the hyperosmolarity-induced reduction in TEER and TJp expression, the NO increase and cytokines upregulation. Conclusions: This study demonstrates the expression of osmolyte transporters in IPEC-J2, which was upregulated upon hyperosmotic treatment. Betaine counteracts changes in intracellular osmolarity by contributing to maintaining the epithelial barrier function and reducing the inflammatory condition. Compatible osmolytes may provide beneficial effects in therapies for diseases characterized by inflammation and TJp-related dysfunctions. Full article

(This article belongs to the Special Issue The Role of Intestinal Epithelial Cells and Their Cellular Interactions)

25 pages, 2942 KiB

Open AccessReview

ABCA3 c.838C>T (p.Arg280Cys, R280C) and c.697C>T (p.Gln233Ter, Q233X, Q233*) as Causative Variants for RDS: A Family Case Study and Literature Review

by Maria Livia Ognean, Mădălina Anciuc-Crauciuc, Radu Galiș, Alex-Emilian Stepan, Mioara Desdemona Stepan, Claudia Bănescu, Florin Grosu, Boris W. Kramer and Manuela Cucerea

Biomedicines 2024, 12(10), 2390; https://doi.org/10.3390/biomedicines12102390 (registering DOI) - 18 Oct 2024

Viewed by 196

Abstract

Background: Respiratory distress syndrome (RDS) is the primary cause of respiratory failure in preterm infants, but it also affects 5–7% of term infants. Dysfunctions in pulmonary surfactant metabolism, resulting from mutations of the lung surfactant genes, are rare diseases, ranging from fatal neonatal [...] Read more.

Background: Respiratory distress syndrome (RDS) is the primary cause of respiratory failure in preterm infants, but it also affects 5–7% of term infants. Dysfunctions in pulmonary surfactant metabolism, resulting from mutations of the lung surfactant genes, are rare diseases, ranging from fatal neonatal RDS to interstitial lung disease, associated with increased morbidity and mortality. This study aims to clarify the clinical significance of ABCA3 variants found in a specific family case, as existing data in the literature are inconsistent. Material and Methods: A family case report was conducted; targeted panel genetic testing identified a variant of the SFTPB gene and two variants of ABCA3 genes. Comprehensive research involving a systematic review of PubMed, Google Scholar databases, and genome browsers was used to clarify the pathogenicity of the two ABCA3 variants found in the index patient. Advanced prediction tools were employed to assess the pathogenicity of the two ABCA3 variants, ensuring the validity and reliability of our findings. Results: The index case exhibited fatal neonatal RDS. Genetic testing revealed the presence of the SFTPB p.Val267Ile variant, which was not previously reported but is a benign variant based on family genetic testing and history. Additionally, two ABCA3 gene variants were identified: c.697C>T, not yet reported, and c.838C>T. These variants were found to affect ABCA3 protein function and were likely associated with neonatal RDS. Prediction tools and data from nine other cases in the literature supported this conclusion. Conclusions: Based on in silico predictors, an analysis of the presented family, and cases described in the literature, it is reasonable to consider reclassifying the two ABCA3 variants identified in the index case as pathogenic/pathogenic. Reclassification will improve genetic counseling accuracy and facilitate correct diagnosis. Full article

(This article belongs to the Special Issue Biomedical Advances in ABC Transporters: From Bench to Bedside)

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28 pages, 790 KiB

Open AccessReview

From Genomics to Metabolomics: Molecular Insights into Osteoporosis for Enhanced Diagnostic and Therapeutic Approaches

by Qingmei Li, Jihan Wang and Congzhe Zhao

Biomedicines 2024, 12(10), 2389; https://doi.org/10.3390/biomedicines12102389 (registering DOI) - 18 Oct 2024

Viewed by 162

Abstract

Osteoporosis (OP) is a prevalent skeletal disorder characterized by decreased bone mineral density (BMD) and increased fracture risk. The advancements in omics technologies—genomics, transcriptomics, proteomics, and metabolomics—have provided significant insights into the molecular mechanisms driving OP. These technologies offer critical perspectives on genetic [...] Read more.

Osteoporosis (OP) is a prevalent skeletal disorder characterized by decreased bone mineral density (BMD) and increased fracture risk. The advancements in omics technologies—genomics, transcriptomics, proteomics, and metabolomics—have provided significant insights into the molecular mechanisms driving OP. These technologies offer critical perspectives on genetic predispositions, gene expression regulation, protein signatures, and metabolic alterations, enabling the identification of novel biomarkers for diagnosis and therapeutic targets. This review underscores the potential of these multi-omics approaches to bridge the gap between basic research and clinical applications, paving the way for precision medicine in OP management. By integrating these technologies, researchers can contribute to improved diagnostics, preventative strategies, and treatments for patients suffering from OP and related conditions. Full article

(This article belongs to the Special Issue Molecular Research on Osteoarthritis and Osteoporosis)

17 pages, 1085 KiB

Open AccessArticle

Enhancing Brain Tumor Diagnosis with L-Net: A Novel Deep Learning Approach for MRI Image Segmentation and Classification

by Lehel Dénes-Fazakas, Levente Kovács, György Eigner and László Szilágyi

Biomedicines 2024, 12(10), 2388; https://doi.org/10.3390/biomedicines12102388 (registering DOI) - 18 Oct 2024

Viewed by 173

Abstract

Background: Brain tumors are highly complex, making their detection and classification a significant challenge in modern medical diagnostics. The accurate segmentation and classification of brain tumors from MRI images are crucial for effective treatment planning. This study aims to develop an advanced neural [...] Read more.

Background: Brain tumors are highly complex, making their detection and classification a significant challenge in modern medical diagnostics. The accurate segmentation and classification of brain tumors from MRI images are crucial for effective treatment planning. This study aims to develop an advanced neural network architecture that addresses these challenges. Methods: We propose L-net, a novel architecture combining U-net for tumor boundary segmentation and a convolutional neural network (CNN) for tumor classification. These two units are coupled such a way that the CNN classifies the MRI images based on the features extracted by the U-net while segmenting the tumor, instead of relying on the original input images. The model is trained on a dataset of 3064 high-resolution MRI images, encompassing gliomas, meningiomas, and pituitary tumors, ensuring robust performance across different tumor types. Results: L-net achieved a classification accuracy of up to 99.6%, surpassing existing models in both segmentation and classification tasks. The model demonstrated effectiveness even with lower image resolutions, making it suitable for diverse clinical settings. Conclusions: The proposed L-net model provides an accurate and unified approach to brain tumor segmentation and classification. Its enhanced performance contributes to more reliable and precise diagnosis, supporting early detection and treatment in clinical applications. Full article

(This article belongs to the Special Issue Diagnosis, Pathogenesis and Treatment of CNS Tumors)

26 pages, 840 KiB

Open AccessReview

Cognitive Impairment and Synaptic Dysfunction in Cardiovascular Disorders: The New Frontiers of the Heart–Brain Axis

by Teresa Soda, Teresa Pasqua, Giovambattista De Sarro and Francesco Moccia

Biomedicines 2024, 12(10), 2387; https://doi.org/10.3390/biomedicines12102387 (registering DOI) - 18 Oct 2024

Viewed by 103

Abstract

Within the central nervous system, synaptic plasticity, fundamental to processes like learning and memory, is largely driven by activity-dependent changes in synaptic strength. This plasticity often manifests as long-term potentiation (LTP) and long-term depression (LTD), which are bidirectional modulations of synaptic efficacy. Strong [...] Read more.

