Biomedicines

23 pages, 2418 KiB

Open AccessProtocol

Collection, Establishment and Assessment of Complex Human Osteocartilaginous Explants for Modeling Osteoarthritis

by Camelia-Mihaela Danceanu-Zara, Adriana Petrovici, Luminita Labusca, Anca Emanuela Minuti, Cristina Stavila, Petru Plamadeala, Crina Elena Tiron, Dragoş Aniţă, Adriana Aniţă and Nicoleta Lupu

Biomedicines 2024, 12(10), 2406; https://doi.org/10.3390/biomedicines12102406 (registering DOI) - 21 Oct 2024

Abstract

With the increasing burden of osteoarthritis worldwide, cost efficient and reliable models are needed to enable the development of innovative therapies or therapeutic interventions. Ex vivo models have been identified as valuable modalities in translational research, bridging the gap between in vitro and [...] Read more.

With the increasing burden of osteoarthritis worldwide, cost efficient and reliable models are needed to enable the development of innovative therapies or therapeutic interventions. Ex vivo models have been identified as valuable modalities in translational research, bridging the gap between in vitro and in vivo models. Osteocartilaginous explants from Osteoarthritis (OA) patients offer an exquisite opportunity for studying OA progression and testing novel therapies. We describe the protocol for establishing human osteocartilaginous explants with or without co-culture of homologous synovial tissue. Furthermore, a detailed protocol for the assessment of explanted tissue in terms of protein content using Western blot and immunohistochemistry is provided. Commentaries regarding the technique of choice, possible variations and expected results are inserted. Full article

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

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21 pages, 2693 KiB

Open AccessReview

Apigenin as a Promising Agent for Enhancing Female Reproductive Function and Treating Associated Disorders

by Alexander V. Sirotkin and Abdel Halim Harrath

Biomedicines 2024, 12(10), 2405; https://doi.org/10.3390/biomedicines12102405 (registering DOI) - 21 Oct 2024

Abstract

Apigenin is an organic flavonoid abundant in some plants such as parsley, chamomile, or celery. Recently, it has been investigated for several of its pharmacological characteristics, such as its ability to act as an antioxidant, reduce inflammation, and inhibit the growth of cancer [...] Read more.

Apigenin is an organic flavonoid abundant in some plants such as parsley, chamomile, or celery. Recently, it has been investigated for several of its pharmacological characteristics, such as its ability to act as an antioxidant, reduce inflammation, and inhibit the growth of cancer cells. The purpose of this review is to provide a summary of the existing knowledge regarding the effects of apigenin on female reproductive systems and its dysfunctions. Apigenin can influence reproductive processes by regulating multiple biological events, including oxidative processes, cell proliferation, apoptosis, cell renewal and viability, ovarian blood supply, and the release of reproductive hormones. It could stimulate ovarian folliculogenesis, as well as ovarian and embryonal cell proliferation and viability, which can lead to an increase in fertility and influence the release of reproductive hormones, which may exert its effects on female reproductive health. Furthermore, apigenin could inhibit the activities of ovarian cancer cells and alleviate the pathological changes in the female reproductive system caused by environmental pollutants, harmful medications, cancer, polycystic ovarian syndrome, ischemia, as well as endometriosis. Therefore, apigenin may have potential as a biostimulator for female reproductive processes and as a therapeutic agent for certain reproductive diseases. Full article

(This article belongs to the Special Issue Advanced Research in Early Pregnancy Loss and Other Pregnancy Complications)

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12 pages, 1377 KiB

Open AccessArticle

miRNA in Machine-Learning-Based Diagnostics of Oral Cancer

by Xinghang Li, Valentina L. Kouznetsova and Igor F. Tsigelny

Biomedicines 2024, 12(10), 2404; https://doi.org/10.3390/biomedicines12102404 (registering DOI) - 21 Oct 2024

Abstract

Background: MicroRNAs (miRNAs) are crucial regulators of gene expression, playing significant roles in various cellular processes, including cancer pathogenesis. Traditional cancer diagnostic methods, such as biopsies and histopathological analyses, while effective, are invasive, costly, and require specialized skills. With the rising global incidence [...] Read more.

