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Biomedicines, Volume 12, Issue 6 (June 2024) – 224 articles

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13 pages, 548 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 (registering DOI) - 18 Jun 2024
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)
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 (registering DOI) - 18 Jun 2024
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
20 pages, 1581 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 (registering DOI) - 18 Jun 2024
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
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 (registering DOI) - 18 Jun 2024
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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 (registering DOI) - 18 Jun 2024
Viewed by 85
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 (registering DOI) - 18 Jun 2024
Viewed by 105
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 (registering DOI) - 18 Jun 2024
Viewed by 78
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 (registering DOI) - 18 Jun 2024
Viewed by 70
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 (registering DOI) - 18 Jun 2024
Viewed by 82
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 (registering DOI) - 18 Jun 2024
Viewed by 111
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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13 pages, 244 KiB  
Article
HLA Association among Thai Patients with Diffuse and Limited Cutaneous Systemic Sclerosis
by Worawit Louthrenoo, Nuntana Kasitanon, Antika Wongthanee, Yuko Okudaira, Asuka Takeuchi, Hiroshi Noguchi, Hidetoshi Inoko and Fujio Takeuchi
Biomedicines 2024, 12(6), 1347; https://doi.org/10.3390/biomedicines12061347 (registering DOI) - 18 Jun 2024
Viewed by 120
Abstract
This study aimed to clarify the association of HLA Class I and II with dcSSc and lcSSc in Thais. HLA typing for 11 gene loci (Class I: HLA-A, B and C, and Class II [HLA-DR, DP and DQ]) was carried out using the [...] Read more.
This study aimed to clarify the association of HLA Class I and II with dcSSc and lcSSc in Thais. HLA typing for 11 gene loci (Class I: HLA-A, B and C, and Class II [HLA-DR, DP and DQ]) was carried out using the Next Generation DNA Sequencing method (three fields) in 92 Thai patients with systemic sclerosis (55 dcSSc, 37 lcSSc) and 135 healthy controls (HCs). The distribution of HLA alleles in patients with dcSSc and lcSSc was compared. When compared with HCs, the AF of A*24:02:01, A*24:07:01, B*27:04:01 and B*27:06 showed an increasing trend in lcSSc patients without statistical significance. DRB1*15:02:01, DRB5*01:02:01, DQA1*01:01:01, DQB1*05:01:24, DPA1*02:01:01 and DPB1*13:01:01 increased significantly in dcSSc patients. DQB1*05:01:24 and DPB1*13:01:01 also increased significantly in lcSSc patients, but less significantly than in dcSSc patients. The association of DPB1*05:01:01 with lcSSc was significantly protective. HLA-A*24:02:01, B*27:06 and C*03:04:01 formed a three-locus haplotype that also constituted an eight-locus haplotype with DRB1*15:02:01, DQA1*01:01:01, DQB1*05:01:24, DPA1*02:01:01 and DPB1*13:01:01. There was a possibility that HLA Class I would play a role in the pathogenesis of lcSSc, while Class II played more of a role in the dcSSc in Thai patients. Full article
(This article belongs to the Special Issue Advanced Research of HLA in Diseases)
14 pages, 3080 KiB  
Article
Frequency-Dependent Neural Modulation of Dorsal Horn Neurons by Kilohertz Spinal Cord Stimulation in Rats
by Dong Wang, Kwan Yeop Lee, Zachary B. Kagan, Kerry Bradley and Dongchul Lee
Biomedicines 2024, 12(6), 1346; https://doi.org/10.3390/biomedicines12061346 - 18 Jun 2024
Viewed by 170
Abstract
Kilohertz high-frequency spinal cord stimulation (kHF-SCS) is a rapidly advancing neuromodulatory technique in the clinical management of chronic pain. However, the precise cellular mechanisms underlying kHF-SCS-induced paresthesia-free pain relief, as well as the neural responses within spinal pain circuits, remain largely unexplored. In [...] Read more.
Kilohertz high-frequency spinal cord stimulation (kHF-SCS) is a rapidly advancing neuromodulatory technique in the clinical management of chronic pain. However, the precise cellular mechanisms underlying kHF-SCS-induced paresthesia-free pain relief, as well as the neural responses within spinal pain circuits, remain largely unexplored. In this study, using a novel preparation, we investigated the impact of varying kilohertz frequency SCS on dorsal horn neuron activation. Employing calcium imaging on isolated spinal cord slices, we found that extracellular electric fields at kilohertz frequencies (1, 3, 5, 8, and 10 kHz) induce distinct patterns of activation in dorsal horn neurons. Notably, as the frequency of extracellular electric fields increased, there was a clear and significant monotonic escalation in neuronal activity. This phenomenon was observed not only in superficial dorsal horn neurons, but also in those located deeper within the dorsal horn. Our study demonstrates the unique patterns of dorsal horn neuron activation in response to varying kilohertz frequencies of extracellular electric fields, and we contribute to a deeper understanding of how kHF-SCS induces paresthesia-free pain relief. Furthermore, our study highlights the potential for kHF-SCS to modulate sensory information processing within spinal pain circuits. These insights pave the way for future research aimed at optimizing kHF-SCS parameters and refining its therapeutic applications in the clinical management of chronic pain. Full article
(This article belongs to the Section Biomedical Engineering and Materials)
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3 pages, 177 KiB  
Editorial
Exploring Novel Frontiers in Cancer Therapy
by Adrian Bogdan Tigu and Ciprian Tomuleasa
Biomedicines 2024, 12(6), 1345; https://doi.org/10.3390/biomedicines12061345 - 18 Jun 2024
Viewed by 159
Abstract
Cancer progression and initiation are sustained by a series of alterations in molecular pathways because of genetic errors, external stimuli and other factors, which lead to an abnormal cellular function that can be translated into uncontrolled cell growth and metastasis [...] Full article
14 pages, 2564 KiB  
Article
CBP/P300 Inhibition Impairs CD4+ T Cell Activation: Implications for Autoimmune Disorders
by Lucas Wilhelmus Picavet, Anoushka A. K. Samat, Jorg Calis, Lotte Nijhuis, Rianne Scholman, Michal Mokry, David F. Tough, Rabinder K. Prinjha, Sebastiaan J. Vastert and Jorg van Loosdregt
Biomedicines 2024, 12(6), 1344; https://doi.org/10.3390/biomedicines12061344 - 18 Jun 2024
Viewed by 173
Abstract
T cell activation is critical for an effective immune response against pathogens. However, dysregulation contributes to the pathogenesis of autoimmune diseases, including Juvenile Idiopathic Arthritis (JIA). The molecular mechanisms underlying T cell activation are still incompletely understood. T cell activation promotes the acetylation [...] Read more.