Within the central nervous system, synaptic plasticity, fundamental to processes like learning and memory, is largely driven by activity-dependent changes in synaptic strength. This plasticity often manifests as long-term potentiation (LTP) and long-term depression (LTD), which are bidirectional modulations of synaptic efficacy. Strong epidemiological and experimental evidence show that the heart–brain axis could be severely compromised by both neurological and cardiovascular disorders. Particularly, cardiovascular disorders, such as heart failure, hypertension, obesity, diabetes and insulin resistance, and arrhythmias, may lead to cognitive impairment, a condition known as cardiogenic dementia. Herein, we review the available knowledge on the synaptic and molecular mechanisms by which cardiogenic dementia may arise and describe how LTP and/or LTD induction and maintenance may be compromised in the CA1 region of the hippocampus by heart failure, metabolic syndrome, and arrhythmias. We also discuss the emerging evidence that endothelial dysfunction may contribute to directly altering hippocampal LTP by impairing the synaptically induced activation of the endothelial nitric oxide synthase. A better understanding of how CV disorders impact on the proper function of central synapses will shed novel light on the molecular underpinnings of cardiogenic dementia, thereby providing a new perspective for more specific pharmacological treatments. Full article

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

13 pages, 902 KiB

Open AccessArticle

Oral Spore-Based Probiotic Supplementation Alters Post-Prandial Expression of mRNA Associated with Gastrointestinal Health

by Brian K. McFarlin, Sarah E. Deemer and Elizabeth A. Bridgeman

Biomedicines 2024, 12(10), 2386; https://doi.org/10.3390/biomedicines12102386 (registering DOI) - 18 Oct 2024

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Abstract

Background/Objectives: Unregulated post-prandial dietary endotoxemia may accumulate over time and underlie the development of chronic disease (e.g., leaky gut, inflammatory bowel disease, etc.), for which oral probiotic supplementation may be a prophylactic. The purpose of this study was to determine if 45 [...] Read more.

Background/Objectives: Unregulated post-prandial dietary endotoxemia may accumulate over time and underlie the development of chronic disease (e.g., leaky gut, inflammatory bowel disease, etc.), for which oral probiotic supplementation may be a prophylactic. The purpose of this study was to determine if 45 d of oral spore-based probiotic supplementation altered gastrointestinal-associated mRNA expression following a high-fat meal. Methods: A subset of apparently healthy individuals from a larger study who had dietary endotoxemia at baseline completed 45 d of supplementation with either a placebo (rice flour; n = 10) or spore-based probiotic (Megasporebiotic™; Novonesis, Kongens Lyngby, Denmark; Bacillus indicus (HU36™), Bacillus subtilis (HU58™), Bacillus coagulans (SC208™), and Bacillus licheniformis (SL-307), and Bacillus clausii (SC109™); n = 10). Venous blood was collected in Paxgene RNA tubes prior to (PRE), 3 h, and 5 h after consumption of a high-fat meal (85% of the daily fat RDA and 65% of the daily calorie needs). Total RNA was analyzed for 579 mRNAs of interest (Nanostring nCounter Sprint; Seattle, WA, USA). After normalization to housekeeping controls and calculation of differential expression relative to PRE and controlled for FDR, 15 mRNAs were determined to be significantly changed at either 3 h and/or 5 h post-prandial in the probiotic group but not in the placebo group. Results: Significant mRNA expressions were associated with gastrointestinal tract barrier function (four mRNAs: BATF3, CCR6, CXCR6, and PDCD2), gastrointestinal immunity (four mRNAs: CLEC5A, IL7, CARD9, and FCER1G), or future IBD risk (seven mRNAs: PD-L1, CSF1R, FAS, BID, FADD, GATA3, and KIR3DL). Conclusions: Collectively, the present findings may support the notion that post-prandial immune response to eating is enhanced following 45 d of probiotic supplementation. Full article

(This article belongs to the Special Issue Epigenetic Regulation and Its Impact for Medicine)

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19 pages, 1159 KiB

Open AccessReview

Pheochromocytoma–Paraganglioma Syndrome: A Multiform Disease with Different Genotype and Phenotype Features

by Mara Giacché, Maria Chiara Tacchetti, Claudia Agabiti-Rosei, Francesco Torlone, Francesco Bandera, Claudia Izzi and Enrico Agabiti-Rosei

Biomedicines 2024, 12(10), 2385; https://doi.org/10.3390/biomedicines12102385 - 18 Oct 2024

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Abstract

Pheochromocytoma and paraganglioma (PPGL) are rare tumors derived from the adrenal medulla and extra-adrenal chromaffin cells. Diagnosis is often challenging due to the great variability in clinical presentation; the complexity of management due to the dangerous effects of catecholamine excess and the potentially [...] Read more.

Pheochromocytoma and paraganglioma (PPGL) are rare tumors derived from the adrenal medulla and extra-adrenal chromaffin cells. Diagnosis is often challenging due to the great variability in clinical presentation; the complexity of management due to the dangerous effects of catecholamine excess and the potentially malignant behavior require in-depth knowledge of the pathology and multidisciplinary management. Nowadays, diagnostic ability has certainly improved and guidelines and consensus documents for treatment and follow-up are available. A major impulse to the development of this knowledge has come from the new findings on the genetic and molecular characteristics of PPGLs. Germline mutation in susceptibility genes is detected in 40% of subjects, with a mutation frequency of 10–12% also in patients with sporadic presentation and genetic testing should be incorporated within clinical care. PPGL susceptibility genes include “old genes” associated with Neurofibromatosis type 1 (NF1 gene), Von Hippel Lindau syndrome (VHL gene) and Multiple Endocrine Neoplasia type 2 syndrome (RET gene), the family of SDHx genes (SDHA, SDHB, SDHC, SDHD, SDHAF2), and genes less frequently involved such as TMEM, MAX, and FH. Each gene has a different risk of relapse, malignancy, and other organ involvement; for mutation carriers, affected or asymptomatic, it is possible to define a tailored long-life surveillance program according to the gene involved. In addition, molecular characterization of the tumor has allowed the identification of somatic mutations in other driver genes, bringing to 70% the PPGLs for which we know the mechanisms of tumorigenesis. This has expanded the catalog of tumor driver genes, which are identifiable in up to 70% of patients Integrated genomic and transcriptomic data over the last 10 years have revealed three distinct major molecular signatures, triggered by pathogenic variants in susceptibility genes and characterized by the activation of a specific oncogenic signaling: the pseudo hypoxic, the kinase, and the Wnt signaling pathways. These molecular clusters show a different biochemical phenotype and clinical behavior; they may also represent the prerequisite for implementing customized therapy and follow-up. Full article

(This article belongs to the Special Issue Adrenal Diseases: An Update)

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9 pages, 914 KiB

Open AccessArticle

The Relationship Between MOTS-c K14Q Polymorphism and Sarcopenia, Blood Lipids, and Mental Health in Older Korean Adults

by Shinuk Kim

Biomedicines 2024, 12(10), 2384; https://doi.org/10.3390/biomedicines12102384 - 18 Oct 2024

Viewed by 223

Abstract

Background/objectives: An East Asian-specific 1382A>C polymorphism in the mitochondrial open reading frame of the 12S rRNA type-c results in an amino acid substitution from Lys (K) to Gln (Q) at the 14th amino acid residue. This study investigated the association between m.1382A>C polymorphism [...] Read more.

