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Editor’s Choice Articles

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

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20 pages, 2071 KiB  
Review
Fourier Transform Ion Cyclotron Resonance Mass Spectrometry Applications for Metabolomics
by Darcy Cochran and Robert Powers
Biomedicines 2024, 12(8), 1786; https://doi.org/10.3390/biomedicines12081786 - 6 Aug 2024
Cited by 3 | Viewed by 2805
Abstract
Metabolomics is an interdisciplinary field that aims to study all metabolites < 1500 Da that are ubiquitously found within all organisms. Metabolomics is experiencing exponential growth and commonly relies on high-resolution mass spectrometry (HRMS). Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) is [...] Read more.
Metabolomics is an interdisciplinary field that aims to study all metabolites < 1500 Da that are ubiquitously found within all organisms. Metabolomics is experiencing exponential growth and commonly relies on high-resolution mass spectrometry (HRMS). Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) is a form of HRMS that is particularly well suited for metabolomics research due to its exceptionally high resolution (105–106) and sensitivity with a mass accuracy in parts per billion (ppb). In this regard, FT-ICR-MS can provide valuable insights into the metabolomics analysis of complex biological systems due to unique capabilities such as the easy separation of isobaric and isomeric species, isotopic fine structure analysis, spatial resolution of metabolites in cells and tissues, and a high confidence (<1 ppm mass error) in metabolite identification. Alternatively, the large and complex data sets, long acquisition times, high cost, and limited access mainly through national mass spectrometry facilities may impede the routine adoption of FT-ICR-MS by metabolomics researchers. This review examines recent applications of FT-ICR-MS metabolomics in the search for clinical and non-human biomarkers; for the analysis of food, beverage, and environmental samples; and for the high-resolution imaging of tissues and other biological samples. We provide recent examples of metabolomics studies that highlight the advantages of FT-ICR-MS for the detailed and reliable characterization of the metabolome. Additionally, we offer some practical considerations for implementing FT-ICR-MS into a research program by providing a list of FT-ICR-MS facilities and by identifying different high-throughput interfaces, varieties of sample types, analysis methods (e.g., van Krevelen diagrams, Kendrick mass defect plot, etc.), and sample preparation and handling protocols used in FT-ICR-MS experiments. Overall, FT-ICR-MS holds great promise as a vital research tool for advancing metabolomics investigations. Full article
(This article belongs to the Collection OMICs and Complex Diseases)
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16 pages, 817 KiB  
Review
Cell-Based Treatment in Acute Myeloid Leukemia Relapsed after Allogeneic Stem Cell Transplantation
by Martina Canichella and Paolo de Fabritiis
Biomedicines 2024, 12(8), 1721; https://doi.org/10.3390/biomedicines12081721 - 1 Aug 2024
Cited by 1 | Viewed by 2150
Abstract
Allogeneic stem cell transplant (ASCT) remains the only treatment option for patients with high-risk acute myeloid leukemia (AML). Recurrence of leukemic cells after ASCT represents a dramatic event associated with a dismal outcome, with a 2-year survival rate of around 20%. Adoptive cell [...] Read more.
Allogeneic stem cell transplant (ASCT) remains the only treatment option for patients with high-risk acute myeloid leukemia (AML). Recurrence of leukemic cells after ASCT represents a dramatic event associated with a dismal outcome, with a 2-year survival rate of around 20%. Adoptive cell therapy (ACT) is a form of cell-based strategy that has emerged as an effective therapy to treat and prevent post-ASCT recurrence. Lymphocytes are the principal cells used in this therapy and can be derived from a hematopoietic stem cell donor, the patient themselves, or healthy donors, after being engineered to express the chimeric antigen receptor (CAR-T and UniCAR-T). In this review, we discuss recent advances in the established strategy of donor lymphocyte infusion (DLI) and the progress and challenges of CAR-T cells. Full article
(This article belongs to the Special Issue Advances in CAR-T Cell Therapy)
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19 pages, 828 KiB  
Review
Inflammaging: The Next Challenge—Exploring the Role of Gut Microbiota, Environmental Factors, and Sex Differences
by Mario Caldarelli, Pierluigi Rio, Andrea Marrone, Vincenzo Giambra, Antonio Gasbarrini, Giovanni Gambassi and Rossella Cianci
Biomedicines 2024, 12(8), 1716; https://doi.org/10.3390/biomedicines12081716 - 1 Aug 2024
Cited by 7 | Viewed by 3278
Abstract
The term ‘inflammaging’ has been coined to describe the chronic state of inflammation derived from ongoing cycles of tissue damage and the subsequent immune responses. This inflammatory status contributes to the decline of organs and physiological functions, accelerates the aging process, and increases [...] Read more.
