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Biomedicines
Volume 12
Issue 6
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Biomedicines, Volume 12, Issue 6 (June 2024) – 244 articles

Cover Story (view full-size image): Accurate diagnosis of Alzheimer’s disease (AD) and Frontotemporal dementia (FTD) represents a health issue due to the absence of disease traits. Biomarkers have gained a pivotal role in clinical trials, as they accurately reflect the underlying pathology in pre- or oligosymptomatic stages of different dementias. Cerebrospinal fluid (CSF) SIMOA biomarkers exhibit increased levels in AD and FTD samples compared to controls. Moreover, novel statistical models based on a combination of different biomarkers and demographics and clinical patients’ characteristics classify the dimensional clinical datasets into confident disease clusters, highlighting the need for more representative samples, variables, and measurements for successful and more efficient cohort clustering. View this paper
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15 pages, 2003 KiB  
Article
Efficacy and Safety of Xylitol Nasal Irrigation after Functional Endoscopic Sinus Surgery: A Randomized Controlled Study
by Rong-San Jiang, Yi-Fang Chiang and Kai-Li Liang
Biomedicines 2024, 12(6), 1377; https://doi.org/10.3390/biomedicines12061377 - 20 Jun 2024
Viewed by 2049
Abstract
Xylitol is considered a naturally occurring antibacterial agent. It is generally believed to enhance the body’s own innate bactericidal mechanisms. It also provides anti-adhesive effects against both Streptococcus pneumoniae and Haemophilus influenza. This study was performed to evaluate the efficacy and safety of [...] Read more.
Xylitol is considered a naturally occurring antibacterial agent. It is generally believed to enhance the body’s own innate bactericidal mechanisms. It also provides anti-adhesive effects against both Streptococcus pneumoniae and Haemophilus influenza. This study was performed to evaluate the efficacy and safety of xylitol nasal irrigation in the postoperative care of functional endoscopic sinus surgery (FESS). Patients with chronic rhinosinusitis who received FESS were recruited and randomly assigned to two groups at one month post-surgery. Thirty-five patients in the xylitol group received 400 mL of 5% xylitol nasal irrigation daily for 2 months, while another 35 in the normal saline (NS) group received 400 mL of NS nasal irrigation daily for 2 months. Prior to FESS, as well as before and after nasal irrigation, sinonasal symptoms were assessed through the 22-item Sino-Nasal Outcome Test Questionnaire. The patients also underwent an endoscopic examination while undergoing nasal function tests, and a cytokine measurement of the nasal lavage and a bacterial culture from the middle meatus were performed. The safety of the nasal irrigation was assessed through any self-reported adverse events, the Eustachian Tube Dysfunction Patient Questionnaire and the eustachian tube function test. The endoscopic scores and olfactory threshold significantly decreased after xylitol irrigation when compared with those before irrigation. The prevalence of Staphylococcus aureus in the nasal secretions also decreased significantly after xylitol irrigation. The amounts of Interleukin-5 and Interleukin-17A were significantly increased in the nasal lavage after xylitol irrigation. No side effects, including those related to eustachian tube function, were seen after nasal irrigation in both groups. Our results showed that xylitol nasal irrigation was both beneficial and safe during the postoperative care of FESS. Full article
(This article belongs to the Special Issue Recent Advances in Chronic Rhinosinusitis and Asthma)
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26 pages, 2875 KiB  
Review
Revolutionizing Brain Tumor Care: Emerging Technologies and Strategies
by Trang T. T. Nguyen, Lloyd A. Greene, Hayk Mnatsakanyan and Christian E. Badr
Biomedicines 2024, 12(6), 1376; https://doi.org/10.3390/biomedicines12061376 - 20 Jun 2024
Viewed by 1752
Abstract
Glioblastoma multiforme (GBM) is one of the most aggressive forms of brain tumor, characterized by a daunting prognosis with a life expectancy hovering around 12–16 months. Despite a century of relentless research, only a select few drugs have received approval for brain tumor [...] Read more.
Glioblastoma multiforme (GBM) is one of the most aggressive forms of brain tumor, characterized by a daunting prognosis with a life expectancy hovering around 12–16 months. Despite a century of relentless research, only a select few drugs have received approval for brain tumor treatment, largely due to the formidable barrier posed by the blood–brain barrier. The current standard of care involves a multifaceted approach combining surgery, irradiation, and chemotherapy. However, recurrence often occurs within months despite these interventions. The formidable challenges of drug delivery to the brain and overcoming therapeutic resistance have become focal points in the treatment of brain tumors and are deemed essential to overcoming tumor recurrence. In recent years, a promising wave of advanced treatments has emerged, offering a glimpse of hope to overcome the limitations of existing therapies. This review aims to highlight cutting-edge technologies in the current and ongoing stages of development, providing patients with valuable insights to guide their choices in brain tumor treatment. Full article
(This article belongs to the Special Issue Glioblastoma: Pathogenetic, Diagnostic and Therapeutic Perspectives)
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9 pages, 1295 KiB  
Brief Report
Results of the Phase 1 Open-Label Safety Study of Umbilical Cord Lining Mesenchymal Stromal/Stem Cells (Corlicyte®) to Heal Chronic Diabetic Foot Ulcers
by Cecilia C. Low Wang, Tae Chong, Garrett Moore, Benjamin Echalier, Nicola Haakonsen, James E. Carter, Jr., David Mathes, Judith Hsia, Toan Thang Phan, Ivor J. Lim and Brian M. Freed
Biomedicines 2024, 12(6), 1375; https://doi.org/10.3390/biomedicines12061375 - 20 Jun 2024
Viewed by 1626
Abstract
Background: Mesenchymal stromal/stem cells (MSCs) play a critical role in wound healing. Corlicyte® is an MSC product derived from allogeneic umbilical cord tissue donated under an institutional review board-approved protocol and processed in accordance with section 501(a)(2)(B) of the Federal Food, Drug, [...] Read more.
Background: Mesenchymal stromal/stem cells (MSCs) play a critical role in wound healing. Corlicyte® is an MSC product derived from allogeneic umbilical cord tissue donated under an institutional review board-approved protocol and processed in accordance with section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act. This open-label phase 1 trial was performed under a United States Food and Drug Administration Investigational New Drug Application to establish the safety and tolerability of Corlicyte® in patients with diabetes and chronic diabetic foot ulcer (DFU). Methods: Escalating doses were applied topically twice a week for up to 8 weeks after ulcer debridement, wound photography, and measurement. Subjects were followed for 4 weeks after the treatment phase. Adverse events were assessed at every visit. Results: Nine subjects in 2 dosing cohorts completed the trial. No subjects experienced a serious adverse reaction to Corlicyte® or the development of anti-human leukocyte antigen (HLA) antibodies. Sixty percentage of subjects in the lower dose cohort experienced ulcer closure by Day 70 of follow-up, while the mean ulcer size was reduced by 54–67% in the other subjects. Conclusions: Topical administration of Corlicyte®, a novel biologic therapy consisting of allogeneic umbilical cord lining MSCs, appeared safe and tolerable and resulted in a significant decrease in ulcer area, demonstrating its potential as a therapy for healing of chronic DFU. Full article
(This article belongs to the Special Issue Peripheral Artery Disease and Diabetic Foot Ulcer: From Bench to Clinic (2nd Edition))
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18 pages, 2692 KiB  
Article
Assessing the Suitability of CHA2DS2-VASc for Predicting Adverse Limb Events and Cardiovascular Outcomes in Peripheral Artery Disease Patients with Percutaneous Transluminal Angioplasty: A Retrospective Cohort Study
by Yu-Tsung Cheng, Fu-Lan Chang, Po-Hsien Li, Wen-Chien Lu and Chien-Shan Chiu
Biomedicines 2024, 12(6), 1374; https://doi.org/10.3390/biomedicines12061374 - 20 Jun 2024
Viewed by 969
Abstract
Patients with peripheral artery disease (PAD) are at high risk of major adverse limb events (MALEs) and major adverse cardiovascular events (MACEs). CHA2DS2-VASc is a prognostic score for atrial fibrillation stroke risk; however, no study has evaluated its predictive [...] Read more.