Background/objectives: An East Asian-specific 1382A>C polymorphism in the mitochondrial open reading frame of the 12S rRNA type-c results in an amino acid substitution from Lys (K) to Gln (Q) at the 14th amino acid residue. This study investigated the association between m.1382A>C polymorphism and sarcopenia, blood lipids, and mental health in older Korean adults. Methods: The study included 683 community-dwelling Korean adults (345 men and 338 women) aged 65 years and older. The m.1382A>C polymorphism was genotyped with a 7500 real-time PCR system. Handgrip strength (HGS) was measured, and appendicular skeletal muscle (ASM) mass was calculated. Demographics, blood lipids, falling risk, nutritional intake, cognition function, and depression were additionally measured. Results: Men carrying the C allele had significantly higher ASM (21.6 ± 3.0 vs. 19.5 ± 2.2 kg, p = 0.018), ASM/height² (7.76 ± 0.76 vs. 7.14 ± 0.62 kg/m², p = 0.012), lean mass (53.3 ± 6.2 vs. 46.5 ± 4.0 kg, p < 0.001), left HGS (33.3 ± 5.0 vs. 28.9 ± 4.0 kg, p = 0.010), and right HGS (35.6 ± 5.3 vs. 30.9 ± 4.3 kg, p = 0.009) than men carrying the A allele. The genotype differences in ASM (p = 0.017), ASM/height² (p = 0.011), lean mass (p < 0.001), left HGS (p = 0.010), and right HGS (p = 0.009) remained significant even after adjusting for all measured covariates. By contrast, no significant differences in other measured parameters were found between women carrying the A and C alleles. Conclusions: Our study findings indicate that the m.1382A>C polymorphism may be used as a genetic biomarker of age-related sarcopenia in older Korean men. Full article

(This article belongs to the Section Molecular Genetics and Genetic Diseases)

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9 pages, 233 KiB

Open AccessCommunication

The Effects of VEGF-A and GSTM1/GSTT1 Variants in the Susceptibility to the Chronic Rhinosinusitis with Nasal Polyposis: A Pilot Genetic Study

by Leandro Azevedo Camargo, Angela Adamski da Silva Reis, Stela Oliveira Rodrigues, Rodrigo da Silva Santos and Melissa Ameloti Gomes Avelino

Biomedicines 2024, 12(10), 2383; https://doi.org/10.3390/biomedicines12102383 - 18 Oct 2024

Viewed by 203

Abstract

Nasal polyps (NPs) are usually part of chronic rhinosinusitis with nasal polyposis (CRSwNP). However, the exact etiology of CRSwNP is still unknown. In addition, the suggested etiological causes are infection, allergy, and immunological disorders, among others, such as genetic predisposition. Moreover, it is [...] Read more.

Nasal polyps (NPs) are usually part of chronic rhinosinusitis with nasal polyposis (CRSwNP). However, the exact etiology of CRSwNP is still unknown. In addition, the suggested etiological causes are infection, allergy, and immunological disorders, among others, such as genetic predisposition. Moreover, it is also suggested that oxygen-free radicals play a vital role in the pathogenesis of nasal polyposis, and inflammatory cells produce free radicals during phagocytosis, which is the primary source of ROS, controlled by the glutathione S-transferase (GST) system. Although, vascular endothelial growth factor (VEGF) plays an important role in angiogenesis, it is closely interwoven with the mobilization of inflammatory cells. This pilot study evaluated the association between genetic variant VEGF-A (rs28357093) and GSTM1/GSTT1 deletion polymorphism in susceptibility to CRSwNP. A case–control study was conducted with 61 individuals diagnosed with CRSwNP and 100 healthy subjects. VEGF-A (rs28357093) and GSTM1/GSTT1 deletion polymorphisms were genotyped by RFLP-PCR and SYBR Green real-time PCR, respectively. Individuals with allergic rhinitis carriers with AC genotype (rs28357093) presented a 4-fold increased risk to CRSwNP (OR = 4.20, 95% CI = 1.31 to 13.50; p = 0.015). This evidence shows that the increased vascular permeability probably causes an inflamed nasal area leading to extensive edema and polyp growth. On the other hand, no association was verified for each genetic variant by inheritance models. Interestingly, the GSTT1 present genotype showed a protective effect on CRSwNP. In conclusion, additional studies that have larger groups in different geographic localizations may be useful to verify and assess the association between genetic variants and CRSwNP. Full article

(This article belongs to the Section Immunology and Immunotherapy)

22 pages, 8431 KiB

Open AccessArticle

Exploring the Mechanisms and Preventive Strategies for the Progression from Idiopathic Pulmonary Fibrosis to Lung Cancer: Insights from Transcriptomics and Genetic Factors

by Kai Xie, Xiaoyan Tan, Zhe Chen, Yu Yao, Jing Luo, Haitao Ma, Yu Feng and Wei Jiang

Biomedicines 2024, 12(10), 2382; https://doi.org/10.3390/biomedicines12102382 - 18 Oct 2024

Viewed by 234

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) leads to excessive fibrous tissue in the lungs, increasing the risk of lung cancer (LC) due to heightened fibroblast activity. Advances in nucleotide point mutation studies offer insights into fibrosis-to-cancer transitions. Methods: A two-sample Mendelian randomization (TSMR) approach [...] Read more.

Background: Idiopathic pulmonary fibrosis (IPF) leads to excessive fibrous tissue in the lungs, increasing the risk of lung cancer (LC) due to heightened fibroblast activity. Advances in nucleotide point mutation studies offer insights into fibrosis-to-cancer transitions. Methods: A two-sample Mendelian randomization (TSMR) approach was used to explore the causal relationship between IPF and LC. A weighted gene co-expression network analysis (WGCNA) identified shared gene modules related to immunogenic cell death (ICD) from transcriptomic datasets. Machine learning selected key genes, and a multi-layer perceptron (MLP) model was developed for IPF prediction and diagnosis. SMR and PheWAS were used to assess the expression of key genes concerning IPF risk. The impact of core genes on immune cells in the IPF microenvironment was explored, and in vivo experiments were conducted to examine the progression from IPF to LC. Results: The TSMR approach indicated a genetic predisposition for IPF progressing to LC. The predictive model, which includes eight ICD key genes, demonstrated a strong predictive capability (AUC = 0.839). The SMR analysis revealed that the elevated expression of MS4A4A was associated with an increased risk of IPF (OR = 1.275, 95% CI: 1.029–1.579; p = 0.026). The PheWAS did not identify any significant traits linked to MS4A4A expression. The rs9265808 locus in MS4A4A was identified as a susceptibility site for the progression of IPF to LC, with mutations potentially reprogramming lung neutrophils and increasing the LC risk. In vivo studies suggested MS4A4A as a promising therapeutic target. Conclusions: A causal link between IPF and LC was established, an effective prediction model was developed, and MS4A4A was highlighted as a therapeutic target to prevent IPF from progressing to LC. Full article

(This article belongs to the Special Issue Biology of Fibroblasts and Fibrosis)

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25 pages, 1116 KiB

Open AccessReview

Insights into CSF-1R Expression in the Tumor Microenvironment

by Caterina Tomassetti, Gaia Insinga, Francesca Gimigliano, Andrea Morrione, Antonio Giordano and Emanuele Giurisato

Biomedicines 2024, 12(10), 2381; https://doi.org/10.3390/biomedicines12102381 - 18 Oct 2024

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Abstract

The colony-stimulating factor 1 receptor (CSF-1R) plays a pivotal role in orchestrating cellular interactions within the tumor microenvironment (TME). Although the CSF-1R has been extensively studied in myeloid cells, the expression of this receptor and its emerging role in other cell types in [...] Read more.