T cell activation is critical for an effective immune response against pathogens. However, dysregulation contributes to the pathogenesis of autoimmune diseases, including Juvenile Idiopathic Arthritis (JIA). The molecular mechanisms underlying T cell activation are still incompletely understood. T cell activation promotes the acetylation of histone 3 at Lysine 27 (H3K27ac) at enhancer and promoter regions of proinflammatory cytokines, thereby increasing the expression of these genes which is essential for T cell function. Co-activators E1A binding protein P300 (P300) and CREB binding protein (CBP), collectively known as P300/CBP, are essential to facilitate H3K27 acetylation. Presently, the role of P300/CBP in human CD4+ T cells activation remains incompletely understood. To assess the function of P300/CBP in T cell activation and autoimmune disease, we utilized iCBP112, a selective inhibitor of P300/CBP, in T cells obtained from healthy controls and JIA patients. Treatment with iCBP112 suppressed T cell activation and cytokine signaling pathways, leading to reduced expression of many proinflammatory cytokines, including IL-2, IFN-γ, IL-4, and IL-17A. Moreover, P300/CBP inhibition in T cells derived from the inflamed synovium of JIA patients resulted in decreased expression of similar pathways and preferentially suppressed the expression of disease-associated genes. This study underscores the regulatory role of P300/CBP in regulating gene expression during T cell activation while offering potential insights into the pathogenesis of autoimmune diseases. Our findings indicate that P300/CBP inhibition could potentially be leveraged for the treatment of autoimmune diseases such as JIA in the future. Full article
(This article belongs to the Special Issue Epigenetic Regulation and Its Impact for Medicine)
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4 pages, 158 KiB  
Editorial
Role of NO in Disease: Good, Bad or Ugly
by Anders O. Larsson and Mats B. Eriksson
Biomedicines 2024, 12(6), 1343; https://doi.org/10.3390/biomedicines12061343 - 18 Jun 2024
Viewed by 283
Abstract
This Special Issue of Biomedicines (https://www [...] Full article
(This article belongs to the Special Issue Role of NO in Disease: Good, Bad or Ugly)
16 pages, 787 KiB  
Review
Tissue-Resident Memory T Cells in Gastrointestinal Cancers: Prognostic Significance and Therapeutic Implications
by Hiromichi Sato, Sikun Meng, Tomoaki Hara, Yoshiko Tsuji, Yasuko Arao, Kazuki Sasaki, Shogo Kobayashi, Eric di Luccio, Takaaki Hirotsu, Taroh Satoh, Yuichiro Doki, Hidetoshi Eguchi and Hideshi Ishii
Biomedicines 2024, 12(6), 1342; https://doi.org/10.3390/biomedicines12061342 - 17 Jun 2024
Viewed by 208
Abstract
Gastrointestinal cancers, which include a variety of esophageal and colorectal malignancies, present a global health challenge and require effective treatment strategies. In the evolving field of cancer immunotherapy, tissue-resident memory T cells (Trm cells) have emerged as important players in the immune response [...] Read more.
