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Biomedicines
Volume 12
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Biomedicines, Volume 12, Issue 12 (December 2024) – 281 articles

Cover Story (view full-size image): Endothelial dysfunction (ED), characterized by impaired vasoreactivity, is an early phase of cardiovascular diseases such as hypertension and atherosclerosis. Endothelial cells (ECs) regulate vascular tone, blood flow, and coagulation while also secreting cytokines, chemokines, and adhesion molecules, making them crucial players in development of cardio-metabolic diseases. Increased sodium chloride (high salt, HS) intake leads to leukocyte activation and impaired vasodilatation via increased oxidative stress, while subpressor doses of angiotensin II (AngII) restore these processes in human/animal models in vivo. This study examines how HS intake affects EC viability, reactive oxygen species (ROS) production, and cell adhesion molecule (CAM) expression and if exposure to AngII in a medium may protect against HS-induced damage. View this paper
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18 pages, 833 KiB  
Review
Comparison of Surgical Interventions for Endometrioma: A Systematic Review of Their Efficacy in Addressing Infertility
by Alexandra Ioannidou, Nikolaos Machairiotis, Sofoklis Stavros, Anastasios Potiris, Theodoros Karampitsakos, Athanasios G. Pantelis and Petros Drakakis
Biomedicines 2024, 12(12), 2930; https://doi.org/10.3390/biomedicines12122930 - 23 Dec 2024
Viewed by 1901
Abstract
Background: Endometriosis is characterized by the presence of endometrial tissue outside the uterus. Beyond medical treatment, surgical intervention is also a viable consideration. However, current guidelines do not clearly indicate whether laparoscopic cystectomy, ablative methods (CO2 laser vaporization, plasma energy), or [...] Read more.
Background: Endometriosis is characterized by the presence of endometrial tissue outside the uterus. Beyond medical treatment, surgical intervention is also a viable consideration. However, current guidelines do not clearly indicate whether laparoscopic cystectomy, ablative methods (CO2 laser vaporization, plasma energy), or sclerotherapy is the preferred option. Methods: We conducted searches in two databases (PubMed and Europe PMC) to retrieve articles containing the keywords ‘surgical intervention for Endometrioma, ovarian reserve, pregnancy rates, fertility’, published between 1 January 2000 and 31 December 2023. We included articles presenting information on surgical intervention for endometrioma and its correlation with infertility parameters. Articles describing conservative treatment were excluded. Data were extracted by two authors using predefined criteria. Results: The initial database search produced 1376 articles, which were narrowed down to 41 relevant articles meeting the eligibility criteria. Conclusions: Laparoscopic cystectomy appears to impact postoperative anti-mullerian hormone levels, showing a stronger correlation with larger cysts and individual factors. CO2 laser vaporization demonstrates favorable results compared to traditional cystectomy. Combining GnRH agonist treatment with assisted reproduction treatment after cystectomy could be considered an alternative method. Plasma energy causes less damage to ovarian function, with pregnancy outcomes comparable to cystectomy. Sclerotherapy shows promising results for ovarian reserve preservation, recurrence rates, and safety. Further studies comparing these techniques are necessary to provide guidance to clinicians. Full article
(This article belongs to the Special Issue Advanced Research in Endometriosis 4.0)
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24 pages, 4570 KiB  
Review
Current Diagnostic, Counseling, and Treatment Options in Non-Severe and Severe Apparently Isolated Fetal Ventriculomegaly
by Mateusz Zamłyński, Marta Grokhovska, Andrea Surányi and Anita Olejek
Biomedicines 2024, 12(12), 2929; https://doi.org/10.3390/biomedicines12122929 - 23 Dec 2024
Viewed by 1234
Abstract
The widening of the vestibular dimension of lateral ventricles > 10 mm should be considered a symptom rather than a definitive diagnosis. In fact, fetal ventriculomegaly (VM) is a defect with ’multifaceted‘ clinical consequences in the child’s further neurodevelopment. Isolated fetal ventriculomegaly can [...] Read more.
The widening of the vestibular dimension of lateral ventricles > 10 mm should be considered a symptom rather than a definitive diagnosis. In fact, fetal ventriculomegaly (VM) is a defect with ’multifaceted‘ clinical consequences in the child’s further neurodevelopment. Isolated fetal ventriculomegaly can cause neurological defects ranging from mild neurodevelopmental delay to severe complications in the form of ongoing palliative care to the death of patients at various developmental periods. The spectrum of compilations often depends on the severity of the ventriculomegaly. In the prenatal period, the combined diagnostic tools include the following: ultrasound/MRI and genetic, infectious tests that form the basis of reliable counseling. We hypothesize that advances in the diagnostic process allow the identification of ‘probably’ isolated forms of severe VM (ISVM). The review authors electronically searched MEDLINE, EMBASE, and the Cochrane Library databases, describing the evidence-based validity and option of prenatal decompression for ISVM. The purpose of this review is to present the evolution of diagnostic techniques and views indicating the possibility and limitations of implementing prenatal decompression in severe ISVM. In conclusion, after reviewing the available data, we want to introduce the idea that perinatal centers are close to or have reached the necessary capability, expertise, and competence to perform ISVM decompression procedures. Endoscopic ventriculostomy of the third ventricle (ETV) appears to be promising, as it seems to be associated with minimal perinatal complications and better neurological outcomes for the newborn. However, long-term follow-up results for the neurodevelopment of patients who underwent ETV have not been reported. Looking ahead, randomized trials with the long-term neurodevelopmental follow-up of children who underwent prenatal decompression due to ISVM are needed. Full article
(This article belongs to the Special Issue Advances in Fetal Medicine and Neonatology)
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21 pages, 3910 KiB  
Article
Bioactivity Evaluation and Phytochemical Characterization of Euonymus alatus (Thunb.) Siebold Leaf Extract
by Won-Joo Yoon, Hye-Ji Min, Hyun-Dong Cho, Hwi-Gon Kim, Wool-Lim Park, Du-Hyun Kim, Hirofumi Tachibana and Kwon-Il Seo
Biomedicines 2024, 12(12), 2928; https://doi.org/10.3390/biomedicines12122928 - 23 Dec 2024
Cited by 1 | Viewed by 944
Abstract
Background: Euonymus alatus (E. alatus) has traditionally been used for medicinal purposes, and its leaves are considered edible. While E. alatus is known for its diverse biological activities, the antioxidant, antidiabetic, and anticancer effects of its leaves extracted using different solvents [...] Read more.
Background: Euonymus alatus (E. alatus) has traditionally been used for medicinal purposes, and its leaves are considered edible. While E. alatus is known for its diverse biological activities, the antioxidant, antidiabetic, and anticancer effects of its leaves extracted using different solvents have not been thoroughly investigated. Methods: This study examined the antioxidant, antidiabetic, anticancer, and life-prolonging effects of Euonymus alatus (E. alatus) leaf extract. Results: The phytochemical analysis showed that the ethanol extract contained the highest levels of polyphenols (347.2 mg/mL) and flavonoids (317.7 mg/mL) compared to the water and methanol extracts. In addition, specific phenolics, such as rutin, ellagic acid, and quercetin, were found in the ethanol extract. Antioxidant assays showed that the ethanol extract exhibited superior DPPH, ABTS radical, and H2O2-scavenging activities, as well as reducing power. In addition, the ethanol extract displayed strong α-glucosidase inhibitory activity in a dose-dependent manner. In cancer cell studies, the ethanol extract selectively inhibited the proliferation of MDA-MB-231 (breast) and LNCaP (prostate) cancer cells without affecting normal cells. Apoptosis induction was confirmed by nuclear condensation and increased caspase-3 activity. Furthermore, treatment with 30 mg/kg/day of the extract extended the lifespan of the tumor-bearing mice to 50 days, with no fatalities, indicating a dose-dependent protective effect. Conclusions: E. alatus leaf ethanol extract has potential as an antioxidant, antidiabetic, anticancer, and life-prolonging agent. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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20 pages, 4103 KiB  
Review
Nanotherapeutic and Nano–Bio Interface for Regeneration and Healing
by Rajiv Kumar, Chinenye Adaobi Igwegbe and Shri Krishna Khandel
Biomedicines 2024, 12(12), 2927; https://doi.org/10.3390/biomedicines12122927 - 23 Dec 2024
Cited by 1 | Viewed by 1264
Abstract
Wound and injury healing processes are intricate and multifaceted, involving a sequence of events from coagulation to scar tissue formation. Effective wound management is crucial for achieving favorable clinical outcomes. Understanding the cellular and molecular mechanisms underlying wound healing, inflammation, and regeneration is [...] Read more.