The term ‘inflammaging’ has been coined to describe the chronic state of inflammation derived from ongoing cycles of tissue damage and the subsequent immune responses. This inflammatory status contributes to the decline of organs and physiological functions, accelerates the aging process, and increases the risk of age-related illnesses and death. During aging, the gut microbiota (GM) undergoes significant changes, including a decreased diversity of species, a decline in beneficial bacteria, and a rise in proinflammatory ones, resulting in persistent low-grade inflammation. Moreover, environmental factors, such as diet and medications, contribute to age-related changes in GM and immune function, preventing or promoting inflammaging. This narrative review aims to clarify the underlying mechanisms of inflammaging and to specifically investigate the influence of GM and several environmental factors on these mechanisms, while also exploring potential differences related to sex. Moreover, lifestyle and pharmacological interventions will be suggested to promote healthy aging. Full article
(This article belongs to the Special Issue Gut Microbiota, Diet, and Immunity: Investigating the Connections and Implications for Disease Development)
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11 pages, 260 KiB  
Article
Testing Reported Associations of Gene Variants with Non-Syndromic Orofacial Clefts in the Polish Population
by Alicja Zawiślak, Krzysztof Woźniak, Gianluca Tartaglia, Beata Kawala, Satish Gupta, Anna Znamirowska-Bajowska, Katarzyna Grocholewicz, Jan Lubiński and Anna Jakubowska
Biomedicines 2024, 12(8), 1700; https://doi.org/10.3390/biomedicines12081700 - 31 Jul 2024
Cited by 2 | Viewed by 1302
Abstract
Orofacial clefts (OFCs) are the second most common birth defect worldwide. The etiology of OFCs involves complex interactions between genetics and environment. Advances in genomic technologies have identified gene variants associated with OFCs. This study aimed to investigate whether selected SNPs in the [...] Read more.
Orofacial clefts (OFCs) are the second most common birth defect worldwide. The etiology of OFCs involves complex interactions between genetics and environment. Advances in genomic technologies have identified gene variants associated with OFCs. This study aimed to investigate whether selected SNPs in the MYH9, MTHFR, MAFB, and SUMO1 genes influence the occurrence of non-syndromic OFCs in the Polish population. The study included 209 individuals with non-syndromic OFCs and 418 healthy controls. Saliva and umbilical cord blood samples were collected for DNA extraction. Four SNPs in the MYH9, MTHFR, MAFB, and SUMO1 genes were genotyped using real-time PCR-based TaqMan assays. Statistical analysis was performed using logistic regression to assess the association between SNPs and OFCs. A significant association was found between the rs7078 CC polymorphism and OFCs (OR = 3.22, CI 1.68–6.17, p < 0.001). No significant associations were identified for the rs1081131, rs13041247, and rs3769817 polymorphisms. The research indicates that the rs7078 polymorphism significantly influences the occurrence of orofacial cleft palate in the Polish population, whereas the rs3769817, rs1801131, and rs13041247 SNPs do not show such a correlation. Full article
(This article belongs to the Special Issue Recent Advances in Oral Medicine)
21 pages, 7127 KiB  
Article
Human-Induced Pluripotent Stem Cell-Derived Neural Stem Cell Therapy Limits Tissue Damage and Promotes Tissue Regeneration and Functional Recovery in a Pediatric Piglet Traumatic-Brain-Injury Model
by Sarah L. Schantz, Sydney E. Sneed, Madison M. Fagan, Morgane E. Golan, Savannah R. Cheek, Holly A. Kinder, Kylee J. Duberstein, Erin E. Kaiser and Franklin D. West
Biomedicines 2024, 12(8), 1663; https://doi.org/10.3390/biomedicines12081663 - 25 Jul 2024
Cited by 2 | Viewed by 2952
Abstract
Traumatic brain injury (TBI) is a leading cause of death and disability in pediatric patients and often results in delayed neural development and altered connectivity, leading to lifelong learning, memory, behavior, and motor function deficits. Induced pluripotent stem cell-derived neural stem cells (iNSCs) [...] Read more.