Patients with peripheral artery disease (PAD) are at high risk of major adverse limb events (MALEs) and major adverse cardiovascular events (MACEs). CHA2DS2-VASc is a prognostic score for atrial fibrillation stroke risk; however, no study has evaluated its predictive ability for MALEs and MACEs in PAD patients who underwent percutaneous transluminal angioplasty. We conducted a retrospective cohort study on patients from Taiwan with PAD. The patients were stratified into four risk groups based on their modified CHA2DS2-VASc score. Cox proportional hazard models, 10-fold cross-validation, and receiver operating characteristic (ROC) analyses were utilized to evaluate the predictive ability of CHA2DS2-VASc for MALEs, MACEs, and MALEs + MACEs. Kaplan–Meier analysis estimated the survival probability of the risk groups. CHA2DS2-VASc was found to be a significant predictor of MACEs (hazard ratio (HR) 3.52 (95% confidence interval (95% CI) 1.00–12.12; p = 0.048), HR 4.18 (95% CI 1.19–14.36; p = 0.023), and HR 5.08 (95% CI 1.49–17.36; p = 0.009), for moderate-, high-, and very high-risk groups, respectively), while for MALEs and MALEs + MACEs, significance was achieved only for the high-risk group using a univariate model. For the multivariate adjusted model, the score was found to be a significant predictor of MACEs for only the very high-risk group, with an HR of 4.67 (95% CI 1.03–21.09; p = 0.045). The score demonstrated an AUC > 0.8, good discrimination (c-index > 0.8), and good calibration for predicting MACEs. However, it failed to achieve good performance for predicting MALEs and MALEs + MACEs. Based on all of the findings, CHA2DS2-VASc could potentially serve as a risk stratification score for predicting MACEs in patients with PAD, but it failed to qualify as a good predictor for MALEs. Full article
(This article belongs to the Special Issue Pathology of Vascular Disease and Heart Failure)
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15 pages, 2751 KiB  
Article
MicroRNA-195-5p Attenuates Intracerebral-Hemorrhage-Induced Brain Damage by Inhibiting MMP-9/MMP-2 Expression
by Yi-Cheng Tsai, Chih-Hui Chang, Yoon Bin Chong, Chieh-Hsin Wu, Hung-Pei Tsai, Tian-Lu Cheng and Chih-Lung Lin
Biomedicines 2024, 12(6), 1373; https://doi.org/10.3390/biomedicines12061373 - 20 Jun 2024
Cited by 2 | Viewed by 1144
Abstract
Intracerebral hemorrhage (ICH) remains a devastating disease with high mortality, and there is a lack of effective strategies to improve functional outcomes. The primary injury of ICH is mechanical damage to brain tissue caused by the hematoma. Secondary injury, resulting from inflammation, red [...] Read more.
Intracerebral hemorrhage (ICH) remains a devastating disease with high mortality, and there is a lack of effective strategies to improve functional outcomes. The primary injury of ICH is mechanical damage to brain tissue caused by the hematoma. Secondary injury, resulting from inflammation, red cell lysis, and thrombin production, presents a potential target for therapeutic intervention. Inflammation, crucial in secondary brain injury, involves both cellular and molecular components. MicroRNAs (miRNAs) are vital regulators of cell growth, differentiation, and apoptosis. Their deregulation may lead to diseases, and modulating miRNA expression has shown therapeutic potential, especially in cancer. Recent studies have implicated miRNAs in the pathogenesis of stroke, affecting endothelial dysfunction, neurovascular integrity, edema, apoptosis, inflammation, and extracellular matrix remodeling. Preclinical and human studies support the use of miRNA-directed gene modulation as a therapeutic strategy for ICH. Our study focused on the effects of miR-195 in ICH models. Neurological tests, including the corner turn and grip tests, indicated that miR-195 treatment led to improvements in motor function impairments caused by ICH. Furthermore, miR-195-5p significantly reduced brain edema in the ipsilateral hemisphere and restored blood–brain barrier (BBB) integrity, as shown by reduced Evans blue dye extravasation. These results suggest miR-195-5p’s potential in attenuating ICH-induced apoptosis, possibly related to its influence on MMP-9 and MMP-2 expression, enzymes associated with secondary brain injury. The anti-apoptotic effects of miR-195-5p, demonstrated through TUNEL assays, further underscore its therapeutic promise in addressing the secondary brain injury and apoptosis associated with ICH. In conclusion, miR-195-5p demonstrates a significant neuroprotective effect against ICH-induced neural damage, brain edema, and BBB disruption, primarily through the downregulation of MMP-9 and MMP-2. Our findings indicate that miR-195-5p holds therapeutic potential in managing cerebral cell death following ICH. Full article
(This article belongs to the Special Issue Molecular Characteristics of Cerebral Ischemia and Their Therapeutic Applications)
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17 pages, 1070 KiB  
Review
A Review of Fetal Development in Pregnancies with Maternal Type 2 Diabetes Mellitus (T2DM)-Associated Hypothalamic-Pituitary-Adrenal (HPA) Axis Dysregulation: Possible Links to Pregestational Prediabetes
by Mathuli Ngema, Nombuso D. Xulu, Phikelelani S. Ngubane and Andile Khathi
Biomedicines 2024, 12(6), 1372; https://doi.org/10.3390/biomedicines12061372 - 20 Jun 2024
Viewed by 1175
Abstract
Research has identified fetal risk factors for adult diseases, forming the basis for the Developmental Origins of Health and Disease (DOHaD) hypothesis. DOHaD suggests that maternal insults during pregnancy cause structural and functional changes in fetal organs, increasing the risk of chronic diseases [...] Read more.
Research has identified fetal risk factors for adult diseases, forming the basis for the Developmental Origins of Health and Disease (DOHaD) hypothesis. DOHaD suggests that maternal insults during pregnancy cause structural and functional changes in fetal organs, increasing the risk of chronic diseases like type 2 diabetes mellitus (T2DM) in adulthood. It is proposed that altered maternal physiology, such as increased glucocorticoid (GC) levels associated with a dysregulated hypothalamic-pituitary-adrenal (HPA) axis in maternal stress and T2DM during pregnancy, exposes the fetus to excess GC. Prenatal glucocorticoid exposure reduces fetal growth and programs the fetal HPA axis, permanently altering its activity into adulthood. This programmed HPA axis is linked to increased risks of hypertension, cardiovascular diseases, and mental disorders in adulthood. With the global rise in T2DM, particularly among young adults of reproductive age, it is crucial to prevent its onset. T2DM is often preceded by a prediabetic state, a condition that does not show any symptoms, causing many to unknowingly progress to T2DM. Studying prediabetes is essential, as it is a reversible stage that may help prevent T2DM-related pregnancy complications. The existing literature focuses on HPA axis dysregulation in T2DM pregnancies and its link to fetal programming. However, the effects of prediabetes on HPA axis function, specifically glucocorticoid in pregnancy and fetal outcomes, are not well understood. This review consolidates research on T2DM during pregnancy, its impact on fetal programming via the HPA axis, and possible links with pregestational prediabetes. Full article
(This article belongs to the Special Issue New Diagnostic and Therapeutic Approaches in Diabetic Microvascular Complications)
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14 pages, 2792 KiB  
Article
Breast Cancer Molecular Subtype Prediction: A Mammography-Based AI Approach
by Ana M. Mota, João Mendes and Nuno Matela
Biomedicines 2024, 12(6), 1371; https://doi.org/10.3390/biomedicines12061371 - 20 Jun 2024
Cited by 1 | Viewed by 1591
Abstract
Breast cancer remains a leading cause of mortality among women, with molecular subtypes significantly influencing prognosis and treatment strategies. Currently, identifying the molecular subtype of cancer requires a biopsy—a specialized, expensive, and time-consuming procedure, often yielding to results that must be supported with [...] Read more.