Wound and injury healing processes are intricate and multifaceted, involving a sequence of events from coagulation to scar tissue formation. Effective wound management is crucial for achieving favorable clinical outcomes. Understanding the cellular and molecular mechanisms underlying wound healing, inflammation, and regeneration is essential for developing innovative therapeutics. This review explored the interplay of cellular and molecular processes contributing to wound healing, focusing on inflammation, innervation, angiogenesis, and the role of cell surface adhesion molecules. Additionally, it delved into the significance of calcium signaling in skeletal muscle regeneration and its implications for regenerative medicine. Furthermore, the therapeutic targeting of cellular senescence for long-term wound healing was discussed. The integration of cutting-edge technologies, such as quantitative imaging and computational modeling, has revolutionized the current approach of wound healing dynamics. The review also highlighted the role of nanotechnology in tissue engineering and regenerative medicine, particularly in the development of nanomaterials and nano–bio tools for promoting wound regeneration. Moreover, emerging nano–bio interfaces facilitate the efficient transport of biomolecules crucial for regeneration. Overall, this review provided insights into the cellular and molecular mechanisms of wound healing and regeneration, emphasizing the significance of interdisciplinary approaches and innovative technologies in advancing regenerative therapies. Through harnessing the potential of nanoparticles, bio-mimetic matrices, and scaffolds, regenerative medicine offers promising avenues for restoring damaged tissues with unparalleled precision and efficacy. This pursuit marks a significant departure from traditional approaches, offering promising avenues for addressing longstanding challenges in cellular and tissue repair, thereby significantly contributing to the advancement of regenerative medicine. Full article
(This article belongs to the Special Issue Materials for Biomedical Engineering and Regenerative Medicine)
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9 pages, 1046 KiB  
Article
Efficacy of Hypoxia-Inducible Factor Prolyl-Hydroxylase Inhibitors in Renal Anemia: Enhancing Erythropoiesis and Long-Term Outcomes in Patients with Chronic Kidney Disease
by Yukina Yoshida, Tomoaki Takata, Sosuke Taniguchi, Kana Kageyama, Yudai Fujino, Hinako Hanada, Yukari Mae, Takuji Iyama, Katsuya Hikita and Hajime Isomoto
Biomedicines 2024, 12(12), 2926; https://doi.org/10.3390/biomedicines12122926 - 23 Dec 2024
Viewed by 1342
Abstract
Background/Objectives: Renal anemia is one of the major complications associated with chronic kidney disease (CKD). Erythropoietin-stimulating agents (ESAs) are commonly used; however, some patients exhibit resistance. Hypoxia-inducible factor prolyl-hydroxylase inhibitors (HIF-PHIs) have emerged as a novel treatment for renal anemia, enhancing erythropoiesis and [...] Read more.
Background/Objectives: Renal anemia is one of the major complications associated with chronic kidney disease (CKD). Erythropoietin-stimulating agents (ESAs) are commonly used; however, some patients exhibit resistance. Hypoxia-inducible factor prolyl-hydroxylase inhibitors (HIF-PHIs) have emerged as a novel treatment for renal anemia, enhancing erythropoiesis and iron metabolism. Methods: We retrospectively analyzed laboratory data related to erythropoiesis from 105 patients with CKD before and after treatment with HIF-PHI or ESA. The dialysis initiation and mortality rates were also assessed over a median follow-up of 614 days. Results: HIF-PHI and ESA significantly increased the hemoglobin levels within 6 months of treatment (9.5 ± 1.0 to 10.7 ± 1.1, p < 0.01, and 9.9 ± 1.5 to 10.7 ± 1.2 g/dL, p < 0.01, respectively). The HIF-PHI group demonstrated a significant decrease in red cell distribution width (14.5 ± 1.9% to 13.8 ± 1.4%, p < 0.01), suggesting improved erythropoiesis, and exhibited a lower cumulative incidence of outcomes. The aged-adjusted multivariate analysis confirmed the independent association between HIF-PHI treatment and reduced risk of cumulative outcome (p = 0.042). Conclusions: HIF-PHIs can serve as an alternative to ESA for managing renal anemia in CKD, improving both hematological parameters and long-term outcomes. Full article
(This article belongs to the Special Issue New Advances in Chronic Kidney Disease: Biology, Diagnosis and Therapy (2nd Edition))
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11 pages, 995 KiB  
Article
Lumbopelvic Muscle Mechanical Properties in Women with Multiple Sclerosis: A Cross-Sectional Case-Controlled Study
by Inés Cruz-Medel, María Ángeles Peña-Toledo, Francisco Alburquerque-Sendín, Daiana Priscila Rodrigues-de-Souza, Cristina Conde-Gavilán, Ana María Jover-Sánchez, Claudia Carmona-Medialdea and Eduardo Agüera-Morales
Biomedicines 2024, 12(12), 2925; https://doi.org/10.3390/biomedicines12122925 - 23 Dec 2024
Viewed by 844
Abstract
Background/Objectives: To compare the lumbopelvic muscle mechanical properties (MMPs) of women with and without multiple sclerosis (MS) and explore relationships between these properties and sociodemographic/clinical characteristics. Methods: This cross-sectional observational study included 22 women with MS and 22 age- and BMI-matched [...] Read more.
Background/Objectives: To compare the lumbopelvic muscle mechanical properties (MMPs) of women with and without multiple sclerosis (MS) and explore relationships between these properties and sociodemographic/clinical characteristics. Methods: This cross-sectional observational study included 22 women with MS and 22 age- and BMI-matched women without MS. MMPs (frequency, stiffness, decrement, relaxation, and creep) of pelvic floor and lumbar paravertebral muscles were assessed using a MyotonPRO device. Sociodemographic and clinical data related to pelvic floor health were also collected. Results: Women with MS showed significant differences in pelvic floor MMPs, including higher frequency (3.26 Hz; 95% CI [2.12, 4.41]), stiffness (90 N/m; 95% CI [55.09, 124.91]), and decrement (0.2; 95% CI [0.09, 0.31]), and lower relaxation (6.15 ms; 95% CI [8.26, 4.05]) and creep (0.24; 95% CI [0.34, 0.13]) compared to women without MS. For lumbar paravertebral muscles, differences were observed only on the right side, with lower frequency (2.15 Hz; 95% CI [0.28, 4.02]) and stiffness (62.17 N/m; 95% CI [10.7, 113.65]) in women with MS. Correlation patterns between MMPs and clinical characteristics differed by group, with moderate correlations found only in the MS group (e.g., EDSS: r = 0.57; p = 0.006; PFDI-20: r = 0.47; p = 0.026). Conclusions: Women with MS exhibit altered pelvic floor MMPs, characterized by reduced tone and stiffness and increased elasticity and viscoelasticity, while lumbar paravertebral differences are minimal. These findings highlight the need for objective MMP assessments in women with MS to guide preventive and therapeutic interventions. Full article
(This article belongs to the Special Issue Emerging Research in Neurorehabilitation)
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13 pages, 4535 KiB  
Article
Tocilizumab in COVID-19: A Double-Edged Sword?
by Bartosz Kudliński, Jacek Zawadzki, Wiktoria Kulińska, Jagoda Kania, Magdalena Murkos, Marta Stolińska, Dominika Zgoła, Anna Noga and Paweł Nowak
Biomedicines 2024, 12(12), 2924; https://doi.org/10.3390/biomedicines12122924 - 23 Dec 2024
Viewed by 937
Abstract
Background/Objectives: SARS-CoV-2 was responsible for the global pandemic. Approximately 10–15% of patients with COVID-19 developed respiratory failure with adult acute respiratory distress syndrome (ARDS), which required treatment in the Intensive Care Unit (ICU). The cytokine storm observed in severe COVID-19 was frequently handled [...] Read more.