Background: MicroRNAs (miRNAs) are crucial regulators of gene expression, playing significant roles in various cellular processes, including cancer pathogenesis. Traditional cancer diagnostic methods, such as biopsies and histopathological analyses, while effective, are invasive, costly, and require specialized skills. With the rising global incidence of cancer, there is a pressing need for more accessible and less invasive diagnostic alternatives. Objective: This research investigates the potential of machine-learning (ML) models based on miRNA attributes as non-invasive diagnostic tools for oral cancer. Methods and Tools: We utilized a comprehensive methodological framework involving the generation of miRNA attributes, including sequence characteristics, target gene associations, and cancer-specific signaling pathways. Results: The miRNAs were classified using various ML algorithms, with the BayesNet classifier demonstrating superior performance, achieving an accuracy of 95% and an area under receiver operating characteristic curve (AUC) of 0.98 during cross-validation. The model’s effectiveness was further validated using independent datasets, confirming its potential clinical utility. Discussion: Our findings highlight the promise of miRNA-based ML models in enhancing early cancer detection, reducing healthcare burdens, and potentially saving lives. Conclusions: This study paves the way for future research into miRNA biomarkers, offering a scalable and adaptable diagnostic approach for various cancers. Full article

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

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13 pages, 2654 KiB

Open AccessCommunication

Absolute Quantitative Targeted Monitoring of Potential Plasma Protein Biomarkers: A Pilot Study on Healthy Individuals

by Alexey S. Kononikhin, Natalia L. Starodubtseva, Alexander G. Brzhozovskiy, Alisa O. Tokareva, Daria N. Kashirina, Natalia V. Zakharova, Anna E. Bugrova, Maria I. Indeykina, Liudmila Kh. Pastushkova, Irina M. Larina, Vladimir A. Mitkevich, Alexander A. Makarov and Evgeny N. Nikolaev

Biomedicines 2024, 12(10), 2403; https://doi.org/10.3390/biomedicines12102403 (registering DOI) - 21 Oct 2024

Abstract

Background/Objectives: The development of blood tests for the early detection of individual predisposition to socially significant diseases remains a pressing issue. Methods: In this pilot study, multiple reaction monitoring mass spectrometry (MRM-MS) with a BAK-270 assay was applied for protein concentrations analysis in [...] Read more.

Background/Objectives: The development of blood tests for the early detection of individual predisposition to socially significant diseases remains a pressing issue. Methods: In this pilot study, multiple reaction monitoring mass spectrometry (MRM-MS) with a BAK-270 assay was applied for protein concentrations analysis in blood plasma from 21 healthy volunteers of the European cohort. Results: The levels of 138 plasma proteins were reliably and precisely quantified in no less than 50% of samples. The quantified proteins included 66 FDA-approved markers of cardiovascular diseases (CVD), and other potential biomarkers of pathologies such as cancer, diabetes mellitus, and Alzheimer’s disease. The analysis of individual variations of the plasma proteins revealed significant differences between the male (11) and female (10) groups. In total, fifteen proteins had a significantly different concentration in plasma; this included four proteins that exhibited changes greater than ±1.5-fold, three proteins (RBP4, APCS, and TTR) with higher levels in males, and one (SHBG) elevated in females. The obtained results demonstrated considerable agreement with the data collected from 20 samples of a North American cohort, which were analyzed with the similar MRM assay. The most significant differences between the cohorts of the two continents were observed in the level of 42 plasma proteins (including 24 FDA markers), of which 17 proteins showed a ≥1.5-fold change, and included proteins increased in North Americans (APOB, CRTAC1, C1QB, C1QC, C9, CRP, HP, IGHG1, IGKV4-1, SERPING1, RBP4, and AZGP1), as well as those elevated in Europeans (APOF, CD5L, HBG2, SELPLG, and TNA). Conclusions: The results suggest a different contribution of specific (patho)physiological pathways (e.g., immune system and blood coagulation) to the development of socially significant diseases in Europeans and North Americans, and they should be taken into account when refining diagnostic panels. Full article