Breast cancer remains a leading cause of mortality among women, with molecular subtypes significantly influencing prognosis and treatment strategies. Currently, identifying the molecular subtype of cancer requires a biopsy—a specialized, expensive, and time-consuming procedure, often yielding to results that must be supported with additional biopsies due to technique errors or tumor heterogeneity. This study introduces a novel approach for predicting breast cancer molecular subtypes using mammography images and advanced artificial intelligence (AI) methodologies. Using the OPTIMAM imaging database, 1397 images from 660 patients were selected. The pretrained deep learning model ResNet-101 was employed to classify tumors into five subtypes: Luminal A, Luminal B1, Luminal B2, HER2, and Triple Negative. Various classification strategies were studied: binary classifications (one vs. all others, specific combinations) and multi-class classification (evaluating all subtypes simultaneously). To address imbalanced data, strategies like oversampling, undersampling, and data augmentation were explored. Performance was evaluated using accuracy and area under the receiver operating characteristic curve (AUC). Binary classification results showed a maximum average accuracy and AUC of 79.02% and 64.69%, respectively, while multi-class classification achieved an average AUC of 60.62% with oversampling and data augmentation. The most notable binary classification was HER2 vs. non-HER2, with an accuracy of 89.79% and an AUC of 73.31%. Binary classification for specific combinations of subtypes revealed an accuracy of 76.42% for HER2 vs. Luminal A and an AUC of 73.04% for HER2 vs. Luminal B1. These findings highlight the potential of mammography-based AI for non-invasive breast cancer subtype prediction, offering a promising alternative to biopsies and paving the way for personalized treatment plans. Full article
(This article belongs to the Special Issue New Insights into Breast Cancer Management: From Tumorigenesis to Personalized Treatments)
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12 pages, 2687 KiB  
Article
Immune Responses to Mycobacterium tuberculosis Infection in the Liver of Diabetic Mice
by Ali Badaoui, Kayvan Sasaninia, Aishvaryaa Shree Mohan, Abrianna Beever, Nala Kachour, Anmol Raien, Afsal Kolloli, Ranjeet Kumar, Santhamani Ramasamy, Selvakumar Subbian and Vishwanath Venketaraman
Biomedicines 2024, 12(6), 1370; https://doi.org/10.3390/biomedicines12061370 - 20 Jun 2024
Viewed by 1151
Abstract
Individuals with uncontrolled diabetes are highly susceptible to tuberculosis (TB) caused by Mycobacterium tuberculosis (M. tb) infection. Novel treatments for TB are needed to address the increased antibiotic resistance and hepatoxicity. Previous studies showed that the administration of liposomal glutathione (L-GSH) [...] Read more.
Individuals with uncontrolled diabetes are highly susceptible to tuberculosis (TB) caused by Mycobacterium tuberculosis (M. tb) infection. Novel treatments for TB are needed to address the increased antibiotic resistance and hepatoxicity. Previous studies showed that the administration of liposomal glutathione (L-GSH) can mitigate oxidative stress, bolster a granulomatous response, and diminish the M. tb burden in the lungs of M. tb-infected mice. Nonetheless, the impact of combining L-GSH with conventional TB treatment (RIF) on the cytokine levels and granuloma formation in the livers of diabetic mice remains unexplored. In this study, we evaluated hepatic cytokine profiles, GSH, and tissue pathologies in untreated and L-GSH, RIF, and L-GSH+RIF treated diabetic (db/db) M. tb-infected mice. Our results indicate that treatment of M. tb-infected db/db mice with L-GSH+RIF caused modulation in the levels of pro-inflammatory cytokines and GSH in the liver and mitigation in the granuloma size in hepatic tissue. Supplementation with L-GSH+RIF led to a decrease in the M. tb burden by mitigating oxidative stress, promoting the production of pro-inflammatory cytokines, and restoring the cytokine balance. These findings highlight the potential of L-GSH+RIF combination therapy for addressing active EPTB, offering valuable insights into innovative treatments for M. tb infections. Full article
(This article belongs to the Special Issue New Challenges in the Study of Diabetes and Related Complications-Pathophysiology, Prevention and Treatment)
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38 pages, 2653 KiB  
Review
Therapeutic Efficacy of Interferon-Gamma and Hypoxia-Primed Mesenchymal Stromal Cells and Their Extracellular Vesicles: Underlying Mechanisms and Potentials in Clinical Translation
by Yu Ling Tan, Maimonah Eissa Al-Masawa, Sue Ping Eng, Mohamad Nasir Shafiee, Jia Xian Law and Min Hwei Ng
Biomedicines 2024, 12(6), 1369; https://doi.org/10.3390/biomedicines12061369 - 20 Jun 2024
Cited by 2 | Viewed by 1807
Abstract
Multipotent mesenchymal stromal cells (MSCs) hold promises for cell therapy and tissue engineering due to their self-renewal and differentiation abilities, along with immunomodulatory properties and trophic factor secretion. Extracellular vesicles (EVs) from MSCs offer similar therapeutic effects. However, MSCs are heterogeneous and lead [...] Read more.
Multipotent mesenchymal stromal cells (MSCs) hold promises for cell therapy and tissue engineering due to their self-renewal and differentiation abilities, along with immunomodulatory properties and trophic factor secretion. Extracellular vesicles (EVs) from MSCs offer similar therapeutic effects. However, MSCs are heterogeneous and lead to variable outcomes. In vitro priming enhances MSC performance, improving immunomodulation, angiogenesis, proliferation, and tissue regeneration. Various stimuli, such as cytokines, growth factors, and oxygen tension, can prime MSCs. Two classical priming methods, interferon-gamma (IFN-γ) and hypoxia, enhance MSC immunomodulation, although standardized protocols are lacking. This review discusses priming protocols, highlighting the most commonly used concentrations and durations, along with mechanisms and in vivo therapeutics effects of primed MSCs and their EVs. The feasibility of up-scaling their production was also discussed. The review concluded that priming with IFN-γ or hypoxia (alone or in combination with other factors) boosted the immunomodulation capability of MSCs and their EVs, primarily via the JAK/STAT and PI3K/AKT and Leptin/JAK/STAT and TGF-β/Smad signalling pathways, respectively. Incorporating priming in MSC and EV production enables translation into cell-based or cell-free therapies for various disorders. Full article
(This article belongs to the Section Gene and Cell Therapy)
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16 pages, 1068 KiB  
Case Report
Pituitary Hyperplasia Due to Longstanding Primary Hypothyroidism: A Case Report and Comprehensive Review of the Literature
by Anna Roux, Daniela Rosso, Daniela Cuboni, Mauro Maccario, Silvia Grottoli, Emanuela Arvat and Valentina Gasco
Biomedicines 2024, 12(6), 1368; https://doi.org/10.3390/biomedicines12061368 - 19 Jun 2024
Viewed by 1266
Abstract
Hypothyroidism is a frequently diagnosed endocrine disorder. Common signs and symptoms include fatigue, cold intolerance, hoarseness, dry skin, constipation, a slow relaxation phase of deep tendon reflexes, and bradycardia. However, some patients may exhibit atypical signs and symptoms, which can result in diagnostic [...] Read more.
Hypothyroidism is a frequently diagnosed endocrine disorder. Common signs and symptoms include fatigue, cold intolerance, hoarseness, dry skin, constipation, a slow relaxation phase of deep tendon reflexes, and bradycardia. However, some patients may exhibit atypical signs and symptoms, which can result in diagnostic confusion. Pituitary hyperplasia resulting from longstanding primary hypothyroidism was first described by Niepce in 1851. It is usually asymptomatic, but sometimes, in addition to symptoms of overt hypothyroidism, patients may complain of headaches, hypopituitarism, visual field impairment, and hyperprolactinemia. Furthermore, on imaging, pituitary hyperplasia can be mistaken for a pituitary adenoma. Distinguishing between the two is crucial, as their management differs; the former often responds to thyroid hormone replacement therapy, while the latter might need treatment with surgery and/or radiotherapy. Here we describe a patient who developed pituitary hyperplasia in the setting of longstanding uncompensated primary hypothyroidism due to a lack of compliance with levothyroxine replacement therapy. We also review the clinical, laboratory, and radiologic findings of the case reports available in the literature up to now in order to improve the knowledge and the care of the disease. Full article
(This article belongs to the Special Issue Thyroid Disease: From Mechanism to Therapeutic Approaches)
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15 pages, 1081 KiB  
Review
Latest Advances in Chondrocyte-Based Cartilage Repair
by Li Yue, Ryan Lim and Brett D. Owens
Biomedicines 2024, 12(6), 1367; https://doi.org/10.3390/biomedicines12061367 - 19 Jun 2024
Viewed by 2422
Abstract
Chondrocyte-based cell therapy has been used for more than 30 years and is still considered to be a promising method of cartilage repair despite some limitations. This review introduces the latest developments of four generations of autologous chondrocyte implantation and current autologous chondrocyte [...] Read more.