Gastrointestinal cancers, which include a variety of esophageal and colorectal malignancies, present a global health challenge and require effective treatment strategies. In the evolving field of cancer immunotherapy, tissue-resident memory T cells (Trm cells) have emerged as important players in the immune response within nonlymphoid tissues. In this review, we summarize the characteristics and functions of Trm cells and discuss their profound implications for patient outcomes in gastrointestinal cancers. Positioned strategically in peripheral tissues, Trm cells have functions beyond immune surveillance, affecting tumor progression, prognosis, and response to immunotherapy. Studies indicate that Trm cells are prognostic markers and correlate positively with enhanced survival. Their presence in the tumor microenvironment has sparked interest in their therapeutic potential, particularly with respect to immune checkpoint inhibitors, which may improve cancer treatment. Understanding how Trm cells work will not only help to prevent cancer spread through effective treatment but will also contribute to disease prevention at early stages as well as vaccine development. The role of Trm cells goes beyond just cancer, and they have potential applications in infectious and autoimmune diseases. This review provides a thorough analysis of Trm cells in gastrointestinal cancers, which may lead to personalized and effective cancer therapies. Full article
(This article belongs to the Special Issue Advances in Diagnosis and Treatment of Cancer in Digestive Organs)
15 pages, 814 KiB  
Article
Exploring Periodontal Conditions, Salivary Markers, and Systemic Inflammation in Patients with Cardiovascular Diseases
by Carmen Silvia Caloian, Petra Șurlin, Andreea Ciurea, Dana Pop, Bogdan Caloian, Daniel Corneliu Leucuța, Adrian Bogdan Țigu, Giulio Rasperini, Iulia Cristina Micu, Alina Stanomir, Andrada Soancă and Alexandra Roman
Biomedicines 2024, 12(6), 1341; https://doi.org/10.3390/biomedicines12061341 - 17 Jun 2024
Viewed by 167
Abstract
(1) Background: This cross-sectional investigation appreciated the role of serum C-reactive protein (CRP), several hematologic-cell markers, and salivary inflammation-related molecules [calprotectin (S100A8/A9), interleukin-1β (IL-1β), kallikrein] to predict periodontitis in patients with atherosclerotic cardiovascular disease (ACVD), arrhythmia, or both. Also, we appreciated the relationship [...] Read more.
(1) Background: This cross-sectional investigation appreciated the role of serum C-reactive protein (CRP), several hematologic-cell markers, and salivary inflammation-related molecules [calprotectin (S100A8/A9), interleukin-1β (IL-1β), kallikrein] to predict periodontitis in patients with atherosclerotic cardiovascular disease (ACVD), arrhythmia, or both. Also, we appreciated the relationship between the inflammatory burden and periodontal destruction with the type of cardiac pathology. (2) Methods: Demographic, behavioral characteristics, periodontal indicators, blood parameters, and saliva samples were collected. (3) Results: All 148 patients exhibited stage II or III/IV periodontitis. Stage III/IV cases exhibited significantly increased S100A8/A9 levels (p = 0.004). A positive correlation between S100A8/A9 and IL-1β [0.35 (<0.001)], kallikrein [0.55 (<0.001)], and CRP [0.28 (<0.001)] was observed. Patients with complex cardiac involvement had a significantly higher number of sites with attachment loss ≥ 5 mm [19 (3–30)] compared to individuals with only arrhythmia [9 (3.25–18)] or ACVD [5 (1–12)] [0.048♦ {0.162/0.496/0.14}]. (4) Conclusions: Severe, extensive attachment loss may be indicative of patients with complex cardiac conditions, which underscores the essential role of periodontal status in relation to systemic diseases. The correlations between the rising trends of the inflammatory parameters suggest a potential interconnection between oral and systemic inflammation. Full article
(This article belongs to the Section Immunology and Immunotherapy)
22 pages, 4002 KiB  
Article
Cannabinol Regulates the Expression of Cell Cycle-Associated Genes in Motor Neuron-like NSC-34: A Transcriptomic Analysis
by Alessandra Trainito, Agnese Gugliandolo, Luigi Chiricosta, Stefano Salamone, Federica Pollastro, Emanuela Mazzon and Maria Lui
Biomedicines 2024, 12(6), 1340; https://doi.org/10.3390/biomedicines12061340 - 17 Jun 2024
Viewed by 182
Abstract
Cannabinoids are reported to have neuroprotective properties and play a role in neurogenesis and neuroplasticity in in vitro and in vivo models. Cannabinol (CBN) is a minor cannabinoid produced by the degradation of Δ9-tetrahydrocannabinol in Cannabis sativa L. and exhibits anti-oxidant, [...] Read more.
Cannabinoids are reported to have neuroprotective properties and play a role in neurogenesis and neuroplasticity in in vitro and in vivo models. Cannabinol (CBN) is a minor cannabinoid produced by the degradation of Δ9-tetrahydrocannabinol in Cannabis sativa L. and exhibits anti-oxidant, analgesic, anti-bacterial, and anti-inflammatory effects. In this study, we explored the biological effects of 20 µM CBN (6.20 µg/mL) on differentiated NSC-34 cells by MTT assay and next-generation sequencing analysis on the transcriptome. KEGG and Gene Ontology enrichment analyses have been performed to evaluate potential CBN-associated processes. Our results highlighted the absence of any cytotoxic effect of CBN. The comparative transcriptomic analysis pointed out the downregulation of Cdkn2a, Cdkn2c and Cdkn2d genes, which are known to suppress the cell cycle. Ccne2, Cdk2, Cdk7, Anapc11, Anapc10, Cdc23, Cdc16, Anapc4, Cdc27, Stag1, Smc3, Smc1a, Nipbl, Pds5a, Pds5b, and Wapl genes, renowned for their role as cell cycle progression activators, were instead upregulated. Our work suggests that CBN regulates the expression of many genes related to the cell cycle, which are required for axonal maturation, migration, and synaptic plasticity, while not affecting the expression of genes involved in cell death or tumorigenesis. Full article
(This article belongs to the Special Issue Therapeutic Potential for Cannabis and Cannabinoids 2.0)
19 pages, 11185 KiB  
Article
Pharmacological Potential of Three Berberine-Containing Plant Extracts Obtained from Berberis vulgaris L., Mahonia aquifolium (Pursh) Nutt., and Phellodendron amurense Rupr.
by Alexandra Ciorîță, Sabina-Emanuela Erhan, Maria Loredana Soran, Ildiko Lung, Augustin Catalin Mot, Sergiu Gabriel Macavei and Marcel Pârvu
Biomedicines 2024, 12(6), 1339; https://doi.org/10.3390/biomedicines12061339 - 17 Jun 2024
Viewed by 185
Abstract
Three berberine-containing plant extracts were investigated for their pharmacological properties. The stems and leaves of Berberis vulgaris, Mahonia aquifolium, and Phellodendron amurense were characterized through scanning electron microscopy. The plant extracts obtained from fresh stem barks were further analyzed through high-performance [...] Read more.