(This article belongs to the Special Issue The Human Proteome in Disease, Diagnostics and Translation into Precision Medicine: Current Status and Future Prospects)

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12 pages, 2685 KiB

Open AccessArticle

Mitochondrial Dysfunction and Ion Imbalance in a Rat Model of Hemodialysis-Induced Myocardial Stunning

by Yuxin Nie, Liyu Lin, Qiang Yang, Jiachang Hu, Minmin Sun, Fangfang Xiang, Xuesen Cao, Jinbo Yu, Yaqiong Wang, Jie Teng, Xiaoqiang Ding, Bo Shen and Zhen Zhang

Biomedicines 2024, 12(10), 2402; https://doi.org/10.3390/biomedicines12102402 (registering DOI) - 20 Oct 2024

Abstract

Background/Objectives: Hemodialysis-induced myocardial stunning (HIMS) is a frequent complication in patients undergoing maintenance hemodialysis, characterized by transient left ventricular dysfunction due to ischemic episodes. Mitochondrial dysfunction and fluctuations in key ions such as potassium (K⁺) and calcium (Ca²⁺) [...] Read more.

Background/Objectives: Hemodialysis-induced myocardial stunning (HIMS) is a frequent complication in patients undergoing maintenance hemodialysis, characterized by transient left ventricular dysfunction due to ischemic episodes. Mitochondrial dysfunction and fluctuations in key ions such as potassium (K⁺) and calcium (Ca²⁺) are implicated in the pathogenesis of HIMS. This study aims to investigate the role of mitochondrial dysfunction and the protective potential of mitochondrial ATP-sensitive potassium channels (mitoK_ATP) in mitigating HIMS. Methods: A 5/6 nephrectomy rat model was established to mimic chronic kidney disease and the subsequent HIMS. The effects of mitoK_ATP channel modulators were evaluated by administering diazoxide (DZX), a mitoK_ATP opener, and 5-hydroxydecanoate (5-HD), a mitoK_ATP blocker, before hemodialysis. Mitochondrial function was assessed by measuring membrane potential, ATP synthase activity, and intramitochondrial Ca²⁺ levels. Myocardial function was evaluated using speckle tracking echocardiography. Results: Rats undergoing hemodialysis exhibited significant reductions in left ventricular strain and synchrony. DZX administration significantly improved mitochondrial function and reduced myocardial strain compared to controls. Conversely, 5-HD worsened mitochondrial swelling and disrupted myocardial function. Higher K⁺ and Ca²⁺ concentrations in the dialysate were associated with improved mitochondrial energy metabolism and myocardial strain. Conclusions: Mitochondrial dysfunction and ion imbalances during hemodialysis are key contributors to HIMS. The activation of mitoK_ATP channels provides mitochondrial protection and may serve as a potential therapeutic strategy to mitigate HIMS. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

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16 pages, 5163 KiB

Open AccessReview

Mechanisms and Assessment of Genotoxicity of Metallic Engineered Nanomaterials in the Human Environment

by Benjamin M. Liu and A. Wallace Hayes

Biomedicines 2024, 12(10), 2401; https://doi.org/10.3390/biomedicines12102401 (registering DOI) - 20 Oct 2024

Abstract

Engineered nanomaterials (ENMs) have a broad array of applications in agriculture, engineering, manufacturing, and medicine. Decades of toxicology research have demonstrated that ENMs can cause genotoxic effects on bacteria, mammalian cells, and animals. Some metallic ENMs (MENMs), e.g., metal or metal oxide nanoparticles [...] Read more.