Chondrocyte-based cell therapy has been used for more than 30 years and is still considered to be a promising method of cartilage repair despite some limitations. This review introduces the latest developments of four generations of autologous chondrocyte implantation and current autologous chondrocyte products. The regeneration of cartilage from adult chondrocytes is limited by culture-induced dedifferentiation and patient age. Cartibeads is an innovative three-step method to produce high-quality hyaline cartilage microtissues, and it is developed from adult dedifferentiated chondrocytes with a high number of cell passages. In addition, allogeneic chondrocyte therapies using the Quantum hollow-fiber bioreactor and several signaling pathways involved in chondrocyte-based cartilage repair are mentioned, such as WNT signaling, the BMP-2/WISP1 pathway, and the FGF19 pathway. Full article
(This article belongs to the Special Issue Advances in Chondrocyte Biology)
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18 pages, 4617 KiB  
Article
Luteolin-7-O-β-d-Glucuronide Attenuated Cerebral Ischemia/Reperfusion Injury: Involvement of the Blood–Brain Barrier
by Xing Fan, Jintao Song, Shuting Zhang, Lihui Lu, Fang Lin, Yu Chen, Shichang Li, Xinxin Jin and Fang Wang
Biomedicines 2024, 12(6), 1366; https://doi.org/10.3390/biomedicines12061366 - 19 Jun 2024
Cited by 1 | Viewed by 1293
Abstract
Ischemic stroke is a common cerebrovascular disease with high mortality, high morbidity, and high disability. Cerebral ischemia/reperfusion injury seriously affects the quality of life of patients. Luteolin-7-O-β-d-glucuronide (LGU) is a major active flavonoid compound extracted from Ixeris sonchifolia (Bge.) Hance, a Chinese medicinal [...] Read more.
Ischemic stroke is a common cerebrovascular disease with high mortality, high morbidity, and high disability. Cerebral ischemia/reperfusion injury seriously affects the quality of life of patients. Luteolin-7-O-β-d-glucuronide (LGU) is a major active flavonoid compound extracted from Ixeris sonchifolia (Bge.) Hance, a Chinese medicinal herb mainly used for the treatment of coronary heart disease, angina pectoris, cerebral infarction, etc. In the present study, the protective effect of LGU on cerebral ischemia/reperfusion injury was investigated in an oxygen–glucose deprivation/reoxygenation (OGD/R) neuronal model and a transient middle cerebral artery occlusion (tMCAO) rat model. In in vitro experiments, LGU was found to improve the OGD/R-induced decrease in neuronal viability effectively by the MTT assay. In in vivo experiments, neurological deficit scores, infarction volume rates, and brain water content rates were improved after a single intravenous administration of LGU. These findings suggest that LGU has significant protective effects on cerebral ischemia/reperfusion injury in vitro and in vivo. To further explore the potential mechanism of LGU on cerebral ischemia/reperfusion injury, we performed a series of tests. The results showed that a single administration of LGU decreased the content of EB and S100B and ameliorated the abnormal expression of tight junction proteins ZO-1 and occludin and metalloproteinase MMP-9 in the ischemic cerebral cortex of the tMCAO 24-h injury model. In addition, LGU also improved the tight junction structure between endothelial cells and the degree of basement membrane degradation and reduced the content of TNF-α and IL-1β in the brain tissue. Thereby, LGU attenuated cerebral ischemia/reperfusion injury by improving the permeability of the blood–brain barrier. The present study provides new insights into the therapeutic potential of LGU in cerebral ischemia. Full article
(This article belongs to the Topic Animal Models of Human Disease 2.0)
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47 pages, 1055 KiB  
Review
A Review of the Association between Exposure to Flame Retardants and Thyroid Function
by Brandon Yeshoua, Horacio Romero Castillo, Mathilda Monaghan and Maaike van Gerwen
Biomedicines 2024, 12(6), 1365; https://doi.org/10.3390/biomedicines12061365 - 19 Jun 2024
Cited by 1 | Viewed by 1130
Abstract
Flame retardants have been shown to cause widespread physiological effects, in particular on endocrine organs such as the thyroid. This review aims to provide an overview of the literature on the association between flame retardants and thyroid function within humans. A search in [...] Read more.
Flame retardants have been shown to cause widespread physiological effects, in particular on endocrine organs such as the thyroid. This review aims to provide an overview of the literature on the association between flame retardants and thyroid function within humans. A search in the National Library of Medicine and National Institutes of Health PubMed database through January 2024 yielded 61 studies that met the inclusion criteria. The most frequently analyzed flame retardants across all thyroid hormones were polybrominated diphenyl ethers (PBDEs), in particular BDE-47 and BDE-99. Ten studies demonstrated exclusively positive associations between flame retardants and thyroid stimulating hormone (TSH). Six studies demonstrated exclusively negative associations between flame retardants and TSH. Twelve studies demonstrated exclusively positive associations for total triiodothyronine (tT3) and total thyroxine (tT4). Five and eight studies demonstrated exclusively negative associations between flame retardants and these same thyroid hormones, respectively. The effect of flame retardants on thyroid hormones is heterogeneous; however, the long-term impact warrants further investigation. Vulnerable populations, including indigenous people, individuals working at e-waste sites, firefighters, and individuals within certain age groups, such as children and elderly, are especially critical to be informed of risk of exposure. Full article
(This article belongs to the Special Issue Environmental Exposures and Human Diseases—Molecular Insights)
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11 pages, 851 KiB  
Review
PKCδ Protects against Lupus Autoimmunity
by Sailee Vijay Chavan, Shreya Desikan, Christopher A J Roman and Chongmin Huan
Biomedicines 2024, 12(6), 1364; https://doi.org/10.3390/biomedicines12061364 - 19 Jun 2024
Viewed by 1098
Abstract
Protein kinase C delta (PKCδ) has emerged as a key protective molecule against systemic lupus erythematosus (SLE or lupus), an autoimmune disease characterized by anti-double stranded (ds) DNA IgGs. Although PKCδ-deficient mice and lupus patients with mutated PRKCD genes clearly demonstrate the requirement [...] Read more.
Protein kinase C delta (PKCδ) has emerged as a key protective molecule against systemic lupus erythematosus (SLE or lupus), an autoimmune disease characterized by anti-double stranded (ds) DNA IgGs. Although PKCδ-deficient mice and lupus patients with mutated PRKCD genes clearly demonstrate the requirement for PKCδ in preventing lupus autoimmunity, this critical tolerance mechanism remains poorly understood. We recently reported that PKCδ acts as a key regulator of B cell tolerance by selectively deleting anti-dsDNA B cells in the germinal center (GC). PKCδ’s tolerance function is activated by sphingomyelin synthase 2 (SMS2), a lipid enzyme whose expression is generally reduced in B cells from lupus patients. Moreover, pharmacologic strengthening of the SMS2/PKCδ tolerance pathway alleviated lupus pathogenesis in mice. Here, we review relevant publications in order to provide mechanistic insights into PKCδ’s tolerance activity and discuss the potential significance of therapeutically targeting PKCδ’s tolerance activity in the GC for selectively inhibiting lupus autoimmunity. Full article
(This article belongs to the Special Issue Protein Kinase C Signalling in Health and Disease: A Commemorative Issue in Honor of Prof. Yasutomi Nishizuka)
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13 pages, 3450 KiB  
Article
Fabrication and Optimization of Poly(ε-caprolactone) Microspheres Loaded with S-Nitroso-N-Acetylpenicillamine for Nitric Oxide Delivery
by Syed Baseeruddin Alvi, Nooruddin Pracha, Mahmoud Shalaan, Pankaj Singh Dholaniya, Muhamad Mergaye, Divya Sridharan and Mahmood Khan
Biomedicines 2024, 12(6), 1363; https://doi.org/10.3390/biomedicines12061363 - 19 Jun 2024
Viewed by 862
Abstract
Heart disease is one of the leading causes of death in the United States and throughout the world. While there are different techniques for reducing or preventing the impact of heart disease, nitric oxide (NO) is administered as nitroglycerin for reversing angina or [...] Read more.