Background/Objectives: SARS-CoV-2 was responsible for the global pandemic. Approximately 10–15% of patients with COVID-19 developed respiratory failure with adult acute respiratory distress syndrome (ARDS), which required treatment in the Intensive Care Unit (ICU). The cytokine storm observed in severe COVID-19 was frequently handled with steroids. Synergically, tocilizumab, an anti-interleukin-6 receptor monoclonal antibody, gained popularity as a cytokine storm-suppressing agent. However, immunosuppression was proven to increase the predisposition to infections with resistant bacteria. Our study aimed to assess the relationship between positive tests for secondary infections and the survival of patients with severe COVID-19-attributed ARDS treated with immunosuppressive agents. Methods: This study included 342 patients qualified for the ICU and mechanical ventilation (MV). The patients were divided based on the type of immunomodulating therapy and the culture tests results. Results: The results showed the highest survival rate among patients <61 years, favoring the combined treatment (tocilizumab + steroids). Atrial fibrillation (AF) and coronary heart disease (CHD) correlated with a lower survival rate than other comorbidities. Tocilizumab was associated with an increased risk of positive pathogen cultures, which could potentially cause secondary infections; however, the survival rate among these patients was higher. Conclusions: MV and ICU procedures as well as the application of tocilizumab significantly decreased the mortality rate in patients with severe COVID-19-related ARDS. The suppression of cytokine storms played a crucial role in survival. Tocilizumab was found to be both efficient and safe despite the ‘side effect’ of the increased risk of positive results for secondary infections. Full article
(This article belongs to the Special Issue State-of-the-Art Drug Discovery and Development in Poland (2nd Edition))
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13 pages, 1964 KiB  
Case Report
Treatment Outcomes and Toxicities of Multiple Tyrosin Kinase Inhibitors for Metastatic Medullary Thyroid Cancer: A Case Series
by Marilda Mormando, Rosa Lauretta, Giulia Puliani, Marta Bianchini, Maria Elena Spoltore and Marialuisa Appetecchia
Biomedicines 2024, 12(12), 2923; https://doi.org/10.3390/biomedicines12122923 - 23 Dec 2024
Viewed by 869
Abstract
Background: The current possible treatments of advanced medullary carcinoma (MTC) include different drugs belonging to the class of tyrosine kinase inhibitors (TKIs): vandetanib, cabozantinb, and selpercatinib. Although the effects of these TKIs have been well described in clinical trials, the real-practice evidence [...] Read more.
Background: The current possible treatments of advanced medullary carcinoma (MTC) include different drugs belonging to the class of tyrosine kinase inhibitors (TKIs): vandetanib, cabozantinb, and selpercatinib. Although the effects of these TKIs have been well described in clinical trials, the real-practice evidence of the effectiveness and safety of these treatment is scant. This real-world case series aims to describe a niche of patients with advanced MTC treated with more than one TKI by focusing on treatment responses and any reported adverse events (AEs) and to provide additional insight on the individualized approach to the management of metastatic MTC. Methods: Five patients with a diagnosis of metastastic MTC, treated with at least two different molecules of TKIs, were retrospectively selected. Results: Three patients obtained a partial response (one with cabozantinb, one with selpercatinib, and one with vandetanib), and two patients obtained disease stability (both of them treated with all three TKIs, the first two lines discontinued for AEs). The AE profile agreed with the known clinical trials AEs except for non-neoplastic ascites related to selpercatinib and lung cavitations of non-neoplastic tissue related to cabozantinb. The latter was an AE never described so far in patients receiving TKIs. Conclusions: The best management of MTC relies on an individualized approach, keeping in mind and dealing with the potential toxicity in order to minimize the treatment withdrawal. Full article
(This article belongs to the Special Issue An Update on Mechanisms and Treatments for Thyroid Cancer in Current Oncology)
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12 pages, 2452 KiB  
Article
The Effect of Increasing the Body’s Core Temperature and Improving Blood Flow by Using Far-Infrared Rays Emitted from Functional Loess Bio-Balls
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(12), 2922; https://doi.org/10.3390/biomedicines12122922 - 23 Dec 2024
Viewed by 924
Abstract
Background: Low-energy far-infrared rays (FIRs) are widely used in the treatment of wounds, lymphedema, and various vascular diseases, and various types of products that emit infrared rays are being used at home for patients with blood flow-related diseases without experimental evidence. Methods: Blood [...] Read more.
Background: Low-energy far-infrared rays (FIRs) are widely used in the treatment of wounds, lymphedema, and various vascular diseases, and various types of products that emit infrared rays are being used at home for patients with blood flow-related diseases without experimental evidence. Methods: Blood flow and epidermal temperature were measured while applying conductive heat and FIRs via an electric mat (non-intervention) or a loess bio-ball mat (intervention). Results: In the control group (n = 30), there was a minimal change in blood flow and epidermal temperature in the right and left middle fingers (LMF, RMF) as the mat temperature gradually increased. In the experimental group (n = 30), when the mat temperature increased from 25 °C to 50 °C, the blood flow increased by 39.80% in the LMF and by 41.83% in the RMF. In addition, the epidermal temperature increased by 8.78% in the LMF and by 8.44% in the RMF. Conclusions: The FIRs emitted from loess bio-balls can be applied to alleviate symptoms not only in patients with blood flow problems in medical settings but also in people who complain of discomfort due to blood flow disorders or cold hands and feet during their daily life and sleep. Full article
(This article belongs to the Section Biomedical Engineering and Materials)
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11 pages, 2098 KiB  
Article
Acute Myeloid Leukemia with Normal Cytogenetics and NPM1-Mutation: Impact of Mutation Topography on Outcomes
by Mingyue Zhao, Mingyue Liao, Robert Peter Gale, Meijie Zhang, Lixin Wu, Nan Yan, Lixia Liu, Jiayue Qin, Shanbo Cao, Yingjun Chang, Qian Jiang, Lanping Xu, Xiaohui Zhang, Xiaojun Huang, Hao Jiang and Guorui Ruan
Biomedicines 2024, 12(12), 2921; https://doi.org/10.3390/biomedicines12122921 - 23 Dec 2024
Cited by 1 | Viewed by 1003
Abstract
Background: About half of adults with acute myeloid leukemia with normal cytogenetics (CN-AML) have NPM1 mutations. There is controversy regarding their prognosis and best therapy. Methods: We studied 150 subjects with these features using targeted regional sequencing. Prognostic stratification was carried [...] Read more.
Background: About half of adults with acute myeloid leukemia with normal cytogenetics (CN-AML) have NPM1 mutations. There is controversy regarding their prognosis and best therapy. Methods: We studied 150 subjects with these features using targeted regional sequencing. Prognostic stratification was carried out based on risk factors, and we assessed the effects of two post-remission strategies with and without transplant across risk cohorts. Results: In multi-variable analyses, a positive MRD test after the second consolidation cycle (HR = 6.00; 95% CI [3.31, 10.85]; p < 0.001), DNMT3A mutations (HR = 3.01 [1.57, 5.78]; p < 0.001), FLT3-ITD mutation with high variant allele frequency (HR = 4.40 [1.89, 10.24]; p < 0.001) and DDX11 mutations (HR = 4.38 [2.38, 8.04]; p < 0.001) were independently correlated with higher cumulative incidence of relapse (CIR) and worse leukemia-free survival (LFS) (HR = 5.49 [3.01, 10.04]; p < 0.001; HR = 2.99 [1.60, 5.62]; p < 0.001; HR = 4.20 [1.87, 9.40]; p < 0.001; and HR = 4.22, 95% CI [1.99, 8.95], p < 0.001). Subjects with ≥1 high-risk co-variate who received a transplant had a lower CIR and better LFS, whereas others did not. Conclusions: We identified co-variates associated with CIR and LFS in subjects of NPM1-mutated CN-AML. Full article
(This article belongs to the Section Molecular Genetics and Genetic Diseases)
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23 pages, 410 KiB  
Review
Passive Immunisation in the Treatment of Infectious Diseases Related to Highly Potent Bacterial Toxins
by Marta Prygiel, Ewa Mosiej, Karol Wdowiak and Aleksandra Anna Zasada
Biomedicines 2024, 12(12), 2920; https://doi.org/10.3390/biomedicines12122920 - 23 Dec 2024
Cited by 1 | Viewed by 1215
Abstract
The discovery of microbial toxins as the primary factors responsible for disease manifestations and the discovery that these toxins could be neutralised by antitoxins are linked to the birth of immunology. In the late 19th century, the serum or plasma of animals or [...] Read more.
The discovery of microbial toxins as the primary factors responsible for disease manifestations and the discovery that these toxins could be neutralised by antitoxins are linked to the birth of immunology. In the late 19th century, the serum or plasma of animals or patients who had recovered from infectious diseases or who had been immunised with a relevant antigen began to be used to treat or prevent infections. Before the advent of widespread vaccination campaigns, antitoxins played a key role in the treatment and prevention of diseases such as diphtheria and tetanus. A significant reduction in mortality following the introduction of antitoxins confirmed their efficacy. Serum therapy remains an important measure for post-exposure prophylaxis and for the treatment of unvaccinated or incompletely vaccinated patients. For the botulinum toxin, antitoxin therapy continues to be the sole available treatment. The manuscript contains a summary of the most important information on the passive immunoprophylaxis used in the treatment of diphtheria, tetanus, and botulism, all representing diseases in which symptoms are driven by the activity of highly potent bacterial toxins. Full article
(This article belongs to the Special Issue Mechanisms, Implications, and Therapeutic Targets in Infectious Diseases)
3 pages, 151 KiB  
Editorial
Feature Collection in Peptide Therapeutics: Current Applications and Future Directions
by Bernard Lebleu
Biomedicines 2024, 12(12), 2919; https://doi.org/10.3390/biomedicines12122919 - 23 Dec 2024
Cited by 1 | Viewed by 842
Abstract
The use of peptides in medicine began long ago with peptidic hormones [...] Full article
(This article belongs to the Section Gene and Cell Therapy)
10 pages, 484 KiB  
Communication
Safety Concerns in Neurological Clinical Trials: A Challenge That the FDA Must Resolve
by Sarfaraz K. Niazi
Biomedicines 2024, 12(12), 2918; https://doi.org/10.3390/biomedicines12122918 - 22 Dec 2024
Cited by 2 | Viewed by 1216
Abstract
Background: Monoclonal antibodies approved by the FDA, lecanemab, donanemab, and aducanumab, are failing to meet the expected efficacy to treat early Alzheimer’s disease, and aducanumab has been recalled. Methods: Recently, it was reported that the clinical trials of these antibodies may have [...] Read more.