Three berberine-containing plant extracts were investigated for their pharmacological properties. The stems and leaves of Berberis vulgaris, Mahonia aquifolium, and Phellodendron amurense were characterized through scanning electron microscopy. The plant extracts obtained from fresh stem barks were further analyzed through high-performance liquid chromatography, revealing berberine concentrations, among berbamine and palmatine. The plant extracts were further tested for their anticancer potential against 2D and 3D human skin melanoma (A375) and lung adenocarcinoma (A549) cell lines. The concentrations at which 50% of the cells are affected was determined by the viability assay and it was shown that B. vulgaris, the plant extract with the highest berberine concentration, is the most efficient inhibitor (0.4% extract concentration for the 2D model and 3.8% for the 3D model). The membrane integrity and nitrate/nitrite concentration assays were consistent with the viability results and showed effective anticancer potential. For further investigations, the B. vulgaris extract was used to obtain silver nanoparticles, which were characterized through transmission electron microscopy, energy dispersive spectroscopy, and X-ray diffraction. The formed nanoparticles have a uniform size distribution and are suited for future investigations in the field of biomedical applications, together with the B. vulgaris plant extract. Full article
(This article belongs to the Special Issue Phytochemicals: Current Status and Future Prospects)
12 pages, 556 KiB  
Article
Electromyographic Characteristics of Postactivation Effect in Dopamine-Dependent Spectrum Models Observed in Parkinson’s Disease and Schizophrenia
by Alexander Meigal, Liudmila Gerasimova-Meigal, Anna Kuzmina, Elena Antonen, Alexandra Peskova and Mark Burkin
Biomedicines 2024, 12(6), 1338; https://doi.org/10.3390/biomedicines12061338 - 17 Jun 2024
Viewed by 179
Abstract
This study aimed to test the hypothesis that the postactivation effect (PAE, involuntary normal muscle tone) is modified by dopaminergic mechanisms. The PAE was tested with surface electromyography (sEMG) in the “off medication” phase in participants with Parkinson’s disease (PDoff) and [...] Read more.
This study aimed to test the hypothesis that the postactivation effect (PAE, involuntary normal muscle tone) is modified by dopaminergic mechanisms. The PAE was tested with surface electromyography (sEMG) in the “off medication” phase in participants with Parkinson’s disease (PDoff) and in the “on medication” state in participants with schizophrenia (SZon), which modeled hypodopaminegic conditions, and in participants with PD “on medication” (PDon) and in participants with SZ “off medication” (SZoff) state which modeled the hyperdopaminergic conditions. Healthy age-matched participants constituted the control group (HC, n = 11). In hyperdopaminergic models, PAE was triggered in 71.3% of participants in SZoff and in 35.7% in PDon conditions. In the hypodopaminergic models, PAE was triggered in 12% in SZon and in 21.4% in PDoff conditions. In the HC group, PAE was present in 91% of participants. In the HC and PD groups, the mean frequency and correlation dimension of sEMG at PAE was higher than that during voluntary isometric contraction. In conclusion, in hypodopaminergic models, PAE triggering was inhibited. The manifestations and EMG characteristics of PAE in people with PD or SZ may indicate dopaminergic dysfunction. Full article
(This article belongs to the Section Neurobiology and Clinical Neuroscience)
17 pages, 3923 KiB  
Article
The Role of Macrophage Inhibitory Factor in TAA-Induced Liver Fibrosis in Mice: Modulatory Effects of Betaine
by Tatjana Radosavljevic, Dusan Vukicevic, Jasmina Djuretić, Kristina Gopcevic, Milica Labudovic Borovic, Sanja Stankovic, Janko Samardzic, Milica Radosavljevic, Danijela Vucevic and Vladimir Jakovljevic
Biomedicines 2024, 12(6), 1337; https://doi.org/10.3390/biomedicines12061337 - 17 Jun 2024
Viewed by 266
Abstract
Macrophage inhibitory factor (MIF) is a multipotent cytokine, involved in the inflammatory response to infections or injuries. This study investigates the role of MIF in liver fibrosis and the modulating effect of betaine on MIF in thioacetamide (TAA)-induced liver fibrosis. The wild-type and [...] Read more.