The colony-stimulating factor 1 receptor (CSF-1R) plays a pivotal role in orchestrating cellular interactions within the tumor microenvironment (TME). Although the CSF-1R has been extensively studied in myeloid cells, the expression of this receptor and its emerging role in other cell types in the TME need to be further analyzed. This review explores the multifaceted functions of the CSF-1R across various TME cellular populations, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), dendritic cells (DCs), cancer-associated fibroblasts (CAFs), endothelial cells (ECs), and cancer stem cells (CSCs). The activation of the CSF-1R by its ligands, colony-stimulating factor 1 (CSF-1) and Interleukin-34 (IL-34), regulates TAM polarization towards an immunosuppressive M2 phenotype, promoting tumor progression and immune evasion. Similarly, CSF-1R signaling influences MDSCs to exert immunosuppressive functions, hindering anti-tumor immunity. In DCs, the CSF-1R alters antigen-presenting capabilities, compromising immune surveillance against cancer cells. CSF-1R expression in CAFs and ECs regulates immune modulation, angiogenesis, and immune cell trafficking within the TME, fostering a pro-tumorigenic milieu. Notably, the CSF-1R in CSCs contributes to tumor aggressiveness and therapeutic resistance through interactions with TAMs and the modulation of stemness features. Understanding the diverse roles of the CSF-1R in the TME underscores its potential as a therapeutic target for cancer treatment, aiming at disrupting pro-tumorigenic cellular crosstalk and enhancing anti-tumor immune responses. Full article

(This article belongs to the Special Issue The Molecular Mechanisms Underlying the Activation and Regulation of Signaling Pathways in Cancer)

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10 pages, 1808 KiB

Open AccessCase Report

Management of Foot Ulcers and Chronic Wounds with Amniotic Membrane in Comorbid Patients: A Successful Experience

by Mónica Rodríguez-Valiente, Ana M. García-Hernández, Cristina Fuente-Mora, Javier Sánchez-Gálvez, Eva María García-Vizcaino, Elena Tristante Barrenechea, Gregorio Castellanos Escrig, Sergio David Liarte Lastra and Francisco Jose Nicolás

Biomedicines 2024, 12(10), 2380; https://doi.org/10.3390/biomedicines12102380 - 18 Oct 2024

Viewed by 225

Abstract

Chronic wounds are defined as those with disturbances in normal healing. They involve symptoms like exudate, odor, pain or impaired mobility, severely impacting life quality. In the case of patients with additional comorbidities, these are known to aggravate the healing impairment. Amniotic membrane [...] Read more.

Chronic wounds are defined as those with disturbances in normal healing. They involve symptoms like exudate, odor, pain or impaired mobility, severely impacting life quality. In the case of patients with additional comorbidities, these are known to aggravate the healing impairment. Amniotic membrane (AM) is gaining attention for its regenerative potential, as it has shown promise in treating hard-to-heal wounds, such as diabetic foot ulcers. This work examines a series of five patients who, while suffering an array of other chronic conditions, were treated with AM for the management of non-healing chronic ulcers. Inclusion criteria involved patients with lesions that have been active at least for six weeks and resistant to multiple treatments, accompanied by complex underlying pathologies affecting cardiovascular, immune or renal functions. Exclusion criteria included untreated active infections and patients undergoing other experimental treatments. The mean age of the patients was 68.4 ± 5.2 years. Wounds were treated once a week with AM, following standardized procedures. The variables measured included pain levels, microorganism presence, wound reduction and the number of AM applications to recovery. The median pain VAS score decreased significantly from seven at the start to two at the end of procedures. Four out of five patients achieved complete epithelialization, while the remaining patient showed significant reductions of 40% in wound size after 14 months. Our results confirm how the application of AM is a safe and effective resource for the management of chronic wounds in patients with serious comorbidities, enhancing patients’ quality of life, firstly by reducing pain, later by allowing recovery. Future research, including molecular analyses of wound exudates before and after AM treatment, can contribute to better understanding and fine tuning of this therapeutic resource. Full article

(This article belongs to the Special Issue Wound Healing: From Basic to Clinical Research)

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12 pages, 1236 KiB

Open AccessArticle

High-Definition Trans-Spinal Current Stimulation Improves Balance and Somatosensory Control: A Randomised, Placebo-Controlled Trial

by Teni Steingräber, Leon von Grönheim, Michel Klemm, Jan Straub, Lea Sasse and Jitka Veldema

Biomedicines 2024, 12(10), 2379; https://doi.org/10.3390/biomedicines12102379 - 18 Oct 2024

Viewed by 241

Abstract

Objectives: To investigate and compare the effects of three different high-definition (HD) non-invasive current stimulation (NICS) protocols on the spinal cord on support balance and somatosensory abilities in healthy young people. Methods: Fifty-eight students were enrolled in this crossover study. All participants underwent [...] Read more.

Objectives: To investigate and compare the effects of three different high-definition (HD) non-invasive current stimulation (NICS) protocols on the spinal cord on support balance and somatosensory abilities in healthy young people. Methods: Fifty-eight students were enrolled in this crossover study. All participants underwent application of (i) 1.5 mA anodal high-definition trans spinal direct current stimulation (HD-tsDCS), (ii) 1.5 mA cathodal HD-tsDCS, (iii) 1.5 mA high-definition trans spinal alternating current stimulation (HD-tsACS), and (iv) sham HD-tsDCS/ACS over the eighth thoracic vertebra in a randomised order. Balance (Y Balance test), deep sensitivity (Tuning Fork Test), and superficial sensitivity (Monofilament Test) of the lower limbs were tested immediately before and after each intervention. Results: Balance ability improved significantly following anodal HD-tsDCS and HD-tsACS compared with that following sham HD-tsDCS/ACS. Similarly, deep sensitivity increased significantly with anodal HD-tsDCS and HD-tsACS compared to that with sham HD-tsDCS/ACS and cathodal HD-tsDCS. Furthermore, superficial sensitivity improved significantly following anodal HD-tsDCS compared with that after HD-tsACS and cathodal HD-tsDCS. Conclusions: Our data show that HD-tsNICS effectively modulates the balance and somatosensory control of the lower limbs. Several diseases are associated with illness-induced changes in the spinal network in parallel with sensorimotor disabilities. Non-invasive spinal modulation may be a favourable alternative to conventional brain applications in rehabilitation. Future studies should therefore investigate these promising approaches among cohorts of patients with disabilities. Full article

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

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14 pages, 1809 KiB

Open AccessArticle

Causal Relationship Between Sjögren’s Syndrome and Gut Microbiota: A Two-Sample Mendelian Randomization Study

by Xinrun Wang, Minghui Liu and Weiping Xia

Biomedicines 2024, 12(10), 2378; https://doi.org/10.3390/biomedicines12102378 - 18 Oct 2024

Viewed by 324

Abstract

Background: Gut microbiota have been previously reported to be related to a variety of immune diseases. However, the causal connection between Sjögren’s syndrome (SS) and gut microbiota has yet to be clarified. Methods: We employed a two-sample Mendelian randomization (MR) analysis to evaluate [...] Read more.