Background: Monoclonal antibodies approved by the FDA, lecanemab, donanemab, and aducanumab, are failing to meet the expected efficacy to treat early Alzheimer’s disease, and aducanumab has been recalled. Methods: Recently, it was reported that the clinical trials of these antibodies may have violated patient’s rights and subjected them to high, likely lethal risk. The challenge with developing antibodies to treat neurological disorders is their poor blood–brain barrier (BBB) penetration if the antibody must enter the brain, resulting in almost negligible brain bioavailability, requiring high dosing that can be toxic. Results: The reported efficacy of these drugs should also be reviewed, considering the placebo effects, since all antibodies have shown severe side effects that are not prevented by the placebo responses. In this critical and urgent advice to the FDA, I am suggesting a guideline amendment to all clinical trials requiring proof of sufficient brain bioavailability at the site of action, where it is known. Conclusions: For antibodies to cross the blood–brain barrier, there are proven options such as conjugating with transferrin protein, making clinical trials in its absence more questionable. Full article
(This article belongs to the Special Issue Biomedical and Biochemical Basis of Neurodegenerative Diseases)
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12 pages, 1608 KiB  
Article
Thermal Water Reduces the Inflammatory Process Induced by the SARS-CoV-2 Spike Protein in Human Airway Epithelial Cells In Vitro
by Anna Scanu, Maria Chiara Maccarone, Fabrizio Caldara, Gianluca Regazzo, Roberto Luisetto and Stefano Masiero
Biomedicines 2024, 12(12), 2917; https://doi.org/10.3390/biomedicines12122917 - 21 Dec 2024
Viewed by 1053
Abstract
Background: Although treatments using thermal water have yielded beneficial effects in respiratory tract infections, the effects of thermal water under experimental conditions similar to those triggered by SARS-CoV-2 have yet to be evaluated. This study aimed to assess whether thermal water could [...] Read more.
Background: Although treatments using thermal water have yielded beneficial effects in respiratory tract infections, the effects of thermal water under experimental conditions similar to those triggered by SARS-CoV-2 have yet to be evaluated. This study aimed to assess whether thermal water could interfere with the interaction between SARS-CoV-2 and host cells and influence inflammatory factors. Methods: Human nasal epithelial primary cells (HNEpCs) were stimulated with SARS-CoV-2 spike protein in the presence or absence of thermal water or tap water. Cell viability, cytokine concentration, ACE2 and TMPRSS2 levels, and ACE2 activity were determined in the cell cultures. Results: Exposure of HNEpCs to spike protein increased IL-6, IL-8, and IL-1β production, with decreased production observed in the presence of thermal water at an optimal dose. Treatment of cells with tap water did not affect cytokine release in unstimulated or spike-stimulated cells. Spike-protein-stimulated HNEpCs showed reduced levels of ACE2, which were partially restored only in the presence of thermal water. Spike protein did not affect the TMPRSS2 levels of the cell lysates. Stimulation with spike protein induced an increase in the concentration of both receptors in the supernatants, while treatment with thermal water reduced TMPRSS2 levels in both the cells and supernatants. Stimulation with spike protein increased ACE2 activity, which was reduced with thermal water. Conclusions: This study shows the regulatory effects of mineral-rich thermal water on spike-protein-induced pro-inflammatory cytokine production and the amount and activity of receptors mainly involved in viral entry, suggesting a potential use of this treatment as a support therapy for SARS-CoV-2 infection of the upper respiratory tract. Full article
(This article belongs to the Special Issue Inflammation, Immunity, and Tissue Regeneration: New Treatments and Future Directions)
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22 pages, 10397 KiB  
Article
Mannich Base Derived from Lawsone Inhibits PKM2 and Induces Neoplastic Cell Death
by Lucas Rubini-Dias, Tácio V. A. Fernandes, Michele P. de Souza, Déborah Hottz, Afonso T. Arruda, Amanda de A. Borges, Gabriel Ouverney, Fernando de C. da Silva, Luana da S. M. Forezi, Gabriel Limaverde-Sousa and Bruno K. Robbs
Biomedicines 2024, 12(12), 2916; https://doi.org/10.3390/biomedicines12122916 - 21 Dec 2024
Viewed by 1174
Abstract
Background/Objectives: Pyruvate kinase M2, a central regulator of cancer cell metabolism, has garnered significant attention as a promising target for disrupting the metabolic adaptability of tumor cells. This study explores the potential of the Mannich base derived from lawsone (MB-6a) to [...] Read more.
Background/Objectives: Pyruvate kinase M2, a central regulator of cancer cell metabolism, has garnered significant attention as a promising target for disrupting the metabolic adaptability of tumor cells. This study explores the potential of the Mannich base derived from lawsone (MB-6a) to interfere with PKM2 enzymatic activity both in vitro and in silico. Methods: The antiproliferative potential of MB-6a was tested using MTT assay in various cell lines, including SCC-9, Hep-G2, HT-29, B16-F10, and normal human gingival fibroblast (HGF). The inhibition of PKM2 mediated by MB-6a was assessed using an LDH-coupled assay and by measuring ATP production. Docking studies and molecular dynamics calculations were performed using Autodock 4 and GROMACS, respectively, on the tetrameric PKM2 crystallographic structure. Results: The Mannich base 6a demonstrated selective cytotoxicity against all cancer cell lines tested without affecting cell migration, with the highest selectivity index (SI) of 4.63 in SCC-9, followed by B16-F10 (SI = 3.9), Hep-G2 (SI = 3.4), and HT-29 (SI = 2.03). The compound effectively inhibited PKM2 glycolytic activity, leading to a reduction of ATP production both in the enzymatic reaction and in cells treated with this naphthoquinone derivative. MB-6a showed favorable binding to PKM2 in the ATP-bound monomers through docking studies (PDB ID: 4FXF; binding affinity scores ranging from −6.94 to −9.79 kcal/mol) and MD simulations, revealing binding affinities stabilized by key interactions including hydrogen bonds, halogen bonds, and hydrophobic contacts. Conclusions: The findings suggest that MB-6a exerts its antiproliferative activity by disrupting cell glucose metabolism, consequently reducing ATP production and triggering energetic collapse in cancer cells. This study highlights the potential of MB-6a as a lead compound targeting PKM2 and warrants further investigation into its mechanism of action and potential clinical applications. Full article
(This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy—Second Edition)
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15 pages, 618 KiB  
Article
Is Ultrasonography an Effective Method for Diagnosing Degenerative Changes in the Temporomandibular Joint?
by Barbara Wojciechowska, Arkadiusz Szarmach, Adam Michcik, Maciej Sikora and Barbara Drogoszewska
Biomedicines 2024, 12(12), 2915; https://doi.org/10.3390/biomedicines12122915 - 21 Dec 2024
Cited by 2 | Viewed by 1069
Abstract
Background: The accurate diagnosis of degenerative joint diseases (DJDs) of the temporomandibular joint (TMJ) presents a significant clinical challenge due to their progressive nature and the complexity of associated structural changes. These conditions, characterized by cartilage degradation, subchondral bone remodeling, and eventual joint [...] Read more.