Macrophage inhibitory factor (MIF) is a multipotent cytokine, involved in the inflammatory response to infections or injuries. This study investigates the role of MIF in liver fibrosis and the modulating effect of betaine on MIF in thioacetamide (TAA)-induced liver fibrosis. The wild-type and knockout MIF−/− C57BL/6 mice were divided into the following groups: control; Bet group, which received betaine; MIF−/−; MIF−/−+Bet; TAA group, which received TAA; TAA+Bet; MIF−/−+TAA; and MIF−/−+TAA+Bet group. After eight weeks of treatment, liver tissue was collected for further analysis. The results revealed that TAA-treated MIF-deficient mice had elevated levels of hepatic TGF-β1 and PDGF-BB, as well as MMP-2, MMP-9, and TIMP-1 compared to TAA-treated wild-type mice. However, the administration of betaine to TAA-treated MIF-deficient mice reduced hepatic TGF-β1 and PDGF-BB levels and also the relative activities of MMP-2, MMP-9 and TIMP-1, albeit less effectively than in TAA-treated mice without MIF deficiency. Furthermore, the antifibrogenic effect of MIF was demonstrated by an increase in MMP2/TIMP1 and MMP9/TIMP1 ratios. The changes in the hepatic levels of fibrogenic factors were confirmed by a histological examination of liver tissue. Overall, the dual nature of MIF highlights its involvement in the progression of liver fibrosis. Its prooxidant and proinflammatory effects may exacerbate tissue damage and inflammation initially, but its antifibrogenic activity suggests a potential protective role against fibrosis development. The study showed that betaine modulates the antifibrogenic effects of MIF in TAA-induced liver fibrosis, by decreasing TGF-β1, PDGF-BB, MMP-2, MMP-9, TIMP-1, and the deposition of ECM (Coll1 and Coll3) in the liver. Full article
(This article belongs to the Section Gene and Cell Therapy)
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15 pages, 1351 KiB  
Article
The Endothelial Glycocalyx in Pig-to-Baboon Cardiac Xenotransplantation—First Insights
by Martin Bender, Jan-Michael Abicht, Bruno Reichart, Maria Leuschen, Felicia Wall, Julia Radan, Elisabeth Neumann, Maren Mokelke, Ines Buttgereit, Sebastian Michel, Reinhard Ellgass, Katja Gieseke, Stig Steen, Audrius Paskevicius, Joachim Denner, Antonia W. Godehardt, Ralf R. Tönjes, Christian Hagl, David Ayares, Eckhard Wolf, Michael Schmoeckel, Paolo Brenner, Martin B. Müller and Matthias Länginadd Show full author list remove Hide full author list
Biomedicines 2024, 12(6), 1336; https://doi.org/10.3390/biomedicines12061336 - 16 Jun 2024
Viewed by 374
Abstract
Cardiac xenotransplantation has seen remarkable success in recent years and is emerging as the most promising alternative to human cardiac allotransplantation. Despite these achievements, acute vascular rejection still presents a challenge for long-term xenograft acceptance and new insights into innate and adaptive immune [...] Read more.
Cardiac xenotransplantation has seen remarkable success in recent years and is emerging as the most promising alternative to human cardiac allotransplantation. Despite these achievements, acute vascular rejection still presents a challenge for long-term xenograft acceptance and new insights into innate and adaptive immune responses as well as detailed characterizations of signaling pathways are necessary. In allotransplantation, endothelial cells and their sugar-rich surface—the endothelial glycocalyx—are known to influence organ rejection. In xenotransplantation, however, only in vitro data exist on the role of the endothelial glycocalyx so far. Thus, in the current study, we analyzed the changes of the endothelial glycocalyx components hyaluronan, heparan sulfate and syndecan-1 after pig-to-baboon cardiac xenotransplantations in the perioperative (n = 4) and postoperative (n = 5) periods. These analyses provide first insights into changes of the endothelial glycocalyx after pig-to-baboon cardiac xenotransplantation and show that damage to the endothelial glycocalyx seems to be comparable or even less pronounced than in similar human settings when current strategies of cardiac xenotransplantation are applied. At the same time, data from the experiments where current strategies, like non-ischemic preservation, growth inhibition or porcine cytomegalovirus (a porcine roseolovirus (PCMV/PRV)) elimination could not be applied indicate that damage of the endothelial glycocalyx also plays an important role in cardiac xenotransplantation. Full article
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28 pages, 10163 KiB  
Article
External Support of Autologous Internal Jugular Vein Grafts with FRAME Mesh in a Porcine Carotid Artery Model
by Jaroslav Chlupac, Jan Frank, David Sedmera, Ondrej Fabian, Zuzana Simunkova, Iveta Mrazova, Tomas Novak, Zdenka Vanourková, Oldrich Benada, Zdenek Pulda, Theodor Adla, Martin Kveton, Alena Lodererova, Ludek Voska, Jan Pirk and Jiri Fronek
Biomedicines 2024, 12(6), 1335; https://doi.org/10.3390/biomedicines12061335 - 16 Jun 2024
Viewed by 201
Abstract
Background: Autologous vein grafts are widely used for bypass procedures in cardiovascular surgery. However, these grafts are susceptible to failure due to vein graft disease. Our study aimed to evaluate the impact of the latest-generation FRAME external support on vein graft remodeling in [...] Read more.