Engineered nanomaterials (ENMs) have a broad array of applications in agriculture, engineering, manufacturing, and medicine. Decades of toxicology research have demonstrated that ENMs can cause genotoxic effects on bacteria, mammalian cells, and animals. Some metallic ENMs (MENMs), e.g., metal or metal oxide nanoparticles TiO₂ and CuO, induce genotoxicity via direct DNA damage and/or reactive oxygen species-mediated indirect DNA damage. There are various physical features of MENMs that may play an important role in promoting their genotoxicity, for example, size and chemical composition. For a valid genotoxicity assessment of MENMs, general considerations should be given to various factors, including, but not limited to, NM characterization, sample preparation, dosing selection, NM cellular uptake, and metabolic activation. The recommended in vitro genotoxicity assays of MENMs include hprt gene mutation assay, chromosomal aberration assay, and micronucleus assay. However, there are still knowledge gaps in understanding the mechanisms underlying the genotoxicity of MENMs. There are also a variety of challenges in the utilization and interpretation of the genotoxicity assessment assays of MENMs. In this review article, we provide mechanistic insights into the genotoxicity of MENMs in the human environment. We review advances in applying new endpoints, biomarkers, and methods to the genotoxicity assessments of MENMs. The guidance of the United States, the United Kingdom, and the European Union on the genotoxicity assessments of MENMs is also discussed. Full article

(This article belongs to the Special Issue Novel Biomarkers and Technologies in the Research and Diagnosis of Human Diseases)

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25 pages, 299 KiB

Open AccessArticle

Hepatitis C Infection Is Not a Cardiovascular Risk Factor in Young Adults

by Paweł Rajewski, Małgorzata Pawłowska, Dorota Kozielewicz, Dorota Dybowska, Anita Olczak and Jakub Cieściński

Biomedicines 2024, 12(10), 2400; https://doi.org/10.3390/biomedicines12102400 (registering DOI) - 20 Oct 2024

Abstract

Background: Cardiovascular diseases are one of the leading causes of hospitalization and death in Poland and around the world and are still an ongoing problem for modern medicine. Despite advances in diagnosis and treatment, both conservative and invasive, the prevention of cardiovascular [...] Read more.

Background: Cardiovascular diseases are one of the leading causes of hospitalization and death in Poland and around the world and are still an ongoing problem for modern medicine. Despite advances in diagnosis and treatment, both conservative and invasive, the prevention of cardiovascular disease directed at reducing risk factors remains a problem. The main classical risk factors for the development of cardiovascular disease in Poland include hypertension, lipid disorders, obesity, diabetes and smoking. A new non-classical risk factor is HCV infection. Most of the studies on the impact of HCV infection on cardiovascular disease involve elderly populations with long-term infections and advanced liver fibrosis. Methods: Hence, we set out to analyze the prevalence of risk factors and cardiovascular disease in a population of young adults under 45 years of age infected with HCV, according to gender, HCV genotype and the duration of infection. The study group consisted of 217 patients of both sexes aged 21 to 45 years (mean age 36 years). Results: No cardiovascular disease was found among the young adults infected with HCV in the study group. The most common risk factor was cigarette smoking, which affected 20.7% of the subjects, followed by hypertension (12%) and diabetes mellitus (5.5%); the prevalence was lower than in the general population. Most of the patients were characterized as overweight, with a mean BMI of 26.39 kg/m². The mean values of other metabolic parameters—total cholesterol, LDL, HDL, uric acid and glucose—were within the population norm. The mean value of CRP was 1.43, which may indicate a moderate cardiovascular risk. Conclusions: Based on the conducted research, it was found that HCV infection in young individuals was not a risk factor for cardiovascular diseases, and the prevalence of risk factors was similar to that in the general population. The effect of HCV on the increase in C-reactive protein requires further study. The early detection of HCV infection and treatment can be considered as a prevention of cardiovascular disease. Full article

(This article belongs to the Special Issue Cardiac and Vascular Diseases: Pathogenesis, Pharmacological Treatments, Advances in Therapies (2nd Edition))

21 pages, 4467 KiB

Open AccessArticle

The Generation of ROS by Exposure to Trihalomethanes Promotes the IκBα/NF-κB/p65 Complex Dissociation in Human Lung Fibroblast

by Minerva N�jera-Mart�nez, Israel Lara-Vega, Jhonatan Avilez-Alvarado, Nataraj S. Pagadala, Ricardo Dzul-Caamal, Mar�a Lilia Dom�nguez-L�pez, Jack Tuszynski and Armando Vega-L�pez

Biomedicines 2024, 12(10), 2399; https://doi.org/10.3390/biomedicines12102399 (registering DOI) - 20 Oct 2024

Abstract

Background: Disinfection by-products used to obtain drinking water, including halomethanes (HMs) such as CH₂Cl₂, CHCl₃, and BrCHCl₂, induce cytotoxicity and hyperproliferation in human lung fibroblasts (MRC-5). Enzymes such as superoxide dismutase (SOD), catalase (CAT), and [...] Read more.