Background: Gut microbiota have been previously reported to be related to a variety of immune diseases. However, the causal connection between Sjögren’s syndrome (SS) and gut microbiota has yet to be clarified. Methods: We employed a two-sample Mendelian randomization (MR) analysis to evaluate the causal connection between gut microbiota and SS, utilizing summary statistics from genome-wide association studies (GWASs) obtained from the MiBioGen and FinnGen consortia. The inverse variance weighted (IVW) approach represents the primary method of Mendelian randomization (MR) analysis. Sensitivity analysis was used to eliminate instrumental variables heterogeneity and horizontal pleiotropy. In addition, we performed an analysis using independent GWAS summary statistics for SS from the European Bioinformatics Institute (EBI) dataset for further verify our results. Results: IVW results demonstrated that the phylum Lentisphaerae (OR = 0.79, 95% CI: 0.63–0.99, p = 0.037), class Deltaproteobacteria (OR = 0.67, 95% CI: 0.47–0.96, p = 0.030), family Porphyromonadaceae (OR = 0.60, 95% CI: 0.38–0.94, p = 0.026), genus Eubacterium coprostanoligenes group (OR = 0.61, 95% CI: 0.4–0.93, p = 0.021), genus Blautia (OR = 0.62, 95% CI: 0.43–0.90, p = 0.012), genus Butyricicoccus (OR = 0.61, 95% CI: 0.42–0.90, p = 0.012), genus Escherichia.Shigella (OR = 0.7, 95% CI: 0.49–0.99, p = 0.045) and genus Subdoligranulum (OR = 0.61, 95% CI: 0.44–0.86, p = 0.005) exhibited protective effects on SS. Relevant heterogeneity of horizontal pleiotropy or instrumental variables was not detected. Furthermore, repeating our results with an independent cohort provided by the EBI dataset, only the genus Eubacterium coprostanoligenes group remained significantly associated with the protective effect on SS (OR = 0.41, 95% CI: 0.18–0.91, p = 0.029). Two-step MR analysis further revealed that genus Eubacterium coprostanoligenes group exerts its protective effect by reducing CXCL6 levels in SS (OR, 0.87; 95% CI = 0.76–0.99, p = 0.033). Conclusions: Our study using two-sample MR analysis identified a causal association between multiple genera and SS. A two-step MR result calculated that genus Eubacterium coprostanoligenes group mediated its protective effect by reducing CXCL6 levels in SS. However, the datasets available from the MiBioGen and FinnGen consortia do not provide sufficient information or comprehensive demographic data for subgroup analyses. Additional validation using various omics technologies is necessary to comprehend the development of SS in the intricate interplay between genes and the environment over a period of time. Full article

(This article belongs to the Special Issue Gut Microbiota, Diet, and Immunity: Investigating the Connections and Implications for Disease Development)

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32 pages, 1387 KiB

Open AccessReview

Dyslipidemia in Peritoneal Dialysis: Implications for Peritoneal Membrane Function and Patient Outcomes

by Natalia Stepanova

Biomedicines 2024, 12(10), 2377; https://doi.org/10.3390/biomedicines12102377 - 17 Oct 2024

Viewed by 306

Abstract

Dyslipidemia is a common metabolic complication in patients undergoing peritoneal dialysis (PD) and has traditionally been viewed primarily in terms of cardiovascular risk. Current guidelines do not recommend initiating lipid-lowering therapy in dialysis patients due to insufficient evidence of its benefits on cardiovascular [...] Read more.

Dyslipidemia is a common metabolic complication in patients undergoing peritoneal dialysis (PD) and has traditionally been viewed primarily in terms of cardiovascular risk. Current guidelines do not recommend initiating lipid-lowering therapy in dialysis patients due to insufficient evidence of its benefits on cardiovascular mortality. However, the impact of dyslipidemia in PD patients may extend beyond cardiovascular concerns, influencing PD-related outcomes such as the peritoneal ultrafiltration rate, residual kidney function, PD technique survival, and overall mortality. This review challenges the traditional perspective by discussing dyslipidemia’s potential role in PD-related complications, which may account for the observed link between dyslipidemia and increased all-cause mortality in PD patients. It explores the pathophysiology of dyslipidemia in PD, the molecular mechanisms linking dyslipidemia to peritoneal membrane dysfunction, and summarizes clinical evidence supporting this hypothesis. In addition, this paper examines the potential for therapeutic strategies to manage dyslipidemia to improve peritoneal membrane function and patient outcomes. The review calls for future research to investigate dyslipidemia as a potential contributor to peritoneal membrane dysfunction and to develop targeted interventions for PD patients. Full article

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

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13 pages, 694 KiB

Open AccessArticle

A Clinical Evaluation of the Role of Autoimmunity in the Relation Between Erosions and Bone Mineral Density in Rheumatoid Arthritis

by Margaux Moret, Caroline Morizot, Marcelo de Carvalho Bittencourt, Edem Allado, Isabelle Chary-Valckenaere and Damien Loeuille

Biomedicines 2024, 12(10), 2376; https://doi.org/10.3390/biomedicines12102376 - 17 Oct 2024

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Abstract

Background/objectives: Both erosions and osteoporosis in rheumatoid arthritis (RA) have common mechanisms. The aim of this study was to evaluate the relationship between erosion and bone mineral density (BMD) in RA and whether it can be driven by autoimmunity. Methods: Patients fulfilling the [...] Read more.

Background/objectives: Both erosions and osteoporosis in rheumatoid arthritis (RA) have common mechanisms. The aim of this study was to evaluate the relationship between erosion and bone mineral density (BMD) in RA and whether it can be driven by autoimmunity. Methods: Patients fulfilling the ACR 1987- or ACR/EULAR 2010-criteriae for RA. performed radiographs (erosions evaluated by the modified Sharp/van der Heidje erosion score) and biology for anti-citrullinated peptide antibodies (ACPAs), rheumatoid factors (RFs) and anti-nuclear antibodies (ANAs) at intervals of less than 2 years from dual-energy X-ray absorptiometry (DXA) for BMD assessment. Results: A total of 149 patients were included, (75.8% women, mean age of 62 y.o (SD 9.61) and a median disease duration of 132 months [60; 240]). A total of 61.1% patients were ACPA positive, 79.9% were erosive and 10.7% had a hip or spine T-score ≤ −2.5. A higher erosion score was associated with a lower BMD (value: −0.222; p = 0.009) and T-score (value −0.397; p < 0.0001) in the hip. ACPA status was associated with a higher erosion score (63.0 (53.2) vs. 45.5 (44.1) for ACPA- (p = 0.04)). ACPA titers were associated with a lower BMD in the hip (value −0.216; p = 0.01). In linear regression, erosion and BMD were still associated, but this association is not driven by ACPA status or titer. Conclusions: In RA patients, erosions and BMD are inversely associated but this relationship does not seem to be driven by autoimmunity only. However, the presence of ACPA or erosion should lead to osteoporosis screening. Full article

(This article belongs to the Special Issue Molecular Research on Osteoarthritis and Osteoporosis)

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13 pages, 1874 KiB

Open AccessArticle

Ultrasound-Guided Venous Puncture Reduces Groin Complications in Electrophysiological Procedures

by Yannick Teumer, Daniel Eckart, Lyuboslav Katov, Markus Graf, Carlo Bothner, Wolfgang Rottbauer and Karolina Weinmann-Emhardt

Biomedicines 2024, 12(10), 2375; https://doi.org/10.3390/biomedicines12102375 - 17 Oct 2024

Viewed by 371

Abstract

Background: In electrophysiological procedures, multiple punctures on the femoral vein can be necessary depending on the number of catheters required. The femoral vein is typically located indirectly by using its anatomical relationship to the artery as a reference. However, this conventional approach [...] Read more.