Traumatic brain injury (TBI) is a leading cause of death and disability in pediatric patients and often results in delayed neural development and altered connectivity, leading to lifelong learning, memory, behavior, and motor function deficits. Induced pluripotent stem cell-derived neural stem cells (iNSCs) may serve as a novel multimodal therapeutic as iNSCs possess neuroprotective, regenerative, and cell-replacement capabilities post-TBI. In this study, we evaluated the effects of iNSC treatment on cellular, tissue, and functional recovery in a translational controlled cortical impact TBI piglet model. Five days post-craniectomy (n = 6) or TBI (n = 18), iNSCs (n = 7) or PBS (n = 11) were injected into perilesional brain tissue. Modified Rankin Scale (mRS) neurological evaluation, magnetic resonance imaging, and immunohistochemistry were performed over the 12-week study period. At 12-weeks post-transplantation, iNSCs showed long-term engraftment and differentiation into neurons, astrocytes, and oligodendrocytes. iNSC treatment enhanced endogenous neuroprotective and regenerative activities indicated by decreasing intracerebral immune responses, preserving endogenous neurons, and increasing neuroblast formation. These cellular changes corresponded with decreased hemispheric atrophy, midline shift, and lesion volume as well as the preservation of cerebral blood flow. iNSC treatment increased piglet survival and decreased mRS scores. The results of this study in a predictive pediatric large-animal pig model demonstrate that iNSC treatment is a robust multimodal therapeutic that has significant promise in potentially treating human pediatric TBI patients. Full article
(This article belongs to the Special Issue Recent Advances in Traumatic Brain Injury Using Large Animal Models)
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12 pages, 954 KiB  
Article
Post-COVID-19 Pain Is Not Associated with DNA Methylation Levels of the ACE2 Promoter in COVID-19 Survivors Hospitalized Due to SARS-CoV-2 Infection
by César Fernández-de-las-Peñas, Gema Díaz-Gil, Antonio Gil-Crujera, Stella M. Gómez-Sánchez, Silvia Ambite-Quesada, Anabel Franco-Moreno, Pablo Ryan-Murua, Juan Torres-Macho, Oscar J. Pellicer-Valero, Lars Arendt-Nielsen and Rocco Giordano
Biomedicines 2024, 12(8), 1662; https://doi.org/10.3390/biomedicines12081662 - 25 Jul 2024
Viewed by 1346
Abstract
One of theories explaining the development of long-lasting symptoms after an acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection include changes in the methylation pattern of the host. The current study aimed to investigate whether DNA methylation levels associated with the angiotensin-converting [...] Read more.