Background: The accurate diagnosis of degenerative joint diseases (DJDs) of the temporomandibular joint (TMJ) presents a significant clinical challenge due to their progressive nature and the complexity of associated structural changes. These conditions, characterized by cartilage degradation, subchondral bone remodeling, and eventual joint dysfunction, necessitate reliable and efficient imaging techniques for early detection and effective management. Cone-beam computed tomography (CBCT) is widely regarded as the gold standard for evaluating osseous changes in the TMJ, offering detailed visualization of bony structures. However, ultrasonography (US) has emerged as a promising alternative, offering a non-invasive and radiation-free option for assessing TMJ disorders. This study aims to evaluate the diagnostic accuracy of US in identifying degenerative changes in the TMJ, with CBCT serving as the definitive diagnostic reference. By analyzing the sensitivity, specificity, and predictive values of US in detecting key degenerative markers—such as subchondral erosion, osteophytes, and joint space narrowing—this investigation seeks to assess its utility as a screening tool and its potential integration into clinical workflows. Methods: Forty adult patients presenting temporomandibular joint disorders were included in our cross-sectional study. Each patient underwent a clinical examination and was subjected to cone-beam computed tomography (CBCT) and ultrasonography (US). A statistical analysis was performed to compare the imaging results from CBCT and US. Results: The results are summarized in three tables. The first table presents a comparative analysis of radiological outcomes in patients with temporomandibular joint disorders using different imaging techniques. CBCT demonstrated higher sensitivity in detecting osteophytes in the right mandibular head (27.50% vs. 7.50%, p = 0.027) and higher detection rates for erosions, though without a significant advantage over US. The second table analyzes the consistency of diagnostic results between CBCT and US. A moderate agreement was observed for detecting normal bone structures, with AC1 values of 0.58 for the right and 0.68 for the left mandibular head (p < 0.001). The third table evaluates the diagnostic accuracy of US compared to CBCT. US demonstrated a positive predictive value (PPV) of 90% for detecting normal conditions, indicating its high reliability as a screening tool for normal findings. US demonstrates higher effectiveness in ruling out certain issues due to its high specificity and negative predictive value. However, its lower sensitivity in detecting abnormalities may lead to both false-positive and false-negative results. Conclusions: US holds significant promise as a screening modality for detecting normal anatomical features of the temporomandibular joint, its limitations in identifying more complex degenerative changes necessitate a cautious and integrated approach to TMJ diagnostics. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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14 pages, 666 KiB  
Review
Cancer Therapy-Related Cardiac Dysfunction: A Review of Current Trends in Epidemiology, Diagnosis, and Treatment
by Panagiotis Theofilis, Panayotis K. Vlachakis, Evangelos Oikonomou, Maria Drakopoulou, Paschalis Karakasis, Anastasios Apostolos, Konstantinos Pamporis, Konstantinos Tsioufis and Dimitris Tousoulis
Biomedicines 2024, 12(12), 2914; https://doi.org/10.3390/biomedicines12122914 - 21 Dec 2024
Cited by 1 | Viewed by 1847
Abstract
Cancer therapy-related cardiac dysfunction (CTRCD) has emerged as a significant concern with the rise of effective cancer treatments like anthracyclines and targeted therapies such as trastuzumab. While these therapies have improved cancer survival rates, their unintended cardiovascular side effects can lead to heart [...] Read more.
Cancer therapy-related cardiac dysfunction (CTRCD) has emerged as a significant concern with the rise of effective cancer treatments like anthracyclines and targeted therapies such as trastuzumab. While these therapies have improved cancer survival rates, their unintended cardiovascular side effects can lead to heart failure, cardiomyopathy, and arrhythmias. The pathophysiology of CTRCD involves oxidative stress, mitochondrial dysfunction, and calcium dysregulation, resulting in irreversible damage to cardiomyocytes. Inflammatory cytokines, disrupted growth factor signaling, and coronary atherosclerosis further contribute to this dysfunction. Advances in cardio-oncology have led to the early detection of CTRCD using cardiac biomarkers like troponins and imaging techniques such as echocardiography and cardiac magnetic resonance (CMR). These tools help identify asymptomatic patients at risk of cardiac events before the onset of clinical symptoms. Preventive strategies, including the use of cardioprotective agents like beta-blockers, angiotensin-converting enzyme inhibitors, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors have shown promise in reducing the incidence of CTRCD. This review summarizes the mechanisms, detection methods, and emerging treatments for CTRCD, emphasizing the importance of interdisciplinary collaboration between oncologists and cardiologists to optimize care and improve both cancer and cardiovascular outcomes. Full article
(This article belongs to the Special Issue Acute and Chronic Heart Failure: Pathophysiology and New Therapeutic Developments)
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16 pages, 3981 KiB  
Article
Integration of Stromal Cells and Hydrogel Below Epithelium Results in Optimal Barrier Properties of Small Intestine Organoid Models
by Melis Asal, Maria Thon, Taco Waaijman, Hetty J. Bontkes, Sandra J. van Vliet, Reina E. Mebius and Susan Gibbs
Biomedicines 2024, 12(12), 2913; https://doi.org/10.3390/biomedicines12122913 - 21 Dec 2024
Viewed by 1189
Abstract
Background/Objectives: The barrier properties of the human small intestine play a crucial role in regulating digestion, nutrient absorption and drug metabolism. Current in vitro organotypic models consist only of an epithelium, which does not take into account the possible role of stromal [...] Read more.
Background/Objectives: The barrier properties of the human small intestine play a crucial role in regulating digestion, nutrient absorption and drug metabolism. Current in vitro organotypic models consist only of an epithelium, which does not take into account the possible role of stromal cells such as fibroblasts or the extracellular matrix (ECM) which could contribute to epithelial barrier properties. Therefore, the aim of this study was to determine whether these stromal cells or ECM were beneficial or detrimental to barrier function when incorporated into an organotypic human small intestine model. Methods: Intestinal epithelial cell lines or primary cell organoids derived from the epithelial stem cells of the small intestine were cultivated either on a porous Transwell membrane (epithelial model) or on a primary small intestinal stromal cell-populated collagen-fibrin hydrogel (full thickness model). Results: Both models expressed villin (enterocytes), lysozyme (Paneth cells), Ki67 (proliferative cells) and zonula occludens-1 (tight junctions). The polarized epithelial barriers of the full thickness models demonstrated a significant decrease in transepithelial electrical resistance (TEER) with values comparable to that found in the native small intestine in contrast to the higher TEER values observed in the epithelial models. This correlated to an increase in secreted zonulin, a regulator of intestine permeability, in the full thickness models. The decreased TEER values were due to both the stromal cells and the choice of the hydrogel versus the Transwell membrane. Moreover, erythropoietin and epithelial growth factor secretion, which have roles in regulating barrier integrity, directly correlated with the changes in TEER and permeability. Conclusions: This study emphasizes the importance of different cell types being incorporated into small intestine models and, also, the influence of the scaffold or matrix used. Full article
(This article belongs to the Special Issue The Role of Intestinal Epithelial Cells and Their Cellular Interactions)
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18 pages, 328 KiB  
Review
Therapeutic Potential of Nutritional Aryl Hydrocarbon Receptor Ligands in Gut-Related Inflammation and Diseases
by Fu-Chen Huang
Biomedicines 2024, 12(12), 2912; https://doi.org/10.3390/biomedicines12122912 - 20 Dec 2024
Cited by 1 | Viewed by 899
Abstract
A solid scientific foundation is required to build the concept of personalized nutrition developed to promote health and a vision of disease prevention. Growing evidence indicates that nutrition can modulate the immune system through metabolites, which are either generated via microbiota metabolism or [...] Read more.
A solid scientific foundation is required to build the concept of personalized nutrition developed to promote health and a vision of disease prevention. Growing evidence indicates that nutrition can modulate the immune system through metabolites, which are either generated via microbiota metabolism or host digestion. The aryl hydrocarbon receptor (AhR) plays a crucial role in regulating immune responses, particularly in the gut, and has emerged as a key modulator of gut-mediated inflammation and related diseases. AhR is a ligand-activated transcription factor that responds to environmental, dietary, and microbial-derived signals, influencing immune balance and maintaining intestinal homeostasis. Nutritional AhR ligands play a significant role in modulating intestinal immunity and the function of mucosal immune cells, thereby exerting clinical effects on colitis and innate immunity. Additionally, they have the capacity to orchestrate autophagy, phagocytic cell function, and intestinal epithelial tight junctions. Therapeutic strategies aimed at enhancing AhR activity, restoring gut integrity, and optimizing immune responses hold promise as avenues for future research and potential treatments for critically ill patients. Full article
(This article belongs to the Special Issue Feature Reviews in Gastrointestinal Diseases)
16 pages, 988 KiB  
Article
Impact of Rhegmatogenous Retinal Detachment on Macular Vascular and Functional Integrity
by María Dolores Díaz-Barreda, Ana Boned-Murillo, Isabel Bartolomé-Sesé, María Sopeña-Pinilla, Elvira Orduna-Hospital, Guisela Fernández-Espinosa and Isabel Pinilla
Biomedicines 2024, 12(12), 2911; https://doi.org/10.3390/biomedicines12122911 - 20 Dec 2024
Viewed by 734
Abstract
Objectives: This study aimed to evaluate the correlations between optical coherence tomography angiography (OCTA), best corrected visual acuity (BCVA), and macular integrity assessment (MAIA) microperimetry (MP) in both a control group and patients with rhegmatogenous retinal detachment (RRD). Additionally, it assessed differences between [...] Read more.