Background: Autologous vein grafts are widely used for bypass procedures in cardiovascular surgery. However, these grafts are susceptible to failure due to vein graft disease. Our study aimed to evaluate the impact of the latest-generation FRAME external support on vein graft remodeling in a preclinical model. Methods: We performed autologous internal jugular vein interposition grafting in porcine carotid arteries for one month. Four grafts were supported with a FRAME mesh, while seven unsupported grafts served as controls. The conduits were examined through flowmetry, angiography, macroscopy, and microscopy. Results: The one-month patency rate of FRAME-supported grafts was 100% (4/4), whereas that of unsupported controls was 43% (3/7, Log-rank p = 0.071). On explant angiography, FRAME grafts exhibited significantly more areas with no or mild stenosis (9/12) compared to control grafts (3/21, p = 0.0009). Blood flow at explantation was higher in the FRAME grafts (145 ± 51 mL/min) than in the controls (46 ± 85 mL/min, p = 0.066). Area and thickness of neo-intimal hyperplasia (NIH) at proximal anastomoses were similar for the FRAME and the control groups: 5.79 ± 1.38 versus 6.94 ± 1.10 mm2, respectively (p = 0.558) and 480 ± 95 vs. 587 ± 52 μm2/μm, respectively (p = 0.401). However, in the midgraft portions, the NIH area and thickness were significantly lower in the FRAME group than in the control group: 3.73 ± 0.64 vs. 6.27 ± 0.64 mm2, respectively (p = 0.022) and 258 ± 49 vs. 518 ± 36 μm2/μm, respectively (p = 0.0002). Conclusions: In our porcine model, the external mesh FRAME improved the patency of vein-to-carotid artery grafts and protected them from stenosis, particularly in the mid regions. The midgraft neo-intimal hyperplasia was two-fold thinner in the meshed grafts than in the controls. Full article
17 pages, 734 KiB  
Review
The Importance of Sleep in Overcoming Childhood Obesity and Reshaping Epigenetics
by Erika Richter, Priyadarshni Patel, Jeganathan Ramesh Babu, Xu Wang and Thangiah Geetha
Biomedicines 2024, 12(6), 1334; https://doi.org/10.3390/biomedicines12061334 - 15 Jun 2024
Viewed by 286
Abstract
The development of childhood obesity is a complex process influenced by a combination of genetic predisposition and environmental factors, such as sleep, diet, physical activity, and socioeconomic status. Long-term solutions for decreasing the risk of childhood obesity remain elusive, despite significant advancements in [...] Read more.
The development of childhood obesity is a complex process influenced by a combination of genetic predisposition and environmental factors, such as sleep, diet, physical activity, and socioeconomic status. Long-term solutions for decreasing the risk of childhood obesity remain elusive, despite significant advancements in promoting health and well-being in school and at home. Challenges persist in areas such as adherence to interventions, addressing underlying social determinants, and individual differences in response to treatment. Over the last decade, there has been significant progress in epigenetics, along with increased curiosity in gaining insights into how sleep and lifestyle decisions impact an individual’s health. Epigenetic modifications affect the expression of genes without causing changes to the fundamental DNA sequence. In recent years, numerous research studies have explored the correlation between sleep and the epigenome, giving a better understanding of DNA methylation, histone modification, and non-coding RNAs. Although significant findings have been made about the influence of sleep on epigenetics, a notable gap exists in the literature concerning sleep-related genes specifically associated with childhood obesity. Consequently, it is crucial to delve deeper into this area to enhance our understanding. Therefore, this review primarily focuses on the connection between sleep patterns and epigenetic modifications in genes related to childhood obesity. Exploring the interplay between sleep, epigenetics, and childhood obesity can potentially contribute to improved overall health outcomes. This comprehensive review encompasses studies focusing on sleep-related genes linked to obesity. Full article
(This article belongs to the Special Issue Epigenetic Regulation and Its Impact for Medicine)
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16 pages, 1633 KiB  
Review
Unveiling the Significance of HLA and KIR Diversity in Underrepresented Populations
by Lucía Santiago-Lamelas, Patricia Castro-Santos, Ángel Carracedo, Jordi Olloquequi and Roberto Díaz-Peña
Biomedicines 2024, 12(6), 1333; https://doi.org/10.3390/biomedicines12061333 - 15 Jun 2024
Viewed by 214
Abstract
Human leukocyte antigen (HLA) molecules and their relationships with natural killer (NK) cells, specifically through their interaction with killer-cell immunoglobulin-like receptors (KIRs), exhibit robust associations with the outcomes of diverse diseases. Moreover, genetic variations in HLA and KIR immune system genes offer limitless [...] Read more.
Human leukocyte antigen (HLA) molecules and their relationships with natural killer (NK) cells, specifically through their interaction with killer-cell immunoglobulin-like receptors (KIRs), exhibit robust associations with the outcomes of diverse diseases. Moreover, genetic variations in HLA and KIR immune system genes offer limitless depths of complexity. In recent years, a surge of high-powered genome-wide association studies (GWASs) utilizing single nucleotide polymorphism (SNP) arrays has occurred, significantly advancing our understanding of disease pathogenesis. Additionally, advances in HLA reference panels have enabled higher resolution and more reliable imputation, allowing for finer-grained evaluation of the association between sequence variations and disease risk. However, it is essential to note that the majority of these GWASs have focused primarily on populations of Caucasian and Asian origins, neglecting underrepresented populations in Latin America and Africa. This omission not only leads to disparities in health care access but also restricts our knowledge of novel genetic variants involved in disease pathogenesis within these overlooked populations. Since the KIR and HLA haplotypes prevalent in each population are clearly modelled by the specific environment, the aim of this review is to encourage studies investigating HLA/KIR involvement in infection and autoimmune diseases, reproduction, and transplantation in underrepresented populations. Full article
(This article belongs to the Special Issue Advanced Research of HLA in Diseases)
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11 pages, 1181 KiB  
Article
Role of Spinal Cholecystokinin Octapeptide, Nociceptin/Orphanin FQ, and Hemokinin-1 in Diabetic Allodynia
by Takafumi Hayashi, Syu-ichi Kanno, Chizuko Watanabe, Damiana Scuteri, Yasuyuki Agatsuma, Akiyoshi Hara, Giacinto Bagetta, Tsukasa Sakurada and Shinobu Sakurada
Biomedicines 2024, 12(6), 1332; https://doi.org/10.3390/biomedicines12061332 - 15 Jun 2024
Viewed by 175
Abstract
A complication of diabetes is neuropathic pain, which is difficult to control with medication. We have confirmed that neuropathic pain due to mechanical allodynia in diabetic mice is mediated by a characteristic neuropeptide in the spinal cord. We evaluated the strength of mechanical [...] Read more.