Heart disease is one of the leading causes of death in the United States and throughout the world. While there are different techniques for reducing or preventing the impact of heart disease, nitric oxide (NO) is administered as nitroglycerin for reversing angina or chest pain. Unfortunately, due to its gaseous and short-lived half-life, NO can be difficult to study or even administer. Therefore, controlled delivery of NO is desirable for therapeutic use. In the current study, the goal was to fabricate NO-releasing microspheres (MSs) using a donor molecule, S-Nitroso-N-Acetyl penicillamine, (SNAP), and encapsulating it in poly(ε-caprolactone) (PCL) using a single-emulsion technique that can provide sustained delivery of NO to cells over time without posing any toxicity risks. Optimization of the fabrication process was performed by varying the duration of homogenization (5, 10, and 20 min) and its effect on entrapment efficiency and size. The optimized SNAP-MS had an entrapment efficiency of ˃50%. Furthermore, we developed a modified method for NO detection by using NO microsensors to detect the NO release from SNAP-MSs in real time, showing sustained release behavior. The fabricated SNAP-MSs were tested for biocompatibility with HUVECs (human umbilical vein endothelial cells), which were found to be biocompatible. Lastly, we tested the effect of controlled NO delivery to human induced pluripotent stem-derived cardiomyocytes (hiPSC-CMs) via SNAP-MSs, which showed a significant improvement in the electrophysiological parameters and alleviated anoxic stress. Full article
(This article belongs to the Special Issue Recent Advances in Ischemic Heart Diseases)
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15 pages, 1950 KiB  
Article
The Assessment of the Association of Proton Pump Inhibitor Usage with Chronic Kidney Disease Progression through a Process Mining Approach
by Kaile Chen, Farhad Abtahi, Hong Xu, Carlos Fernandez-Llatas, Juan-Jesus Carrero and Fernando Seoane
Biomedicines 2024, 12(6), 1362; https://doi.org/10.3390/biomedicines12061362 - 19 Jun 2024
Viewed by 905
Abstract
Previous studies have suggested an association between Proton Pump Inhibitors (PPIs) and the progression of chronic kidney disease (CKD). This study aims to assess the association between PPI use and CKD progression by analysing estimated glomerular filtration rate (eGFR) trajectories using a process [...] Read more.
Previous studies have suggested an association between Proton Pump Inhibitors (PPIs) and the progression of chronic kidney disease (CKD). This study aims to assess the association between PPI use and CKD progression by analysing estimated glomerular filtration rate (eGFR) trajectories using a process mining approach. We conducted a retrospective cohort study from 1 January 2006 to 31 December 2011, utilising data from the Stockholm Creatinine Measurements (SCREAM). New users of PPIs and H2 blockers (H2Bs) with CKD (eGFR < 60) were identified using a new-user and active-comparator design. Process mining discovery is a technique that discovers patterns and sequences in events over time, making it suitable for studying longitudinal eGFR trajectories. We used this technique to construct eGFR trajectory models for both PPI and H2B users. Our analysis indicated that PPI users exhibited more complex and rapidly declining eGFR trajectories compared to H2B users, with a 75% increased risk (adjusted hazard ratio [HR] 1.75, 95% confidence interval [CI] 1.49 to 2.06) of transitioning from moderate eGFR stage (G3) to more severe stages (G4 or G5). These findings suggest that PPI use is associated with an increased risk of CKD progression, demonstrating the utility of process mining for longitudinal analysis in epidemiology, leading to an improved understanding of disease progression. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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15 pages, 2609 KiB  
Article
BRCA1, BRCA2 and PALB2 mRNA Expression as Prognostic Markers in Patients with Early Breast Cancer
by Ina Shehaj, Slavomir Krajnak, Katrin Almstedt, Yaman Degirmenci, Sophia Herzog, Antje Lebrecht, Valerie Catherine Linz, Roxana Schwab, Kathrin Stewen, Walburgis Brenner, Annette Hasenburg, Marcus Schmidt and Anne-Sophie Heimes
Biomedicines 2024, 12(6), 1361; https://doi.org/10.3390/biomedicines12061361 - 19 Jun 2024
Cited by 1 | Viewed by 1022
Abstract
Breast cancer (BC) poses a challenge in establishing new treatment strategies and identifying new prognostic and predictive markers due to the extensive genetic heterogeneity of BC. Very few studies have investigated the impact of mRNA expression of these genes on the survival of [...] Read more.
Breast cancer (BC) poses a challenge in establishing new treatment strategies and identifying new prognostic and predictive markers due to the extensive genetic heterogeneity of BC. Very few studies have investigated the impact of mRNA expression of these genes on the survival of BC patients. Methods: We examined the impact of the mRNA expression of breast cancer gene type 1 (BRCA1), breast cancer gene type 2 (BRCA2), and partner and localizer of BRCA2 (PALB2) on the metastasis-free survival (MFS) of patients with early BC using microarray gene expression analysis. Results: The study was performed in a cohort of 461 patients with a median age of 62 years at initial diagnosis. The median follow-up time was 147 months. We could show that the lower expression of BRCA1 and BRCA2 is significantly associated with longer MFS (p < 0.050). On the contrary, the lower expression of PALB2 was correlated with a shorter MFS (p = 0.049). Subgroup survival analysis identified the prognostic influence of mRNA expression for BRCA1 among patients with luminal-B-like BC and for BRCA2 and PALB2 in the subset of patients with luminal-A-like BC (p < 0.050). Conclusions: According to our observations, BRCA1, BRCA2, and PALB2 expression might become valuable biomarkers of disease progression. Full article
(This article belongs to the Special Issue New Insights into Breast Cancer Management: From Tumorigenesis to Personalized Treatments)
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22 pages, 1660 KiB  
Review
Virus-Induced MicroRNA Modulation and Systemic Sclerosis Disease
by Irene Soffritti, Maria D’Accolti, Francesca Bini, Eleonora Mazziga, Dario Di Luca, Clara Maccari, Maria-Cristina Arcangeletti and Elisabetta Caselli
Biomedicines 2024, 12(6), 1360; https://doi.org/10.3390/biomedicines12061360 - 19 Jun 2024
Viewed by 1253
Abstract
MicroRNAs (miRNAs) are short noncoding RNA sequences that regulate gene expression at the post-transcriptional level. They are involved in the regulation of multiple pathways, related to both physiological and pathological conditions, including autoimmune diseases, such as Systemic Sclerosis (SSc). Specifically, SSc is recognized [...] Read more.
MicroRNAs (miRNAs) are short noncoding RNA sequences that regulate gene expression at the post-transcriptional level. They are involved in the regulation of multiple pathways, related to both physiological and pathological conditions, including autoimmune diseases, such as Systemic Sclerosis (SSc). Specifically, SSc is recognized as a complex and multifactorial disease, characterized by vascular abnormalities, immune dysfunction, and progressive fibrosis, affecting skin and internal organs. Among predisposing environmental triggers, evidence supports the roles of oxidative stress, chemical agents, and viral infections, mostly related to those sustained by beta-herpesviruses such as HCMV and HHV-6. Dysregulated levels of miRNA expression have been found in SSc patients compared to healthy controls, at both the intra- and extracellular levels, providing a sort of miRNA signature of the SSc disease. Notably, HCMV/HHV-6 viral infections were shown to modulate the miRNA profile, often superposing that observed in SSc, potentially promoting pathological pathways associated with SSc development. This review summarizes the main data regarding miRNA alterations in SSc disease, highlighting their potential as prognostic or diagnostic markers for SSc disease, and the impact of the putative SSc etiological agents on miRNA modulation. Full article
(This article belongs to the Special Issue MicroRNA and Its Role in Human Health)
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14 pages, 2885 KiB  
Article
Triple Combinations of Histone Lysine Demethylase Inhibitors with PARP1 Inhibitor–Olaparib and Cisplatin Lead to Enhanced Cytotoxic Effects in Head and Neck Cancer Cells
by Dawid Dorna, Robert Kleszcz and Jarosław Paluszczak
Biomedicines 2024, 12(6), 1359; https://doi.org/10.3390/biomedicines12061359 - 19 Jun 2024
Cited by 2 | Viewed by 1158
Abstract
PARP inhibitors are used to treat cancers with a deficient homologous recombination (HR) DNA repair pathway. Interestingly, recent studies revealed that HR repair could be pharmacologically impaired by the inhibition of histone lysine demethylases (KDM). Thus, we investigated whether KDM inhibitors could sensitize [...] Read more.