Background: Disinfection by-products used to obtain drinking water, including halomethanes (HMs) such as CH₂Cl₂, CHCl₃, and BrCHCl₂, induce cytotoxicity and hyperproliferation in human lung fibroblasts (MRC-5). Enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) modulate these damages through their biotransformation processes, potentially generating toxic metabolites. However, the role of the oxidative stress response in cellular hyperproliferation, modulated by nuclear factor-kappa B (NF-κB), remains unclear. Methods: In this study, MRC-5 cells were treated with these compounds to evaluate reactive oxygen species (ROS) production, lipid peroxidation, phospho-NF-κB/p65 (Ser536) levels, and the activities of SOD, CAT, and GPx. Additionally, the interactions between HMs and ROS with the IκBα/NF-κB/p65 complex were analyzed using molecular docking. Results: Correlation analysis among biomarkers revealed positive relationships between pro-oxidant damage and antioxidant responses, particularly in cells treated with CH₂Cl₂ and BrCHCl₂. Conversely, negative relationships were observed between ROS levels and NF-κB/p65 levels in cells treated with CH₂Cl₂ and CHCl₃. The estimated relative free energy of binding using thermodynamic integration with the p65 subunit of NF-κB was −3.3 kcal/mol for BrCHCl₂, −3.5 kcal/mol for both CHCl₃ and O₂^•, and −3.6 kcal/mol for H₂O₂. Conclusions: Chloride and bromide atoms were found in close contact with IPT domain residues, particularly in the RHD region involved in DNA binding. Ser281 is located within this domain, facilitating the phosphorylation of this protein. Similarly, both ROS interacted with the IPT domain in the RHD region, with H₂O₂ forming a side-chain oxygen interaction with Leu280 adjacent to the phosphorylation site of p65. However, the negative correlation between ROS and phospho-NF-κB/p65 suggests that steric hindrance by ROS on the C-terminal domain of NF-κB/p65 may play a role in the antioxidant response. Full article

(This article belongs to the Special Issue Fibroblasts: Insights from Molecular and Pathophysiology Perspectives)

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21 pages, 2792 KiB

Open AccessArticle

Three-Dimensional Model Analysis Revealed Differential Cytotoxic Effects of the NK-92 Cell Line and Primary NK Cells on Breast and Ovarian Carcinoma Cell Lines Mediated by Variations in Receptor–Ligand Interactions and Soluble Factor Profiles

by Nadezhda A. Alekseeva, Anna A. Boyko, Marina A. Shevchenko, Maria V. Grechikhina, Maria A. Streltsova, Ludmila G. Alekseeva, Alexander M. Sapozhnikov, Sergey M. Deyev and Elena I. Kovalenko

Biomedicines 2024, 12(10), 2398; https://doi.org/10.3390/biomedicines12102398 (registering DOI) - 20 Oct 2024

Abstract

Background/objectives: The functional activity of a certain tumor determines the effectiveness of primary NK cells and NK-92 cell line-based cancer therapy; their therapeutic effectiveness against different tumors can vary. This work provides a direct simultaneous comparison of the cytotoxic effects of in vitro-activated [...] Read more.