A complication of diabetes is neuropathic pain, which is difficult to control with medication. We have confirmed that neuropathic pain due to mechanical allodynia in diabetic mice is mediated by a characteristic neuropeptide in the spinal cord. We evaluated the strength of mechanical allodynia in mice using von Frey filaments. When mice were intravenously injected with streptozotocin, mechanical allodynia appeared 3 days later. Antibodies of representative neuropeptides were intrathecally (i.t.) administered to allodynia-induced mice 7 days after the intravenous administration of streptozotocin, and allodynia was reduced by anti-cholecystokinin octapeptide antibodies, anti-nociceptin/orphanin FQ antibodies, and anti-hemokinin-1 antibodies. In contrast, i.t.-administered anti-substance P antibodies, anti-somatostatin antibodies, and anti-angiotensin II antibodies did not affect streptozotocin-induced diabetic allodynia mice. Mechanical allodynia was attenuated by the i.t. administration of CCK-B receptor antagonists and ORL-1 receptor antagonists. The mRNA level of CCK-B receptors in streptozotocin-induced diabetic allodynia mice increased in the spinal cord, but not in the dorsal root ganglion. These results indicate that diabetic allodynia is caused by cholecystokinin octapeptide, nociceptin/orphanin FQ, and hemokinin-1 released from primary afferent neurons in the spinal cord that transmit pain to the brain via the spinal dorsal horn. Full article
20 pages, 723 KiB  
Review
Recent Insights into Cellular and Molecular Mechanisms of Defective Angiogenesis in Systemic Sclerosis
by Eloisa Romano, Irene Rosa, Bianca Saveria Fioretto and Mirko Manetti
Biomedicines 2024, 12(6), 1331; https://doi.org/10.3390/biomedicines12061331 - 14 Jun 2024
Viewed by 295
Abstract
In systemic sclerosis (SSc, or scleroderma), defective angiogenesis, clinically manifesting with abnormal capillary architecture and severe capillary reduction, represents a hallmark of early-stage disease, usually preceding the onset of tissue fibrosis, and is caused by several cellular and molecular mechanisms affecting microvascular endothelial [...] Read more.
In systemic sclerosis (SSc, or scleroderma), defective angiogenesis, clinically manifesting with abnormal capillary architecture and severe capillary reduction, represents a hallmark of early-stage disease, usually preceding the onset of tissue fibrosis, and is caused by several cellular and molecular mechanisms affecting microvascular endothelial cells with different outcomes. Indeed, once damaged, endothelial cells can be dysfunctionally activated, thus becoming unable to undergo angiogenesis and promoting perivascular inflammation. They can also undergo apoptosis, transdifferentiate into profibrotic myofibroblasts, or acquire a senescence-associated secretory phenotype characterized by the release of exosomes and several profibrotic and proinflammatory mediators. In this narrative review, we aimed to give a comprehensive overview of recent studies dealing with the cellular and molecular mechanisms underlying SSc defective angiogenesis and the related endothelial cell dysfunctions, mainly the endothelial-to-mesenchymal transition process. We also discussed potential novel vascular treatment strategies able to restore the angiogenic process and reduce the endothelial-to-mesenchymal transition in this complex disease. Full article
(This article belongs to the Special Issue Angiogenesis)
15 pages, 1194 KiB  
Article
Importance of T1-Mapping Sequence in Patients with Hypertrophic Cardiomyopathy without Foci of Non-Ischemic Myocardial Injury in Late Gadolinium Enhancement Sequence
by Natalia Zdebik, Rafał Poręba and Paweł Gać
Biomedicines 2024, 12(6), 1330; https://doi.org/10.3390/biomedicines12061330 - 14 Jun 2024
Viewed by 269
Abstract
Background: The aim of this study was to assess the importance of T1-mapping sequences in the diagnosis of hypertrophic cardiomyopathy (HCM) in patients without foci of non-ischemic myocardial injury in classic cardiac magnetic resonance (CMR) sequences. Methods: Two groups were compared: 28 patients [...] Read more.