Objectives: This study aimed to evaluate the correlations between optical coherence tomography angiography (OCTA), best corrected visual acuity (BCVA), and macular integrity assessment (MAIA) microperimetry (MP) in both a control group and patients with rhegmatogenous retinal detachment (RRD). Additionally, it assessed differences between the groups and examined whether the time from symptom onset to surgery influenced microvascular or functional changes in the RRD group. Methods: A cross-sectional study was conducted involving 47 patients who had undergone successful RRD surgery with pars plana vitrectomy (PPV) and sulfur-hexafluoride (SF6) gas injection, with or without scleral buckling (SB), and a control group of 136 healthy eyes. All participants underwent comprehensive ophthalmologic examinations, including BCVA, OCTA, and MAIA. In the RRD group, additional data on symptom duration, time from symptom onset to surgery, and time from surgery to testing were collected. Results: The RRD group exhibited significantly worse BCVA (p < 0.001) compared to the control group. Significant differences were found in all MAIA sectors, with controls showing superior macular integrity and average threshold values (p < 0.001). OCTA analysis revealed differences in the superficial capillary plexus (SCP) and deep capillary plexus (DCP) across various sectors, particularly in the foveal avascular zone (FAZ). In the control group, the vertical diameter of the FAZ in the SCP was positively correlated with most MAIA sectors, while in the DCP, correlations were seen in nearly all sectors. The RRD group showed fewer correlations between OCTA and MAIA, and no significant correlations were found between OCTA parameters and BCVA. However, there were correlations between the time from surgery to testing and MAIA outcomes, indicating improved results with longer intervals. Earlier surgical intervention after symptom onset was associated with better microvascular outcomes. Conclusions: RRD group exhibited significant impairments in BCVA, retinal sensitivity, and microvascular parameters compared to healthy controls. Correlations between OCTA findings and microperimetry were stronger in the control group, whereas the RRD group showed fewer and weaker associations. Full article
(This article belongs to the Section Cell Biology and Pathology)
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24 pages, 845 KiB  
Review
Bile Acids in Inflammatory Bowel Disease: From Pathophysiology to Treatment
by Samantha H. Bai, Arun Chandnani and Siyan Cao
Biomedicines 2024, 12(12), 2910; https://doi.org/10.3390/biomedicines12122910 - 20 Dec 2024
Cited by 1 | Viewed by 2109
Abstract
Inflammatory bowel disease (IBD) is a chronic condition that affects about 7 million people worldwide, and new therapies are needed. Understanding the complex roles that bile acids (BAs) play in IBD may lead to the development of novel IBD treatments independent of direct [...] Read more.
Inflammatory bowel disease (IBD) is a chronic condition that affects about 7 million people worldwide, and new therapies are needed. Understanding the complex roles that bile acids (BAs) play in IBD may lead to the development of novel IBD treatments independent of direct immunosuppression. This review discusses the latest discoveries in the roles BAs play in IBD pathogenesis and explores how these discoveries offer promising new therapeutic targets to treat IBD and improve patient outcomes. Several therapies discussed include specific BA receptor (BAR) agonists, dietary therapies, supplements, probiotics, and mesenchymal stem cell therapies that have all been shown to decrease IBD disease activity. Full article
(This article belongs to the Special Issue Crohn's Disease and Ulcerative Colitis: From Pathophysiology to Novel Therapeutic Approaches (2nd Edition))
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13 pages, 4450 KiB  
Article
The Use and Benefits of Focused Shockwaves for the Diagnosis of Myofascial Pain Syndrome by Examining Myofascial Trigger Points in Low Back Pain
by Hannes Müller-Ehrenberg, Federico Giordani, Alessandra Müller-Ehrenberg and Richard Stange
Biomedicines 2024, 12(12), 2909; https://doi.org/10.3390/biomedicines12122909 - 20 Dec 2024
Cited by 1 | Viewed by 2044
Abstract
Background/Objectives: Low back pain (LBP) is a widespread public health issue, with myofascial pain syndrome (MPS) being a common cause, affecting 67–100% of patients. However, there are significant challenges in the diagnostic process due to the subjective and unreliable nature of manual [...] Read more.
Background/Objectives: Low back pain (LBP) is a widespread public health issue, with myofascial pain syndrome (MPS) being a common cause, affecting 67–100% of patients. However, there are significant challenges in the diagnostic process due to the subjective and unreliable nature of manual palpation. Focused Extracorporeal Shockwave Therapy (F-ESWT), traditionally used for MPS treatment, offers a reproducible and non-invasive mechanical stimulus, making it a potential diagnostic tool. This study evaluated F-ESWT’s diagnostic efficiency in chronic LBP patients by focusing on “recognition” and “referral” of pain. Methods: twenty-eight participants were screened for myofascial trigger points (MTrPs) in the lumbar, gluteal, and thigh regions. Identified MTrPs were stimulated using F-ESWT, and patient feedback was recorded. Results: data showed high diagnostic accuracy for muscles such as the quadratus lumborum, gluteus medius, and gluteus minimus muscles, achieving “referral” rates of 96%, 95%, and 92% and “recognition” rates of 84%, 86%, and 85%, respectively. Other structures like adductors, iliopsoas, erector spinae, and biceps femoris muscle showed consistent but lower diagnostic rates. Conclusions: the study’s findings indicate that F-ESWT effectively reproduces pain patterns, offering a precise, reproducible, and non-invasive diagnostic approach for MPS in chronic LBP. However, they also highlight the necessity for detailed diagnostic criteria in managing myofascial pain. Full article
(This article belongs to the Special Issue Recent Advances in Shockwave Therapy for Musculoskeletal and Soft-Tissue Disorders)
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28 pages, 3739 KiB  
Review
The Interplay of Molecular Factors and Morphology in Human Placental Development and Implantation
by Ioana Vornic, Victor Buciu, Cristian George Furau, Flavia Zara, Dorin Novacescu, Alina Cristina Barb, Alin Adrian Cumpanas, Silviu Constantin Latcu, Ioan Sas, Denis Serban, Talida Georgiana Cut and Cristina Stefania Dumitru
Biomedicines 2024, 12(12), 2908; https://doi.org/10.3390/biomedicines12122908 - 20 Dec 2024
Viewed by 2223
Abstract
The placenta is a vital organ that supports fetal development by mediating nutrient and gas exchange, regulating immune tolerance, and maintaining hormonal balance. Its formation and function are tightly linked to the processes of embryo implantation and the establishment of a robust placental-uterine [...] Read more.
The placenta is a vital organ that supports fetal development by mediating nutrient and gas exchange, regulating immune tolerance, and maintaining hormonal balance. Its formation and function are tightly linked to the processes of embryo implantation and the establishment of a robust placental-uterine interface. Recent advances in molecular biology and histopathology have shed light on the key regulatory factors governing these processes, including trophoblast invasion, spiral artery remodeling, and the development of chorionic villi. This review integrates morphological and molecular perspectives on placental development, emphasizing the roles of cytokines, growth factors, and signaling pathways, such as VEGF and Notch signaling, in orchestrating implantation and placental formation. The intricate interplay between molecular regulation and morphological adaptations highlights the placenta’s critical role as a dynamic interface in pregnancy. This review synthesizes current findings to offer clinicians and researchers a comprehensive understanding of the placenta’s role in implantation, emphasizing its importance in maternal-fetal medicine. By integrating these insights, the review lays the groundwork for advancing diagnostic and therapeutic approaches that can enhance pregnancy outcomes and address related complications effectively. Full article
(This article belongs to the Special Issue Role of Factors in Embryo Implantation and Placental Development)
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11 pages, 1784 KiB  
Article
The Effects of Beta-Blockers on Leukocytes and the Leukocyte Subpopulation in Heart Failure Patients
by Anca Daniela Farcaş, Mirela Anca Stoia, Diana Larisa Mocan-Hognogi, Cerasela Mihaela Goidescu, Alexandra Florina Cocoi and Florin Petru Anton
Biomedicines 2024, 12(12), 2907; https://doi.org/10.3390/biomedicines12122907 - 20 Dec 2024
Viewed by 988
Abstract
Background/Objectives: Some specific types of white blood cells (WBCs) and the neutrophil/lymphocyte ratio (NLR) are independent predictors of outcome for heart failure (HF) patients. WBC redistribution is induced by catecholamines, and therefore we evaluate how different types of beta-blockers (BBs) influence it. Methods: [...] Read more.