Background/objectives: The functional activity of a certain tumor determines the effectiveness of primary NK cells and NK-92 cell line-based cancer therapy; their therapeutic effectiveness against different tumors can vary. This work provides a direct simultaneous comparison of the cytotoxic effects of in vitro-activated peripheral NK (pNK) cells and NK-92 cells in spheroid models of BT-474, MCF7 and SKOV-3 carcinomas and uncovers the reasons for the differential effectiveness of NK cells against tumors. Methods: Tumor spheroids of similar size and shape, obtained from agarose molds, were incubated with NK-92 or pNK cells for 24 h. Tumor cell death was detected using flow cytometry or confocal microscopy. Cytokine production, granzyme B levels and NK cell degranulation analyses were performed, along with pNK and target-cell phenotypic characterization. Results: While NK-92 and pNK cells lysed BT-474 spheroids with comparably low efficiency, pNK cells were more capable of eliminating MCF7 and SKOV-3 spheroids than NK-92 cells were. The results of the functional and phenotypic analyses strongly support the participation of the NKG2D-NKG2DL pathway in pNK cell activation induced by the most sensitive cytotoxic attack on SKOV-3 spheroids, whereas the CX3CR1-CX3CL1 axis appears to be involved in the pNK reaction against MCF-7 spheroids. Conclusions: We provide a new approach for the preliminary identification of the most promising NK cell receptors that can alter the effectiveness of cancer therapy depending on the specific tumor type. Using this approach, NK-92 cells or pNK subsets can be selected for further accumulation and/or genetic modification to improve specificity and reactivity. Full article

(This article belongs to the Special Issue The Role of NK Cells in Health and Diseases)

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13 pages, 4837 KiB

Open AccessArticle

Hepatic Bone Morphogenetic Protein and Activin Membrane-Bound Inhibitor Levels Decline in Hepatitis C but Are Not Associated with Progression of Hepatocellular Carcinoma

by Florian Weber, Kirsten Utpatel, Katja Evert, Thomas S. Weiss and Christa Buechler

Biomedicines 2024, 12(10), 2397; https://doi.org/10.3390/biomedicines12102397 (registering DOI) - 19 Oct 2024

Abstract

Background/Objectives: Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) is an antagonist of transforming growth factor (TGF)-β type 1 signaling. BAMBI functions as an anti-fibrotic protein and exerts pro- as well as anti-cancerogenic activities. Our study aimed to correlate hepatocyte BAMBI protein levels [...] Read more.

Background/Objectives: Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) is an antagonist of transforming growth factor (TGF)-β type 1 signaling. BAMBI functions as an anti-fibrotic protein and exerts pro- as well as anti-cancerogenic activities. Our study aimed to correlate hepatocyte BAMBI protein levels in hepatocellular carcinoma (HCC) with T stage, lymph node invasion, vessel invasion, grading, tumor size and Union for International Cancer Control (UICC) stage, as well as with liver inflammation and fibrosis stages. Methods: Hepatocyte BAMBI protein expression was assessed by immunohistochemistry in HCC tissues of 320 patients and non-tumor tissues of 51 patients. Results: In the HCC tissues of the whole cohort and sex-specific analysis, BAMBI protein was not related to T stage, vessel invasion, lymph node invasion, histologic grade, UICC stage and tumor size. Accordingly, BAMBI was not associated with overall survival, recurrence-free and metastasis-free survival. BAMBI protein levels in tumor and non-tumor tissues were not related to inflammation and fibrosis grade. BAMBI protein levels in HCC tissues and non-tumor tissues from HCC patients, which were analyzed by immunoblot in a small cohort and by immunohistochemistry in the tissues of patients described above, were similar. Notably, BAMBI protein was low-abundant in HCC tissues of hepatitis C virus (HCV) compared to hepatitis B virus (HBV)-infected patients with comparable disease severity. Immunoblot analysis revealed reduced BAMBI protein in non-tumor tissues of patients with HCV in comparison to patients with HBV and normal human liver tissues. Conclusions: In summary, this analysis showed that hepatocyte BAMBI protein levels of patients with HCC are related to HCV infection rather than the severity of the underlying liver disease and cancer staging. Full article

(This article belongs to the Special Issue New Challenges in the Study of Liver Diseases: From Molecular Pathogenesis to Therapeutic Approaches—the 3rd Edition)

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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, 2504 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, 1222 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

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)

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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

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, 825 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

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)

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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 D�nes-Fazakas, Levente Kov�cs, Gy�rgy Eigner and L�szl� Szil�gyi

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

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)

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