Background: In electrophysiological procedures, multiple punctures on the femoral vein can be necessary depending on the number of catheters required. The femoral vein is typically located indirectly by using its anatomical relationship to the artery as a reference. However, this conventional approach can lead to significant complications, including bleeding, peri-interventional transfusion, pseudoaneurysms, or arteriovenous fistulas. Despite these risks, there is limited evidence comparing the safety of ultrasound-guided venipuncture versus the conventional technique in electrophysiological procedures. Objective: This study aimed to evaluate the impact of ultrasound-guided venipuncture on vascular access complications in electrophysiological procedures and to identify associated risk factors. Methods: In this single-center trial, patients scheduled for electrophysiological procedures at Ulm University Heart Center, Germany, were enrolled between November 2021 and October 2023. Venipuncture in the groin was performed using either the conventional or an ultrasound-guided approach. The primary composite endpoint was defined as peri-interventional major vascular access complications (Bleeding Academic Research Consortium (BARC) ≥2 bleeding, pseudoaneurysms, arteriovenous fistulas, and peri-interventional transfusion) and minor complications (BARC 1). Results: A total of 1370 patients were included: 749 in the conventional group and 621 in the ultrasound group. The primary endpoint was achieved in 19.2% of the conventional group and 12.1% of the ultrasound group (p < 0.001). An increased sheath diameter and a higher number of venous accesses were identified as risk factors for the primary endpoint. Conclusions: Ultrasound guidance for venous groin puncture in electrophysiological procedures reduces access-related complications, supporting its use with careful attention to sheath size and number. Full article

(This article belongs to the Special Issue Applications of Imaging Technology in Human Diseases)

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11 pages, 248 KiB

Open AccessArticle

The Expression of Genes CYP1A1, CYP1B1, and CYP2J3 in Distinct Regions of the Heart and Its Possible Contribution to the Development of Hypertension

by Maria L. Perepechaeva, Natalia A. Stefanova, Alevtina Y. Grishanova and Nataliya G. Kolosova

Biomedicines 2024, 12(10), 2374; https://doi.org/10.3390/biomedicines12102374 - 17 Oct 2024

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Abstract

Background: It is believed that alterations in the functioning of the cytochrome P450 (CYP), which participates in metabolic transformations of endogenous polyunsaturated fatty acids (PUFAs) (with the formation of cardioprotective or cardiotoxic products), affects the development of age-related cardiovascular diseases and reduces the [...] Read more.

Background: It is believed that alterations in the functioning of the cytochrome P450 (CYP), which participates in metabolic transformations of endogenous polyunsaturated fatty acids (PUFAs) (with the formation of cardioprotective or cardiotoxic products), affects the development of age-related cardiovascular diseases and reduces the effectiveness of some cardioselective drugs. For example, CYP2J2 activation or CYP1B1 inhibition protects against the cardiovascular toxicity of anticancer drugs. It is currently unclear whether CYPs capable of metabolizing arachidonic acid and ω-3 PUFAs to vasodilatory and vasoconstrictive derivatives are expressed in all heart regions. Methods: The work was performed on senescence-accelerated OXYS rats featuring elevated blood pressure, OXYSb rats (an OXYS substrain with normal blood pressure), and Wistar rats as a “healthy” control. The mRNA level was determined in the right and left ventricles, the right and left atria, and the aorta of 1-, 3-, and 12-month-old rats. Results: We showed that all heart regions express CYPs capable of metabolizing arachidonic acid and ω-3 PUFAs and revealed significant differences between heart regions both in the mRNA level of genes CYP1B1, CYP2J3, and CYP1A1 and in the time course of expression changes with age. Conclusions: We noticed that expression levels of these CYPs in the heart regions and aorta differ between hypertensive OXYS rats, normotensive OXYSb rats, and healthy Wistar rats but could not detect any clear-cut patterns associated with the hypertensive status of OXYS rats. Full article

(This article belongs to the Special Issue Animal Models for the Study of Cardiovascular Physiology)

20 pages, 27817 KiB

Open AccessArticle

Development and Characterization of a Three-Dimensional Organotypic In Vitro Oral Cancer Model with Four Co-Cultured Cell Types, Including Patient-Derived Cancer-Associated Fibroblasts

by Yuka Aizawa, Kenta Haga, Nagako Yoshiba, Witsanu Yortchan, Sho Takada, Rintaro Tanaka, Eriko Naito, Tatsuya Abé, Satoshi Maruyama, Manabu Yamazaki, Jun-ichi Tanuma, Kazuyo Igawa, Kei Tomihara, Shinsaku Togo and Kenji Izumi

Biomedicines 2024, 12(10), 2373; https://doi.org/10.3390/biomedicines12102373 - 17 Oct 2024

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Abstract

Background/Objectives: Cancer organoids have emerged as a valuable tool of three-dimensional (3D) cell cultures to investigate tumor heterogeneity and predict tumor behavior and treatment response. We developed a 3D organotypic culture model of oral squamous cell carcinoma (OSCC) to recapitulate the tumor–stromal interface [...] Read more.

Background/Objectives: Cancer organoids have emerged as a valuable tool of three-dimensional (3D) cell cultures to investigate tumor heterogeneity and predict tumor behavior and treatment response. We developed a 3D organotypic culture model of oral squamous cell carcinoma (OSCC) to recapitulate the tumor–stromal interface by co-culturing four cell types, including patient-derived cancer-associated fibroblasts (PD-CAFs). Methods: A stainless-steel ring was used twice to create the horizontal positioning of the cancer stroma (adjoining normal oral mucosa connective tissue) and the OSCC layer (surrounding normal oral mucosa epithelial layer). Combined with a structured bi-layered model of the epithelial component and the underlying stroma, this protocol enabled us to construct four distinct portions mimicking the oral cancer tissue arising in the oral mucosa. Results: In this model, α-smooth muscle actin-positive PD-CAFs were localized in close proximity to the OSCC layer, suggesting a crosstalk between them. Furthermore, a linear laminin-γ2 expression was lacking at the interface between the OSCC layer and the underlying stromal layer, indicating the loss of the basement membrane-like structure. Conclusions: Since the specific 3D architecture and polarity mimicking oral cancer in vivo provides a more accurate milieu of the tumor microenvironment (TME), it could be crucial in elucidating oral cancer TME. Full article

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

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9 pages, 266 KiB

Open AccessArticle

Incidental Parathyroidectomy After Thyroid Surgery: A Single-Center Study

by Roberta Granata, Antonio Zanghì, Marianna Scribano, Giordana Riccioli, Francesca Privitera, Sandro La Vignera, Rosita Angela Condorelli, Francesco Leonforte, Antonio Mistretta, Aldo Eugenio Calogero and Massimiliano Veroux

Biomedicines 2024, 12(10), 2372; https://doi.org/10.3390/biomedicines12102372 - 17 Oct 2024

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Abstract

Background: Hypoparathyroidism with hypocalcemia is the most frequent complication after thyroid surgery. Many risk factors have been involved in the development of this complication, with conflicting results. Incidental parathyroidectomy (IP) may be a frequent cause of postoperative hypocalcemia. In this study, we have [...] Read more.