PARP inhibitors are used to treat cancers with a deficient homologous recombination (HR) DNA repair pathway. Interestingly, recent studies revealed that HR repair could be pharmacologically impaired by the inhibition of histone lysine demethylases (KDM). Thus, we investigated whether KDM inhibitors could sensitize head and neck cancer cells, which are usually HR proficient, to PARP inhibition or cisplatin. Therefore, we explored the effects of double combinations of KDM4–6 inhibitors (ML324, CPI-455, GSK-J4, and JIB-04) with olaparib or cisplatin, or their triple combinations with both drugs, on the level of DNA damage and apoptosis. FaDu and SCC-040 cells were treated with individual compounds and their combinations, and cell viability, apoptosis, DNA damage, and gene expression were assessed using the resazurin assay, Annexin V staining, H2A.X activation, and qPCR, respectively. Combinations of KDM inhibitors with cisplatin enhanced cytotoxic effects, unlike combinations with olaparib. Triple combinations of KDM inhibitors with cisplatin and olaparib exhibited the best cytotoxic activity, which was associated with DNA damage accumulation and altered expression of genes associated with apoptosis induction and cell cycle arrest. In conclusion, triple combinations of KDM inhibitors (especially GSK-J4 and JIB-04) with cisplatin and olaparib represent a promising strategy for head and neck cancer treatment. Full article
(This article belongs to the Special Issue Natural and Synthetic Molecules with Anticancer Activity: Pharmacological Basis and Mechanistic Insight)
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13 pages, 3030 KiB  
Article
Loss of c-Kit in Endothelial Cells Protects against Hindlimb Ischemia
by Gustavo Falero-Diaz, Catarina de A. Barboza, Roberto I. Vazquez-Padron, Omaida C. Velazquez and Roberta M. Lassance-Soares
Biomedicines 2024, 12(6), 1358; https://doi.org/10.3390/biomedicines12061358 - 19 Jun 2024
Viewed by 889
Abstract
Background: Critical limb ischemia (CLI) is the end stage of peripheral artery disease (PAD), and around 30% of CLI patients are ineligible for current treatments. The angiogenic benefits of c-Kit have been reported in the ischemia scenario; however, the present study demonstrates the [...] Read more.
Background: Critical limb ischemia (CLI) is the end stage of peripheral artery disease (PAD), and around 30% of CLI patients are ineligible for current treatments. The angiogenic benefits of c-Kit have been reported in the ischemia scenario; however, the present study demonstrates the effects of specific endothelial c-Kit signaling in arteriogenesis during hindlimb ischemia. Methods: We created conditional knockout mouse models that decrease c-Kit (c-Kit VE-Cadherin CreERT2—c-Kit) or its ligand (SCF VE-Cadherin CreERT2—SCF) specifically in endothelial cells (ECs) after tamoxifen treatment. These mice and a control group (wild-type VE-Cadherin CreERT2—WT) were subjected to hindlimb ischemia or aortic crush to evaluate perfusion/arteriogenesis and endothelial barrier permeability, respectively. Results: Our data confirmed the lower gene expression of c-Kit and SCF in the ECs of c-Kit and SCF mice, respectively. In addition, we confirmed the lower percentage of ECs positive for c-Kit in c-Kit mice. Further, we found that c-Kit and SCF mice had better limb perfusion and arteriogenesis compared to WT mice. We also demonstrated that c-Kit and SCF mice had a preserved endothelial barrier after aortic crush compared to WT. Conclusions: Our data demonstrate the deleterious effects of endothelial SCF/c-Kit signaling on arteriogenesis and endothelial barrier integrity. Full article
(This article belongs to the Special Issue Animal Models for the Study of Cardiovascular Physiology)
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13 pages, 656 KiB  
Article
Vitamin D3 (Calcitriol) Monotherapy Decreases Tumor Growth, Increases Survival, and Correlates with Low Neutrophil-to-Lymphocyte Ratio in a Murine HPV-16-Related Cancer Model
by Alejandra E. Hernández-Rangel, Gustavo A. Hernandez-Fuentes, Daniel A. Montes-Galindo, Carmen A. Sanchez-Ramirez, Ariana Cabrera-Licona, Margarita L. Martinez-Fierro, Iram P. Rodriguez-Sanchez, Idalia Garza-Veloz, Janet Diaz-Martinez, Juan C. Casarez-Price, Jorge E. Plata-Florenzano, Hector Ochoa-Díaz-Lopez, Angel Lugo-Trampe and Iván Delgado-Enciso
Biomedicines 2024, 12(6), 1357; https://doi.org/10.3390/biomedicines12061357 - 18 Jun 2024
Viewed by 1365
Abstract
Vitamin D3 or calcitriol (VitD3) has been shown to have anticancer and anti-inflammatory activity in in vitro models and clinical studies. However, its effect on HPV-16-related cancer has been sparsely explored. In this study, we aimed to determine whether monotherapy or combination therapy [...] Read more.
Vitamin D3 or calcitriol (VitD3) has been shown to have anticancer and anti-inflammatory activity in in vitro models and clinical studies. However, its effect on HPV-16-related cancer has been sparsely explored. In this study, we aimed to determine whether monotherapy or combination therapy with cisplatin (CP) reduces tumor growth and affects survival and systemic inflammation. Treatments were administered to C57BL/6 mice with HPV-16-related tumors (TC-1 cells) as follows: (1) placebo (100 µL vehicle, olive oil, orally administered daily); (2) VitD3 (3.75 µg/kg calcitriol orally administered daily); (3) CP (5 mg/kg intraperitoneally, every 7 days); and (4) VitD3+CP. Tumor growth was monitored for 25 days, survival for 60 days, and the neutrophil-to-lymphocyte ratio (NLR) was evaluated on days 1 (baseline), 7, and 14. VitD3+CP showed greater success in reducing tumor volume compared to CP monotherapy (p = 0.041), while no differences were observed between CP and VitD3 monotherapy (p = 0.671). Furthermore, VitD3+CP prolonged survival compared to CP (p = 0.036) and VitD3 (p = 0.007). Additionally, at day 14 the VitD3 and VitD3+CP groups showed significantly lower NLR values than the CP group (p < 0.05, for both comparisons). Vitamin D3 could be a promising adjuvant in the treatment of cervical cancer or solid tumors and deserves further investigation. Full article
(This article belongs to the Special Issue The Role of Inflammatory Cytokines in Cancer Progression 2.0)
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6 pages, 190 KiB  
Editorial
Cardiovascular and Metabolic Disease: New Treatments and Future Directions 2.0
by Alfredo Caturano
Biomedicines 2024, 12(6), 1356; https://doi.org/10.3390/biomedicines12061356 - 18 Jun 2024
Cited by 2 | Viewed by 962
Abstract
Over recent decades, cardiovascular diseases (CVDs) and metabolic disorders have emerged as major global health challenges, exacting a heavy toll on human lives and burdening healthcare systems worldwide [...] Full article
(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions 2.0)
20 pages, 2660 KiB  
Article
Optimised, Broad NGS Panel for Inherited Eye Diseases to Diagnose 1000 Patients in Poland
by Ewa Matczyńska, Marta Beć-Gajowniczek, Larysa Sivitskaya, Elżbieta Gregorczyk, Przemysław Łyszkiewicz, Robert Szymańczak, Maria Jędrzejowska, Edward Wylęgała, Maciej R. Krawczyński, Sławomir Teper and Anna Boguszewska-Chachulska
Biomedicines 2024, 12(6), 1355; https://doi.org/10.3390/biomedicines12061355 - 18 Jun 2024
Cited by 2 | Viewed by 1391
Abstract
Advances in gene therapy and genome editing give hope that new treatments will soon be available for inherited eye diseases that together affect a significant proportion of the adult population. New solutions are needed to make genetic diagnosis fast and affordable. This is [...] Read more.