One of theories explaining the development of long-lasting symptoms after an acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection include changes in the methylation pattern of the host. The current study aimed to investigate whether DNA methylation levels associated with the angiotensin-converting enzyme 2 (ACE2) promoter are different when comparing individuals previously hospitalized due to COVID-19 who then developed long-lasting post-COVID pain with those previously hospitalized due to COVID-19 who did not develop post-COVID-19 pain symptoms. Non-stimulated saliva samples were obtained from a cohort of 279 (mean age: 56.5, SD: 13.0 years old, 51.5% male) COVID-19 survivors who needed hospitalization. Clinical data were collected from hospital medical records. Participants were asked to disclose pain symptoms developed during the first three months after hospital admission due to COVID-19 and persisting at the time of the interview. Methylations of five CpG dinucleotides in the ACE2 promoter were quantified (as percentages). Participants were evaluated up to 17.8 (SD: 5.3) months after hospitalization. Thus, 39.1% of patients exhibited post-COVID-19 pain. Most patients (77.05%) in the cohort developed localized post-COVID-19 pain. Headache and pain in the lower extremity were experienced by 29.4% of the patients. Seven patients received a post-infection diagnosis of fibromyalgia based on the presence of widespread pain characteristics (11.6%) and other associated symptoms. No significant differences in methylation percentages at any CpG location of the ACE2 promoter were identified when comparing individuals with and without post-COVID-19 pain. The current study did not observe differences in methylation levels of the ACE2 promoter depending on the presence or absence of long-lasting post-COVID-19 pain symptoms in individuals who needed hospitalization due to COVID-19 during the first wave of the pandemic. Full article
(This article belongs to the Special Issue Latest Research in Post-COVID (Long COVID): Pathological and Treatment Studies of Sequelae and Complications—2nd Edition)
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15 pages, 13837 KiB  
Article
Cordycepin Augments the Efficacy of Anti-PD1 against Colon Cancer
by Wen-Kuei Chang, Yen-Ting Chen, Chin-Ping Lin, Chia-Jung Wang, Hui-Ru Shieh, Chih-Wen Chi, Tung-Hu Tsai and Yu-Jen Chen
Biomedicines 2024, 12(7), 1568; https://doi.org/10.3390/biomedicines12071568 - 15 Jul 2024
Cited by 1 | Viewed by 1767
Abstract
Colon cancer has a poor clinical response to anti-PD1 therapy. This study aimed to evaluate the effect of cordycepin on the efficacy of anti-PD1 treatment in colon cancer. The viability of CT26 mouse colon carcinoma cells, cell-cycle progression, morphology, and the expression of [...] Read more.
Colon cancer has a poor clinical response to anti-PD1 therapy. This study aimed to evaluate the effect of cordycepin on the efficacy of anti-PD1 treatment in colon cancer. The viability of CT26 mouse colon carcinoma cells, cell-cycle progression, morphology, and the expression of mRNA and protein were assessed. A syngeneic animal model was established by implanting CT26 cells into BALB/c mice for in vivo experiments. Multi-parameter flow cytometry was used to analyze the splenic cell lineages and tumor microenvironment (TME). The in vitro data revealed that cordycepin, but not adenosine, inhibited CT26 cell viability. The protein, but not mRNA, expression levels of A2AR and A2BR were suppressed by cordycepin but not by adenosine in CT26 cells. The combination of cordycepin, but not adenosine, with anti-PD1 exhibited a greater tumor-inhibitory effect than anti-PD1 alone as well as inhibited the expression of A2AR and A2BR in splenic macrophages. In the TME, the combination of cordycepin and anti-PD1 increased the number of CD3+ T cells and neutrophils and decreased the number of natural killer (NK) cells. Overall, cordycepin augmented the antitumor effects of anti-PD1 against mouse colon carcinoma cells and inhibited the expression of the adenosine receptors A2AR and A2BR in splenic macrophages and intratumoral NK cells. Full article
(This article belongs to the Special Issue Tumor Immune Microenvironment and Novel Strategies for Cancer Immunotherapy)
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22 pages, 656 KiB  
Review
The Placenta as a Source of Human Material for Neuronal Repair
by Alessia Dallatana, Linda Cremonesi, Francesco Pezzini, Gianluca Fontana, Giulio Innamorati and Luca Giacomello
Biomedicines 2024, 12(7), 1567; https://doi.org/10.3390/biomedicines12071567 - 15 Jul 2024
Cited by 3 | Viewed by 2776
Abstract
Stem cell therapy has the potential to meet unsolved problems in tissue repair and regeneration, particularly in the neural tissues. However, an optimal source has not yet been found. Growing evidence indicates that positive effects produced in vivo by mesenchymal stem cells (MSCs) [...] Read more.