Background: The aim of this study was to assess the importance of T1-mapping sequences in the diagnosis of hypertrophic cardiomyopathy (HCM) in patients without foci of non-ischemic myocardial injury in classic cardiac magnetic resonance (CMR) sequences. Methods: Two groups were compared: 28 patients with HCM, without any foci of myocardial injury in the late gadolinium enhancement (LGE) sequence (HCM group), and 28 patients without cardiomyopathy (CON group). Classic CMR sequences and T1-mapping sequences were performed. The following parameters were assessed: T1 time of the whole left ventricular myocardium, T1 time of myocardium in the basal, middle and apical layers of the left ventricle, and T1 time in individual segments of the left ventricular myocardium. Myocardial extracellular volume (ECV) was assessed similarly. Results: ECV was significantly higher in the HCM group than in the CON group, for the whole left ventricular myocardium, for the basal and apical layers of the left ventricle, and for segments 1–3, 8, and 13–16 of the left ventricle. Regression analysis showed that a higher left-ventricular mass index (LVMI), a higher body mass index and older age are factors independently associated with a higher ECV of the whole myocardium but only in the group with LVMI ≥ 131.84 g/m2. Conclusion: In patients with HCM without foci of non-ischemic myocardial injury, higher ECV values of the left ventricular myocardium are observed. Full article
18 pages, 3334 KiB  
Article
The Role of Salivary Vascular Endothelial Growth Factor A, Cytokines, and Amino Acids in Immunomodulation and Angiogenesis in Breast Cancer
by Elena A. Sarf, Elena I. Dyachenko and Lyudmila V. Bel’skaya
Biomedicines 2024, 12(6), 1329; https://doi.org/10.3390/biomedicines12061329 - 14 Jun 2024
Viewed by 286
Abstract
In this work, we focused on the analysis of VEGF content in saliva and its relationship with pro-inflammatory cytokines and amino acids involved in immunomodulation and angiogenesis in breast cancer. The study included 230 breast cancer patients, 92 patients with benign breast disease, [...] Read more.
In this work, we focused on the analysis of VEGF content in saliva and its relationship with pro-inflammatory cytokines and amino acids involved in immunomodulation and angiogenesis in breast cancer. The study included 230 breast cancer patients, 92 patients with benign breast disease, and 59 healthy controls. Before treatment, saliva samples were obtained from all participants, and the content of VEGF and cytokines in saliva was determined by an enzyme-linked immunosorbent assay, as well as the content of amino acids by high-performance liquid chromatography. It was found that VEGF was positively correlated with the level of pro-inflammatory cytokines IL-1β (r = 0.6367), IL-6 (r = 0.3813), IL-8 (r = 0.4370), and IL-18 (r = 0.4184). Weak correlations were shown for MCP-1 (r = 0.2663) and TNF-α (r = 0.2817). For the first time, we demonstrated changes in the concentration of VEGF and related cytokines in saliva in different molecular biological subtypes of breast cancer depending on the stage of the disease, differentiation, proliferation, and metastasis to the lymph nodes. A correlation was established between the expression of VEGF and the content of aspartic acid (r = −0.3050), citrulline (r = −0.2914), and tryptophan (r = 0.3382) in saliva. It has been suggested that aspartic acid and citrulline influence the expression of VEGF via the synthesis of the signaling molecule NO, and then tryptophan ensures tolerance of the immune system to tumor cells. Full article
(This article belongs to the Special Issue The Role of Inflammatory Cytokines in Cancer Progression 2.0)
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17 pages, 2376 KiB  
Review
Increase in Vascular Endothelial Growth Factor (VEGF) Expression and the Pathogenesis of iMCD-TAFRO
by Gordan Srkalovic, Sally Nijim, Maya Blanka Srkalovic and David Fajgenbaum
Biomedicines 2024, 12(6), 1328; https://doi.org/10.3390/biomedicines12061328 - 14 Jun 2024
Viewed by 257
Abstract
TAFRO (thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (F/R), renal failure (R), and organomegaly (O)) is a heterogeneous clinical subtype of idiopathic multicentric Castleman disease (iMCD) associated with a significantly poorer prognosis than other subtypes of iMCD. TAFRO symptomatology can also be [...] Read more.
TAFRO (thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (F/R), renal failure (R), and organomegaly (O)) is a heterogeneous clinical subtype of idiopathic multicentric Castleman disease (iMCD) associated with a significantly poorer prognosis than other subtypes of iMCD. TAFRO symptomatology can also be seen in pathological contexts outside of iMCD, but it is unclear if those cases should be considered representative of a different disease entity or simply a severe presentation of other infectious, malignant, and rheumatological diseases. While interleukin-6 (IL-6) is an established driver of iMCD-TAFRO pathogenesis in a subset of patients, the etiology is unknown. Recent case reports and literature reviews on TAFRO patients suggest that vascular endothelial growth factor (VEGF), and the interplay of VEGF and IL-6 in concert, rather than IL-6 as a single cytokine, may be drivers for iMCD-TAFRO pathophysiology, especially renal injury. In this review, we discuss the possible role of VEGF in the pathophysiology and clinical manifestations of iMCD-TAFRO. In particular, VEGF may be involved in iMCD-TAFRO pathology through its ability to activate RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathways. Further elucidating a role for the VEGF-IL-6 axis and additional disease drivers may shed light on therapeutic options for the treatment of TAFRO patients who do not respond to, or otherwise relapse following, treatment with IL-6 targeting drugs. This review investigates the potential role of VEGF in the pathophysiology of iMCD-TAFRO and the potential for targeting related signaling pathways in the future. Full article
(This article belongs to the Special Issue Diagnosis, Pathogenesis and Treatment of TAFRO Syndrome)
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