Background/Objectives: Some specific types of white blood cells (WBCs) and the neutrophil/lymphocyte ratio (NLR) are independent predictors of outcome for heart failure (HF) patients. WBC redistribution is induced by catecholamines, and therefore we evaluate how different types of beta-blockers (BBs) influence it. Methods: The HF patients were clinically evaluated, and blood was drawn to measure N-Terminal pro–B-type natriuretic peptide (NT-proBNP), WBC-differential formula, etc. Results: On admission, 61.16% of patients who used a BB had no significant difference in the number of lymphocytes (Lym) and neutrophils (Neu), but NLR and NT- proBNP were significantly lower compared with those without BB. NT-proBNP correlated with BB dose on admission and was significantly lower in patients treated with Metoprolol (Met) as compared with Carvedilol (Car). The type and dose of BB used was responsible for 6.1% and 5.9% of the variability in the number of Lym and Neu, respectively. Patients treated with ≥100 mg Met/day had a higher Lym number, but not of Neu, with reduced NLR, compared with lower doses. Patients treated with ≥25 mg Car/day had a lower Lym number and a greater Neu number, compared with lower doses, with increased NLR. Conclusions: However, both BBs had the same rehospitalization rate during the 12 month follow-up and had an improved outcome. Full article
(This article belongs to the Special Issue Ischemic Stroke and Myocardial Infarction: Potential Therapeutic Targets and Translational Research)
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22 pages, 5295 KiB  
Article
Genomic Medicine in the Developing World: Cancer Spectrum, Cumulative Risk and Survival Outcomes for Lynch Syndrome Variant Heterozygotes with Germline Pathogenic Variants in the MLH1 and MSH2 Genes
by Lutricia Ndou, Ramadhani Chambuso, Ursula Algar, Adam Boutall, Paul Goldberg and Raj Ramesar
Biomedicines 2024, 12(12), 2906; https://doi.org/10.3390/biomedicines12122906 - 20 Dec 2024
Viewed by 808
Abstract
Background: Although genetic testing has improved our ability to diagnose Lynch syndrome (LS), there is still limited information on the extent of variations in the clinical and genetic landscape among LS variant heterozygotes (LSVH) in Africa. We sought to investigate the cancer [...] Read more.
Background: Although genetic testing has improved our ability to diagnose Lynch syndrome (LS), there is still limited information on the extent of variations in the clinical and genetic landscape among LS variant heterozygotes (LSVH) in Africa. We sought to investigate the cancer spectrum, cumulative risk, and survival outcomes of LSVH with pathogenic/likely pathogenic variants (P/LPVs) in the MLH1 and MSH2 genes using a LS registry in South Africa over the last 30 years. Methods: A retrospective study was conducted to retrieve demographic, clinical, and genetic data of all LSVH with P/LPVs in the MLH1 and MSH2 genes from our LS registry. Genetic data were analyzed according to cancer spectrum, cumulative risk, and crude survival. We used the Chi-squared and t-test to assess differences between groups, and Kaplan–Meier survival analyses were used to analyze the cumulative risk and crude survival outcomes. A p-value < 0.05 at a 95% confidence interval was considered statistically significant. Results: We analyzed a total of 577 LSVH from 109 families. About 450 (78%) and 127 (22%) LSVH harbored a disease-causing mutation in MLH1 and MSH2, respectively. A South African founder PV (MLH1:c.1528C>T) accounted for 74% (n = 426) of all LSVH. CRC was the most common diagnosed cancer in both MLH1 and MSH2 LSVH. MLH1 LSVH had a younger age at cancer diagnosis than MSH2 LSVH (43 vs. 47 years, respectively, p = 0.015). Extracolonic cancers were predominantly higher in female LSVH (n = 33, 35%) than in male LSVH (n = 8, 7%) with the MLH1:c.1528C>T founder PV. The cumulative risk of any cancer and CRC at any age was higher in MLH1 LSVH than in MSH2 LSVH (p = 0.020 and p = 0.036, respectively). LSVH with the MLH1:c.1528C>T PV had a better 10-year overall survival after the first cancer diagnosis, particularly for CRC. Conclusions: LSVH with P/LPVs in the MLH1 and MSH2 genes exhibited significant gene- and sex-specific differences in cancer spectrum, cumulative risk and survival outcomes. Cancer risk and survival estimates described in this study can be used to guide surveillance and genetic counselling for LSVH in our population. Full article
(This article belongs to the Section Molecular Genetics and Genetic Diseases)
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12 pages, 4011 KiB  
Article
GABALAGEN Alleviates Stress-Induced Sleep Disorders in Rats
by Hyun-Jung Park, Sung Ja Rhie, Woojin Jeong, Kyu-Ri Kim, Kyoung-Min Rheu, Bae-Jin Lee and Insop Shim
Biomedicines 2024, 12(12), 2905; https://doi.org/10.3390/biomedicines12122905 - 20 Dec 2024
Cited by 1 | Viewed by 4700
Abstract
(1) Background: Gamma-aminobutyric acid (GABA) is an amino acid and the primary inhibitory neurotransmitter in the brain. GABA has been shown to reduce stress and promote sleep. GABALAGEN (GBL) is the product of fermented fish collagen by Lactobacillus brevis BJ20 and Lactobacillus plantarum [...] Read more.
(1) Background: Gamma-aminobutyric acid (GABA) is an amino acid and the primary inhibitory neurotransmitter in the brain. GABA has been shown to reduce stress and promote sleep. GABALAGEN (GBL) is the product of fermented fish collagen by Lactobacillus brevis BJ20 and Lactobacillus plantarum BJ21, naturally enriched with GABA through the fermentation process and characterized by low molecular weight. (2) Methods: The present study evaluated the GABAA affinity of GBL through receptor binding assay. The sedative effects of GBL were investigated through electroencephalography (EEG) analysis in an animal model of electro foot shock (EFS) stress-induced sleep disorder, and then we examined the expression of orexin and the GABAA receptor in the brain region using immunohistochemistry and an enzyme-linked immunosorbent assay (ELISA). (3) Results: We found that on the binding assay, GBL displayed high affinity to the GABAA receptor. Also, after treatment with GBL, the percentage of the total time in rapid eye movement (REM) and non-rapid eye movement (NREM) sleep was significantly and dose-dependently increased in EFS-induced rats. Consistent with behavioral results, the GBL-treated groups showed that the expression of GABAA receptor immune-positive cells in the VLPO was markedly and dose-dependently increased. Also, the GBL-treated groups showed that the expression of the orexin-A level in LH was significantly decreased. (4) Conclusions: GBL showed efficacy and potential to be used as an anti-stress therapy to treat sleep deprivation through the stimulation of GABAA receptors and the consequent inhibition of orexin activity. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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14 pages, 1681 KiB  
Article
Cerebrospinal Fluid Classical Biomarker Levels in Mixed vs. Pure A+T+ (A+T1+) Alzheimer’s Disease
by Ioanna Tsantzali, Athanasia Athanasaki, Fotini Boufidou, Vasilios C. Constantinides, Maria-Ioanna Stefanou, Christos Moschovos, Christina Zompola, Sotirios G. Paraskevas, Anastasios Bonakis, Sotirios Giannopoulos, Georgios Tsivgoulis, Elisabeth Kapaki and George P. Paraskevas
Biomedicines 2024, 12(12), 2904; https://doi.org/10.3390/biomedicines12122904 - 20 Dec 2024
Viewed by 901
Abstract
Background: Alzheimer’s disease (AD) may present with pure (typical or atypical) and mixed phenotypes, sometimes causing difficulties in (differential) diagnosis. In order to achieve a diagnostic accuracy as high as possible, the diagnosis of AD during life depends on various biomarkers, including [...] Read more.