Advances in gene therapy and genome editing give hope that new treatments will soon be available for inherited eye diseases that together affect a significant proportion of the adult population. New solutions are needed to make genetic diagnosis fast and affordable. This is the first study of such a large group of patients with inherited retinal dystrophies (IRD) and inherited optic neuropathies (ION) in the Polish population. It is based on four years of diagnostic analysis using a broad, targeted NGS approach. The results include the most common pathogenic variants, as well as 91 novel causative variants, including frameshifts in the cumbersome RPGR ORF15 region. The high frequency of the ABCA4 complex haplotype p.(Leu541Pro;Ala1038Val) was confirmed. Additionally, a deletion of exons 22–24 in USH2A, probably specific to the Polish population, was uncovered as the most frequent copy number variation. The diagnostic yield of the broad NGS panel reached 64.3% and is comparable to the results reported for genetic studies of IRD and ION performed for other populations with more extensive WES or WGS methods. A combined approach to identify genetic causes of all known diseases manifesting in the posterior eye segment appears to be the optimal choice given the currently available treatment options and advanced clinical trials. Full article
(This article belongs to the Special Issue Next-Generation Sequencing and Proteomics Research for Retinal Diseases)
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13 pages, 549 KiB  
Article
DNA Methylation Profiles of PSMA6, PSMB5, KEAP1, and HIF1A Genes in Patients with Type 1 Diabetes and Diabetic Retinopathy
by Zane Svikle, Natalia Paramonova, Emīls Siliņš, Leonora Pahirko, Līga Zariņa, Kristīne Baumane, Goran Petrovski and Jelizaveta Sokolovska
Biomedicines 2024, 12(6), 1354; https://doi.org/10.3390/biomedicines12061354 - 18 Jun 2024
Viewed by 1001
Abstract
We explored differences in the DNA methylation statuses of PSMA6, PSMB5, HIF1A, and KEAP1 gene promoter regions in patients with type 1 diabetes and different diabetic retinopathy (DR) stages. Study subjects included individuals with no DR (NDR, n = 41), [...] Read more.
We explored differences in the DNA methylation statuses of PSMA6, PSMB5, HIF1A, and KEAP1 gene promoter regions in patients with type 1 diabetes and different diabetic retinopathy (DR) stages. Study subjects included individuals with no DR (NDR, n = 41), those with non-proliferative DR (NPDR, n = 27), and individuals with proliferative DR or those who underwent laser photocoagulation (PDR/LPC, n = 46). DNA methylation was determined by Zymo OneStep qMethyl technique. The methylation of PSMA6 (NDR 5.9 (3.9–8.7) %, NPDR 4.5 (3.8–5.7) %, PDR/LPC 6.6 (4.7–10.7) %, p = 0.003) and PSMB5 (NDR 2.2 (1.9–3.7) %, NPDR 2.2 (1.9–3.0) %, PDR/LPC 3.2 (2.5–7.1) %, p < 0.01) differed across the groups. Consistent correlations were observed between the methylation levels of HIF1A and PSMA6 in all study groups. DNA methylation levels of PSMA6, PSMB5, and HIF1A genes were positively correlated with the duration of diabetes, HbA1c, and albuminuria in certain study groups. Univariate regression models revealed a significant association between the methylation level z-scores of PSMA6, PSMB5, and HIF1A and severe DR (PSMA6: OR = 1.96 (1.15; 3.33), p = 0.013; PSMB5: OR = 1.90 (1.14; 3.16), p = 0.013; HIF1A: OR = 3.19 (1.26; 8.06), p = 0.014). PSMB5 remained significantly associated with DR in multivariate analysis. Our findings suggest significant associations between the severity of DR and the DNA methylation levels of the genes PSMA6, PSMB5, and HIF1A, but not KEAP1 gene. Full article
(This article belongs to the Special Issue Molecular Research and Recent Advances in Diabetic Retinopathy)
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39 pages, 3853 KiB  
Review
Apigenin: A Bioflavonoid with a Promising Role in Disease Prevention and Treatment
by Khaled S. Allemailem, Ahmad Almatroudi, Hajed Obaid A. Alharbi, Naif AlSuhaymi, Mahdi H. Alsugoor, Fahad M. Aldakheel, Amjad Ali Khan and Arshad Husain Rahmani
Biomedicines 2024, 12(6), 1353; https://doi.org/10.3390/biomedicines12061353 - 18 Jun 2024
Cited by 7 | Viewed by 3610
Abstract
Apigenin is a powerful flavone compound found in numerous fruits and vegetables, and it offers numerous health-promoting benefits. Many studies have evidenced that this compound has a potential role as an anti-inflammatory and antioxidant compound, making it a promising candidate for reducing the [...] Read more.
Apigenin is a powerful flavone compound found in numerous fruits and vegetables, and it offers numerous health-promoting benefits. Many studies have evidenced that this compound has a potential role as an anti-inflammatory and antioxidant compound, making it a promising candidate for reducing the risk of pathogenesis. It has also been found to positively affect various systems in the body, such as the respiratory, digestive, immune, and reproductive systems. Apigenin is effective in treating liver, lung, heart, kidney, neurological diseases, diabetes, and maintaining good oral and skin health. Multiple studies have reported that this compound is capable of suppressing various types of cancer through the induction of apoptosis and cell-cycle arrest, suppressing cell migration and invasion, reduction of inflammation, and inhibiting angiogenesis. When used in combination with other drugs, apigenin increases their efficacy, reduces the risk of side effects, and improves the response to chemotherapy. This review broadly analyzes apigenin’s potential in disease management by modulating various biological activities. In addition, this review also described apigenin’s interaction with other compounds or drugs and the potential role of nanoformulation in different pathogeneses. Further extensive research is needed to explore the mechanism of action, safety, and efficacy of this compound in disease prevention and treatment. Full article
(This article belongs to the Special Issue Bioactive Natural Products for Treatment of Human Disease)
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12 pages, 453 KiB  
Article
Differences between Patients with Sporadic and Familial Pheochromocytoma—Is It Possible to Avoid Genetic Testing in Certain Patients?
by María Consuelo Muñoz, Beatriz Febrero, Miriam Abellán, Antonio Miguel Hernández and José Manuel Rodríguez
Biomedicines 2024, 12(6), 1352; https://doi.org/10.3390/biomedicines12061352 - 18 Jun 2024
Viewed by 693
Abstract
Background: Pheochromocytoma (PHEO) is a rare neuroendocrine tumour with a strong genetic link, which therefore may modify its clinical behaviour and prognosis. The aim of the study is to evaluate the epidemiological and clinical differences between patients with sporadic and familial PHEO, as [...] Read more.