Background: Hypoparathyroidism with hypocalcemia is the most frequent complication after thyroid surgery. Many risk factors have been involved in the development of this complication, with conflicting results. Incidental parathyroidectomy (IP) may be a frequent cause of postoperative hypocalcemia. In this study, we have evaluated the risk factors associated with the IP in a single-center cohort of patients undergoing thyroid surgery. Patients and methods: The incidence and the risk factors for IP were evaluated in 799 patients scheduled for surgical treatment for thyroid disease between January 2018 and December 2023. Parathyroid hormone levels and serum calcium levels, together with the histological specimens, were evaluated in all patients. Results: Post-operative temporary hypocalcemia was present in 239 (29.9%) patients. A total of 144 patients (21.9%) had an incidental parathyroidectomy. Younger patients (<40 years) had the highest risk of having an incidental parathyroidectomy (RR 1.53 (95% CI 1.084–2.161), OR 1.72 (95% CI 1.091–2.710), p = 0.014). Moreover, thyroid cancer (RR 1.4 (95 CI 1.114–1.882) OR 1.68 (95% CI 1.145–2.484), p < 0.05) and the neck dissection (RR 1.75 (95% CI 1.409–2.198) OR 2.38 (95% CI 1.644–3.460), p < 0.001) were strongly associated with the risk of incidental parathyroidectomy. Conclusions: Younger female patients with thyroid cancer and neck dissection were at the highest risk of incidental parathyroidectomy. A meticulous surgical dissection, together with imaging methods for the detection of the parathyroid glands, may reduce the incidence of this complication. Full article

(This article belongs to the Special Issue Thyroid Disorders: Current Status and Future Prospects)

15 pages, 3935 KiB

Open AccessArticle

Oxygen Glucose Deprivation-Induced Lactylation of H3K9 Contributes to M1 Polarization and Inflammation of Microglia Through TNF Pathway

by Lu He, Rui Yin, Weijian Hang, Jinli Han, Juan Chen, Bin Wen and Ling Chen

Biomedicines 2024, 12(10), 2371; https://doi.org/10.3390/biomedicines12102371 - 17 Oct 2024

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Abstract

Background: Hypoxia-induced M1 polarization of microglia and resultant inflammation take part in the damage caused by hypoxic-ischemic encephalopathy (HIE). Histone lactylation, a novel epigenetic modification where lactate is added to lysine residues, may play a role in HIE pathogenesis. This study investigates the [...] Read more.

Background: Hypoxia-induced M1 polarization of microglia and resultant inflammation take part in the damage caused by hypoxic-ischemic encephalopathy (HIE). Histone lactylation, a novel epigenetic modification where lactate is added to lysine residues, may play a role in HIE pathogenesis. This study investigates the role of histone lactylation in hypoxia-induced M1 microglial polarization and inflammation, aiming to provide insights for HIE treatment. Methods: In this study, we assessed the effects of hypoxia on microglial polarization using both an HIE animal model and an oxygen–glucose deprivation cell model. Histone lactylation at various lysine residues was detected by Western blotting. Microglial polarization and inflammatory cytokines were analyzed by immunofluorescence, qPCR, and Western blotting. RNA sequencing, ChIP-qPCR, and siRNA were used to elucidate mechanisms of H3K9 lactylation. Results: H3K9 lactylation increased due to cytoplasmic lactate during M1 polarization. Inhibiting P300 or reducing lactate dehydrogenase A expression decreased H3K9 lactylation, suppressing M1 polarization. Transcriptomic analysis indicated that H3K9 lactylation regulated M1 polarization via the TNF signaling pathway. ChIP-qPCR confirmed H3K9 lactylation enrichment at the TNFα locus, promoting OGD-induced M1 polarization and inflammation. Conclusions: H3K9 lactylation promotes M1 polarization and inflammation via the TNF pathway, identifying it as a potential therapeutic target for neonatal HIE. Full article

(This article belongs to the Special Issue Neuroinflammation and Neuroprotection)

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11 pages, 1589 KiB

Open AccessArticle

Lower Free Thyroxine Levels Are Associated with Diabetic Kidney Disease in Males with Type 2 Diabetes Mellitus: An Observational Cross-Sectional Study

by Jianan Shang, Yixuan Zheng, Meng Zhang, Meng Li, Wei Qiang, Jing Sui, Hui Guo, Bingyin Shi and Mingqian He

Biomedicines 2024, 12(10), 2370; https://doi.org/10.3390/biomedicines12102370 - 17 Oct 2024

Viewed by 356

Abstract

Objectives: We aimed to explore the correlation between thyroid function and diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM). Methods: A total of 7516 T2DM patients were enrolled and grouped according to DKD status. Clinical parameters, including [...] Read more.

Objectives: We aimed to explore the correlation between thyroid function and diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM). Methods: A total of 7516 T2DM patients were enrolled and grouped according to DKD status. Clinical parameters, including blood glucose parameters, thyroid function, and indicators of renal impairment, were collected and compared between the DKD and Non-DKD groups. Correlation analysis and univariate/multivariate logistic regression analyses were performed. Results: Age, T2DM duration, the use of insulin and lipid-lowering drugs, systolic and diastolic blood pressure, body mass index, and fasting blood glucose levels were greater in the DKD group than in the Non-DKD group (p < 0.001). Notably, compared with those in the Non-DKD group, patients in the DKD group had lower triiodothyronine (T3), thyroxine (T4), free triiodothyronine (FT3), and free thyroxine (FT4) levels and higher thyrotropin levels (p < 0.001). Univariate logistic regression analysis revealed that T3, T4, FT3, and FT4 levels were negatively correlated with the risk of DKD. Spearman correlation analysis confirmed that T3, T4, FT3, and FT4 levels were negatively correlated with blood urea nitrogen levels, blood creatinine levels, and the urinary albumin-to-creatinine ratio (p < 0.05). Multivariate logistic regression analysis revealed that a greater FT4 level was a protective factor against DKD in T2DM patients, especially in males, with a cut-off value of 13.35 pmol/L (area under the curve = 0.604). Conclusions: Thyroid hormone levels, especially FT4 levels, were significantly negatively correlated with DKD in T2DM patients. Full article

(This article belongs to the Special Issue Diabetic Nephropathy and Diabetic Atherosclerosis)

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16 pages, 3879 KiB

Open AccessArticle

Prognostic Value of Speckle Tracking Echocardiography-Derived Strain in Unmasking Risk for Arrhythmias in Children with Myocarditis

by Nele Rolfs, Cynthia Huber, Bernd Opgen-Rhein, Isabell Altmann, Felix Anderheiden, Tobias Hecht, Marcus Fischer, Gesa Wiegand, Katja Reineker, Inga Voges, Daniela Kiski, Wiebke Frede, Martin Boehne, Malika Khedim, Daniel Messroghli, Karin Klingel, Eicke Schwarzkopf, Thomas Pickardt, Stephan Schubert, Fatima I. Lunze and Franziska Seidel Show full author list Hide full author list

Biomedicines 2024, 12(10), 2369; https://doi.org/10.3390/biomedicines12102369 - 16 Oct 2024

Viewed by 378

Abstract

Background/Objectives: Risk assessment in pediatric myocarditis is challenging, particularly when left ventricular ejection fraction (LVEF) is preserved. This study aimed to evaluate LV myocardial deformation using speckle-tracking echocardiography (STE)-derived longitudinal +strain (LS) and assessed its diagnostic and prognostic value in children with myocarditis. [...] Read more.