Background: Alzheimer’s disease (AD) may present with pure (typical or atypical) and mixed phenotypes, sometimes causing difficulties in (differential) diagnosis. In order to achieve a diagnostic accuracy as high as possible, the diagnosis of AD during life depends on various biomarkers, including the cerebrospinal fluid (CSF) biomarkers. Methods: Classical CSF AD biomarkers were determined in a total of 61 patients, classified as both beta amyloid- and tau-positive A+T+ (or A+T1+ according to the recently revised Alzheimer Association criteria for diagnosis and staging of AD). Twenty one of these patients fulfilled the criteria for mixed AD (mixed with Lewy bodies, cerebrovascular disease, or normal pressure hydrocephalus), whilst 40 had pure AD. Results: Patients did not differ with respect to gender, education, disease duration, and cognitive status. After controlling for confounding factors, no difference was observed between mixed and pure AD groups in Aβ42 or Aβ42/Aβ40 levels. Although by definition, patients of both groups had abnormal (increased) levels of phospho-tau181, the mixed AD group presented with lower (less abnormal) levels of phospho-tau181 and total tau as compared to the pure group. Conclusions: In patients with AD of comparable cognitive status, mixed AD cases may present with lower levels of tau proteins and, if close to the cut-off values, diagnostic uncertainty may be increased. Full article
(This article belongs to the Special Issue Biomarkers for Neurodegenerative Disorders: From Bench to Bedside)
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15 pages, 365 KiB  
Article
Correlation Between Clinical Indicators and Liver Pathology in Children with Chronic Hepatitis B
by Chenyang Huang, Ying Lu, Ziwei Wang, Qiyu Jiang, Yi Dong, Lili Cao, Jianguo Yan, Zhiqiang Xu, Fuchuan Wang, Yinjie Gao, Junliang Fu, Min Zhang and Fu-Sheng Wang
Biomedicines 2024, 12(12), 2903; https://doi.org/10.3390/biomedicines12122903 - 20 Dec 2024
Viewed by 788
Abstract
Background: Chronic hepatitis B (CHB) in children presents a significant global health challenge, with liver inflammation and fibrosis being critical concerns for disease progression and long-term outcomes. Methods: This retrospective study analyzed 1629 pediatric CHB patients from the Fifth Medical Center of Chinese [...] Read more.
Background: Chronic hepatitis B (CHB) in children presents a significant global health challenge, with liver inflammation and fibrosis being critical concerns for disease progression and long-term outcomes. Methods: This retrospective study analyzed 1629 pediatric CHB patients from the Fifth Medical Center of Chinese PLA General Hospital, spanning from January 2000 to December 2021. Liver biopsies were performed to assess the severity of liver inflammation and fibrosis, which were graded using the Scheuer scoring system. Key clinical indicators, including age, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT), were evaluated for their predictive value in determining disease severity using restricted cubic spline regression models. Results: Significant nonlinear associations were found between the clinical indicators and liver pathology. Older age was strongly associated with increased risks of moderate to severe inflammation (OR 2.21, 95% CI: 1.34–3.63, p = 0.002) and significant fibrosis (OR 2.22, 95% CI: 1.31–3.77, p = 0.003). Elevated ALT levels (≥80 U/L) were correlated with a higher likelihood of moderate to severe inflammation (OR 1.82, 95% CI: 1.05–3.15, p = 0.033), while higher GGT levels (≥50 U/L) were significantly associated with advanced fibrosis (OR 2.62, 95% CI: 1.72–3.99, p < 0.001). Conclusions: Regular monitoring of clinical indicators such as ALT, AST, and GGT levels plays a critical role in identifying pediatric CHB patients at higher risk of moderate to severe inflammation and significant fibrosis. Our findings highlight the value of integrating age and key biochemical markers into non-invasive diagnostic algorithms for the early detection and management of liver pathology in children. Full article
(This article belongs to the Section Microbiology in Human Health and Disease)
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9 pages, 882 KiB  
Article
Obinutuzumab in Combination with Alternative Chlorambucil Schedules in Front-Line Treatment of Chronic Lymphocytic Leukemia: A Study by KroHem, the Croatian Cooperative Group for Hematologic Diseases
by Igor Aurer, Ozren Jakšić, Sandra Bašić-Kinda, Karla Mišura-Jakobac, Jasminka Sinčić-Petričević, Sabina Novaković-Coha, Davor Galušić, Hrvoje Holik, Toni Valković, Dubravka Županić-Krmek, Ida Hude-Dragičević, Vibor Milunović and Vlatko Pejša
Biomedicines 2024, 12(12), 2902; https://doi.org/10.3390/biomedicines12122902 - 20 Dec 2024
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Abstract
Background/Objectives: Obinutuzumab was approved for front-line treatment of chronic lymphocytic leukemia in combination with chlorambucil pulses administered every 2 wks. Alternative schedules of chlorambucil enable the administration of higher total chlorambucil doses, and have better antileukemia activity. So far, evidence on the [...] Read more.
Background/Objectives: Obinutuzumab was approved for front-line treatment of chronic lymphocytic leukemia in combination with chlorambucil pulses administered every 2 wks. Alternative schedules of chlorambucil enable the administration of higher total chlorambucil doses, and have better antileukemia activity. So far, evidence on the feasibility of combining obinutuzumab with alternative chlorambucil schedules is lacking. We performed this retrospective analysis to analyze real life outcomes in chronic lymphocytic leukemia patients receiving a combination of obinutuzumab with different chlorambucil schedules. Methods: This was a retrospective survey performed in order to analyze the feasibility and efficacy of different obinutuzumab and chlorambucil combinations in a real-life setting. Patients receiving this combination as a front-line therapy for chronic lymphocytic leukemia in participating centers, outside of clinical trials, in 2017 and 2018 were included. Results: Seventy-three patients fulfilling entry criteria were identified. Their median age was 76 years, and ranged from 58 to 90 years. The median follow up time was 59 months. The response rate was 89%, with a median progression-free survival time of 27 months, and an overall survival time of 49 months. Chlorambucil was administered as planned in 15 of the 22 (79%) patients treated with chlorambucil pulses every 2 weeks; in 15 of the 42 (34%) patients treated with 7-day courses of chlorambucil administered every 4 weeks; and in 0 of the 10 patients treated with a continuous high dose of chlorambucil (p = 0.002). Changes in treatment schedules were made due to side effects. The progression-free and overall survival rates were similar between the three groups. Conclusions: The combinations of obinutuzumab with more intensive chlorambucil schedules are less feasible, preventing the administration of the intended higher total dose of chlorambucil, and do not improve outcomes in comparison to chlorambucil pulses administered every 2 weeks. Full article
(This article belongs to the Section Cancer Biology and Oncology)
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Article
Proximity Proteomics Reveals USP44 Forms a Complex with BRCA2 in Neuroblastoma Cells and Is Required to Prevent Chromosome Breakage
by Asma Ali, Sajjad Hussain, Tibor Bedekovics, Raymond H. Jeon, Danielle G. May, Kyle J. Roux and Paul J. Galardy
Biomedicines 2024, 12(12), 2901; https://doi.org/10.3390/biomedicines12122901 - 20 Dec 2024
Viewed by 993
Abstract
Background/Objectives: The enzyme ubiquitin-specific protease 44 (USP44) is a deubiquitinating enzyme with identified physiological roles as a tumor suppressor and an oncogene. While some binding partners and substrates are known for USP44, the identification of other interactions may improve our understanding of its [...] Read more.
Background/Objectives: The enzyme ubiquitin-specific protease 44 (USP44) is a deubiquitinating enzyme with identified physiological roles as a tumor suppressor and an oncogene. While some binding partners and substrates are known for USP44, the identification of other interactions may improve our understanding of its role in cancer. We therefore performed a proximity biotinylation study that identified products of several known cancer genes that are associated with USP44, including a novel interaction between BRCA2 and USP44. Methods: We expressed a fusion protein that linked USP44 and mutant Escherichia coli biotin ligase BioID in SH-SY5Y neuroblastoma cells. Control experiments were performed using BioID alone. In duplicate experiments, cells were pulsed with biotin and biotinylated proteins were isolated under denaturing conditions and the proteins were identified by mass spectrometry. The resulting list of proteins were analyzed using Enrichr and cross-referenced with the COSMIC Cancer Gene Census. We validated the association with BRCA2 using immunoprecipitation. The role of USP44 in the Fanconi anemia DNA repair pathway was investigated using chromosome analysis of wild-type or Usp44-knockout cells after exposure to mitomycin C. Results: We identified 146 proteins that were selectively retrieved by the USP44 construct and compared with cells expressing the BioID ligase alone, including 15 gene products encoded by genes on tier 1 of the COSMIC Cancer Gene Census, including BRCA2. The association between USP44 and BRCA2 was validated through immunoprecipitation. We tested the functional role of USP44 in the Fanconi anemia DNA repair pathway through chromosome breakage analysis and found that cells lacking USP44 had a significant increase in chromosome breaks and radial chromosomes. We found that high BRCA2 transcript was correlated with poor survival in neuroblastoma, likely due to its tight association with proliferation in these tumors. Conclusions: Our results identified novel potential binding partners and potential substrates for USP44, including several with direct roles in cancer pathogenesis. Our results identified a novel association between BRCA2 and USP44, and a previously unknown role for USP44 in the Fanconi anemia DNA repair pathway that may contribute to its role in cancer. Full article
(This article belongs to the Special Issue Ubiquitylation and Deubiquitylation in Health and Diseases)
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