Background: Pheochromocytoma (PHEO) is a rare neuroendocrine tumour with a strong genetic link, which therefore may modify its clinical behaviour and prognosis. The aim of the study is to evaluate the epidemiological and clinical differences between patients with sporadic and familial PHEO, as well as the specific differences in the index cases. Methods: A retrospective analysis of 136 patients in a tertiary hospital (1984–2021). Epidemiological, clinical, and histological variables were analysed. Statistics: SPSS 28.0 software was used. Univariate and multivariate logistic regression analyses were performed. p < 0.05 was considered statistically significant. Results: 64.71% of the cases (n = 88) presented a genetic mutation (familial cases). Additionally, 32.39% (n = 23) corresponded to index cases and the rest to screening cases. The main differences between patients with familial and sporadic PHEO were age (OR = 0.93 (0.89–0.97)), blood pressure-related symptoms (OR = 0.22 (0.06–0.89)), bilaterality (OR = 15.49 (3.76–63.84)), and size (OR = 0.70 (0.54–0.92)). Among patients with sporadic PHEO and index cases, only bilaterality was significant (OR = 13.53 (1.24–144.34)). Conclusions: Patients with familial PHEO diagnosed by screening differ from sporadic cases in terms of age, clinical features, and size. However, patients with sporadic PHEO only differ from index cases by a lower presence of bilaterality, which reaffirms the importance of genetic screening of patients with PHEO and their relatives. Full article
(This article belongs to the Special Issue Adrenal Diseases: An Update)
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14 pages, 1155 KiB  
Review
Exploring the Therapeutic Potential of Gene Therapy in Arrhythmogenic Right Ventricular Cardiomyopathy
by Juan Mundisugih, Dhanya Ravindran and Eddy Kizana
Biomedicines 2024, 12(6), 1351; https://doi.org/10.3390/biomedicines12061351 - 18 Jun 2024
Cited by 1 | Viewed by 1554
Abstract
Right dominant arrhythmogenic cardiomyopathy, commonly known as Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), represents a formidable challenge in cardiovascular medicine, as conventional therapies are commonly ineffective in impeding disease progression and the development of end-stage heart failure. Recombinant adeno-associated virus (AAV)-mediated gene therapy presents [...] Read more.
Right dominant arrhythmogenic cardiomyopathy, commonly known as Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), represents a formidable challenge in cardiovascular medicine, as conventional therapies are commonly ineffective in impeding disease progression and the development of end-stage heart failure. Recombinant adeno-associated virus (AAV)-mediated gene therapy presents a promising avenue for targeted therapeutic interventions, potentially revolutionising treatment approaches for ARVC patients. Encouraging results from preclinical studies have sparked optimism about the possibility of curing specific subtypes of ARVC in the near future. This narrative review delves into the dynamic landscape of genetic therapy for ARVC, elucidating its underlying mechanisms and developmental stages, and providing updates on forthcoming trials. Additionally, it examines the hurdles and complexities impeding the successful translation of ARVC genetic therapies into clinical practice. Despite notable scientific advancements, the journey towards implementing genetic therapies for ARVC patients in real-world clinical settings is still in its early phases. Full article
(This article belongs to the Special Issue Advanced Research in Arrhythmogenic Cardiomyopathy)
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11 pages, 1983 KiB  
Review
Neuronal Cell Differentiation of iPSCs for the Clinical Treatment of Neurological Diseases
by Dong-Hun Lee, Eun Chae Lee, Ji young Lee, Man Ryul Lee, Jae-won Shim and Jae Sang Oh
Biomedicines 2024, 12(6), 1350; https://doi.org/10.3390/biomedicines12061350 - 18 Jun 2024
Cited by 1 | Viewed by 1615
Abstract
Current chemical treatments for cerebrovascular disease and neurological disorders have limited efficacy in tissue repair and functional restoration. Induced pluripotent stem cells (iPSCs) present a promising avenue in regenerative medicine for addressing neurological conditions. iPSCs, which are capable of reprogramming adult cells to [...] Read more.
Current chemical treatments for cerebrovascular disease and neurological disorders have limited efficacy in tissue repair and functional restoration. Induced pluripotent stem cells (iPSCs) present a promising avenue in regenerative medicine for addressing neurological conditions. iPSCs, which are capable of reprogramming adult cells to regain pluripotency, offer the potential for patient-specific, personalized therapies. The modulation of molecular mechanisms through specific growth factor inhibition and signaling pathways can direct iPSCs’ differentiation into neural stem cells (NSCs). These include employing bone morphogenetic protein-4 (BMP-4), transforming growth factor-beta (TGFβ), and Sma-and Mad-related protein (SMAD) signaling. iPSC-derived NSCs can subsequently differentiate into various neuron types, each performing distinct functions. Cell transplantation underscores the potential of iPSC-derived NSCs to treat neurodegenerative diseases such as Parkinson’s disease and points to future research directions for optimizing differentiation protocols and enhancing clinical applications. Full article
(This article belongs to the Special Issue Pluripotent Stem Cell: Current Understanding and Future Directions)
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28 pages, 3792 KiB  
Review
The 2021 World Health Organization Central Nervous System Tumor Classification: The Spectrum of Diffuse Gliomas
by Racine Gue and Dhairya A. Lakhani
Biomedicines 2024, 12(6), 1349; https://doi.org/10.3390/biomedicines12061349 - 18 Jun 2024
Viewed by 2420
Abstract
The 2021 edition of the World Health Organization (WHO) classification of central nervous system tumors introduces significant revisions across various tumor types. These updates, encompassing changes in diagnostic techniques, genomic integration, terminology, and grading, are crucial for radiologists, who play a critical role [...] Read more.
The 2021 edition of the World Health Organization (WHO) classification of central nervous system tumors introduces significant revisions across various tumor types. These updates, encompassing changes in diagnostic techniques, genomic integration, terminology, and grading, are crucial for radiologists, who play a critical role in interpreting brain tumor imaging. Such changes impact the diagnosis and management of nearly all central nervous system tumor categories, including the reclassification, addition, and removal of specific tumor entities. Given their pivotal role in patient care, radiologists must remain conversant with these revisions to effectively contribute to multidisciplinary tumor boards and collaborate with peers in neuro-oncology, neurosurgery, radiation oncology, and neuropathology. This knowledge is essential not only for accurate diagnosis and staging, but also for understanding the molecular and genetic underpinnings of tumors, which can influence treatment decisions and prognostication. This review, therefore, focuses on the most pertinent updates concerning the classification of adult diffuse gliomas, highlighting the aspects most relevant to radiological practice. Emphasis is placed on the implications of new genetic information on tumor behavior and imaging findings, providing necessary tools to stay abreast of advancements in the field. This comprehensive overview aims to enhance the radiologist’s ability to integrate new WHO classification criteria into everyday practice, ultimately improving patient outcomes through informed and precise imaging assessments. Full article
(This article belongs to the Special Issue Diagnosis, Pathogenesis and Treatment of CNS Tumors)
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22 pages, 1601 KiB  
Systematic Review
Effects of Cerebellar Non-Invasive Stimulation on Neurorehabilitation in Stroke Patients: An Updated Systematic Review
by Qi Liu, Yang Liu and Yumei Zhang
Biomedicines 2024, 12(6), 1348; https://doi.org/10.3390/biomedicines12061348 - 18 Jun 2024
Viewed by 1408
Abstract
The cerebellum is emerging as a promising target for noninvasive brain stimulation (NIBS). A systematic review was conducted to evaluate the effects of cerebellar NIBS on both motor and other symptoms in stroke rehabilitation, its impact on functional ability, and potential side effects [...] Read more.
The cerebellum is emerging as a promising target for noninvasive brain stimulation (NIBS). A systematic review was conducted to evaluate the effects of cerebellar NIBS on both motor and other symptoms in stroke rehabilitation, its impact on functional ability, and potential side effects (PROSPERO number: CRD42022365697). A systematic electronic database search was performed by using PubMed Central (PMC), EMBASE, and Web of Science, with a cutoff date of November 2023. Data extracted included study details, NIBS methodology, outcome measures, and results. The risk of bias in eligible studies was also assessed. Twenty-two clinical studies involving 1016 participants were finally included, with a focus on outcomes related to post-stroke motor recovery (gait and balance, muscle spasticity, and upper limb dexterity) and other functions (dysphagia and aphasia). Positive effects were observed, especially on motor functions like gait and balance. Some efficiency was also observed in dysphagia rehabilitation. However, findings on language recovery were preliminary and inconsistent. A slight improvement in functional ability was noted, with no serious adverse effects reported. Further studies are needed to explore the effects of cerebellar NIBS on post-stroke non-motor deficits and to understand how cerebellar engagement can facilitate more precise treatment strategies for stroke rehabilitation. Full article
(This article belongs to the Special Issue Emerging Trends in Brain Stimulation)
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