Background/Objectives: Risk assessment in pediatric myocarditis is challenging, particularly when left ventricular ejection fraction (LVEF) is preserved. This study aimed to evaluate LV myocardial deformation using speckle-tracking echocardiography (STE)-derived longitudinal +strain (LS) and assessed its diagnostic and prognostic value in children with myocarditis. Methods: Retrospective STE-derived layer-specific LV LS analysis was performed on echocardiograms from patients within the multicenter, prospective registry for pediatric myocarditis “MYKKE”. Age- and sex-adjusted logistic regression and ROC analysis identified predictors of cardiac arrhythmias (ventricular tachycardia, ventricular fibrillation, atrioventricular blockage III°) and major adverse cardiac events (MACE: need for mechanical circulatory support (MCS), cardiac transplantation, and/or cardiac death). Results: Echocardiograms from 175 patients (median age 15 years, IQR 7.9–16.5 years; 70% male) across 13 centers were included. Cardiac arrhythmias occurred in 36 patients (21%), and MACE in 28 patients (16%). Impaired LV LS strongly correlated with reduced LVEF (r > 0.8). Impaired layer-specific LV LS, reduced LVEF, LV dilatation, and increased BSA-indexed LV mass, were associated with the occurrence of MACE and cardiac arrhythmias. In patients with preserved LVEF, LV LS alone predicted cardiac arrhythmias (p < 0.001), with optimal cutoff values of −18.0% for endocardial LV LS (sensitivity 0.69, specificity 0.94) and –17.0% for midmyocardial LV LS (sensitivity 0.81, specificity 0.75). Conclusions: In pediatric myocarditis, STE-derived LV LS is not only a valuable tool for assessing systolic myocardial dysfunction and predicting MACE but also identifies patients at risk for cardiac arrhythmias, even in the context of preserved LVEF. Full article

(This article belongs to the Special Issue Advances in Myocarditis: Molecular and Immune Mechanisms, Diagnosis and Treatment)

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10 pages, 1197 KiB

Open AccessArticle

Mitochondrial Creatine Kinase 2 (Ckmt2) as a Plasma-Based Biomarker for Evaluating Reperfusion Injury in Acute Myocardial Infarction

by Alexander Lang, Daniel Oehler, Marcel Benkhoff, Yvonne Reinders, Maike Barcik, Khatereh Shahrjerdi, Madlen Kaldirim, Albert Sickmann, Lisa Dannenberg, Amin Polzin, Susanne Pfeiler, Malte Kelm, Maria Grandoch, Christian Jung and Norbert Gerdes

Biomedicines 2024, 12(10), 2368; https://doi.org/10.3390/biomedicines12102368 - 16 Oct 2024

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Abstract

Background/Objectives: Acute myocardial infarction (AMI), characterized by irreversible heart muscle damage and impaired cardiac function caused by myocardial ischemia, is a leading cause of global mortality. The damage associated with reperfusion, particularly mitochondrial dysfunction and reactive oxygen species (ROS) formation, has emerged as [...] Read more.

Background/Objectives: Acute myocardial infarction (AMI), characterized by irreversible heart muscle damage and impaired cardiac function caused by myocardial ischemia, is a leading cause of global mortality. The damage associated with reperfusion, particularly mitochondrial dysfunction and reactive oxygen species (ROS) formation, has emerged as a crucial factor in the pathogenesis of cardiac diseases, leading to the recognition of mitochondrial proteins as potential markers for myocardial damage. This study aimed to identify differentially expressed proteins based on the type of cardiac injury, in particular those with and without reperfusion. Methods: Male C57Bl/6J mice were either left untreated, sham-operated, received non-reperfused AMI, or reperfused AMI. Twenty-four hours after the procedures, left ventricular (LV) function and morphological changes including infarct size were determined using echocardiography and triphenyl tetrazolium chloride (TTC) staining, respectively. In addition, plasma was isolated and subjected to untargeted mass spectrometry and, further on, the ELISA-based validation of candidate proteins. Results: We identified mitochondrial creatine kinase 2 (Ckmt2) as a differentially regulated protein in plasma of mice with reperfused but not non-reperfused AMI. Elevated levels of Ckmt2 were significantly associated with infarct size and impaired LV function following reperfused AMI, suggesting a specific involvement in reperfusion damage. Conclusions: Our study highlights the potential of plasma Ckmt2 as a biomarker for assessing reperfusion injury and its impact on cardiac function and morphology in the acute phase of MI. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Translational Aspects of Ischemia-Reperfusion Injury)

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12 pages, 735 KiB

Open AccessArticle

The Effectiveness of NP001 on the Long-Term Survival of Patients with Amyotrophic Lateral Sclerosis

by Bruce D. Forrest, Namita A. Goyal, Thomas R. Fleming, Paige M. Bracci, Neil R. Brett, Zaeem Khan, Michelle Robinson, Ari Azhir and Michael McGrath

Biomedicines 2024, 12(10), 2367; https://doi.org/10.3390/biomedicines12102367 - 16 Oct 2024

Viewed by 443

Abstract

Background/Objectives: The aim of this study was to estimate the effect of a 6 months’ treatment course of the innate immune modulator NP001 (a pH-adjusted intravenous formulation of purified sodium chlorite), on disease progression, as measured by overall survival (OS) in patients with [...] Read more.

Background/Objectives: The aim of this study was to estimate the effect of a 6 months’ treatment course of the innate immune modulator NP001 (a pH-adjusted intravenous formulation of purified sodium chlorite), on disease progression, as measured by overall survival (OS) in patients with amyotrophic lateral sclerosis. Methods: Blinded survival data were retrospectively collected for 268 of the 273 patients who had participated in two phase 2 placebo-controlled clinical trials of NP001 (ClinicalTrials.gov: NCT01281631 and NCT02794857) and received at least one dose of either 1 mg/kg or 2 mg/kg of NP001 as chlorite based on actual body weight, or placebo. Kaplan–Meier methods were used on the intent-to-treat population to estimate survival probabilities. Results: In the overall population, the median OS was 4.8 months (2.7 years [95% CI: 2.3, 3.5] in the 2 mg/kg NP001group and 2.3 years [95% CI: 1.8, 2.9] in the placebo group). Hazard ratio (HR): 0.77 (95% CI: 0.57, 1.03), p = 0.073. Among patients aged ≤ 65 years, the median OS for the 2 mg/kg NP001 group was 10.8 months (3.3 years [95% CI: 2.4, 3.8] in the 2 mg/kg NP001 group and 2.4 years [95% CI: 1.7, 3.3] in the placebo group). HR: 0.69 (95% CI: 0.50, 0.95). No differences were observed in the 1 mg/kg NP001 group or in patients aged > 65 years. Conclusions: The findings from this study suggest that a 6 months’ treatment course of NP001 resulted in a 4.8-month increase in overall survival in patients with ALS. The findings from this study indicate that targeting inflammation associated with the innate immune system may provide a pathway for new therapeutic options for the treatment of ALS. Full article

(This article belongs to the Section Immunology and Immunotherapy)

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Biomedicines, Volume 12, Issue 10 (October 2024) – 234 articles

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