Stem cell therapy has the potential to meet unsolved problems in tissue repair and regeneration, particularly in the neural tissues. However, an optimal source has not yet been found. Growing evidence indicates that positive effects produced in vivo by mesenchymal stem cells (MSCs) can be due not only to their plasticity but also to secreted molecules including extracellular vesicles (EVs) and the extracellular matrix (ECM). Trophic effects produced by MSCs may reveal the key to developing effective tissue-repair strategies, including approaches based on brain implants or other implantable neural electrodes. In this sense, MSCs will become increasingly valuable and needed in the future. The placenta is a temporary organ devoted to protecting and supporting the fetus. At the same time, the placenta represents an abundant and extremely convenient source of MSCs. Nonetheless, placenta-derived MSCs (P-MSCs) remain understudied as compared to MSCs isolated from other sources. This review outlines the limited literature describing the neuroregenerative effects of P-MSC-derived biomaterials and advocates for exploiting the potential of this untapped source for human regenerative therapies. Full article
(This article belongs to the Special Issue Role of Placenta-Derived Mesenchymal Stem Cells in Human Health and Disease)
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14 pages, 1782 KiB  
Review
Energy Metabolism and Metformin: Effects on Ischemia-Reperfusion Injury in Kidney Transplantation
by Denise V. Nemeth, Leonardo Iannelli, Elena Gangitano, Vito D’Andrea and Maria Irene Bellini
Biomedicines 2024, 12(7), 1534; https://doi.org/10.3390/biomedicines12071534 - 10 Jul 2024
Viewed by 1687
Abstract
Metformin (MTF) is the only biguanide included in the World Health Organization’s list of essential medicines; representing a widespread drug in the management of diabetes mellitus. With its accessibility and affordability being one of its biggest assets, it has become the target of [...] Read more.
Metformin (MTF) is the only biguanide included in the World Health Organization’s list of essential medicines; representing a widespread drug in the management of diabetes mellitus. With its accessibility and affordability being one of its biggest assets, it has become the target of interest for many trying to find alternative treatments for varied pathologies. Over time, an increasing body of evidence has shown additional roles of MTF, with unexpected interactions of benefit in other diseases. Metformin (MTF) holds significant promise in mitigating ischemia-reperfusion injury (IRI), particularly in the realm of organ transplantation. As acceptance criteria for organ transplants expand, IRI during the preservation phase remain a major concern within the transplant community, prompting a keen interest in MTF’s effects. Emerging evidence suggests that administering MTF during reperfusion may activate the reperfusion injury salvage kinase (RISK) pathway. This pathway is pivotal in alleviating IRI in transplant recipients, potentially leading to improved outcomes such as reduced rates of organ rejection. This review aims to contextualize MTF historically, explore its current uses, pharmacokinetics, and pharmacodynamics, and link these aspects to the pathophysiology of IRI to illuminate its potential future role in transplantation. A comprehensive survey of the current literature highlights MTF’s potential to recondition and protect against IRI by attenuating free radical damage, activating AMP-activated protein kinase to preserve cellular energy and promote repair, as well as directly reducing inflammation and enhancing microcirculation. Full article
(This article belongs to the Special Issue Molecular Mechanism of Ischemia and Reperfusion Injury)
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26 pages, 2162 KiB  
Review
Insight into IL-5 as a Potential Target for the Treatment of Allergic Diseases
by Katarzyna Antosz, Joanna Batko, Marta Błażejewska, Antoni Gawor, Jakub Sleziak and Krzysztof Gomułka
Biomedicines 2024, 12(7), 1531; https://doi.org/10.3390/biomedicines12071531 - 10 Jul 2024
Cited by 7 | Viewed by 4997
Abstract
Interleukin-5 functions as a B-cell differentiation factor, but more importantly, in the context of this review, it plays a variety of roles in eosinophil biology, including eosinophil differentiation and maturation in the bone marrow, and facilitates eosinophil migration to tissue sites, usually in [...] Read more.
Interleukin-5 functions as a B-cell differentiation factor, but more importantly, in the context of this review, it plays a variety of roles in eosinophil biology, including eosinophil differentiation and maturation in the bone marrow, and facilitates eosinophil migration to tissue sites, usually in the context of an allergic reaction. Given the availability of selective anti-IL-5 drugs such as mepolizumab and reslizumab, as well as the IL-5 receptor antagonist benralizumab, it is worth investigating whether they could be used in some cases of allergic disease. Asthma has a well-documented involvement of IL-5 in its pathophysiology and has clear benefits in the case of anti-IL-5 therapy; therefore, current knowledge is presented to provide a reference point for the study of less-described diseases such as atopic dermatitis, chronic rhinosinusitis, chronic spontaneous urticaria, and its association with both IL-5 and anti-IL-5 treatment options. We then review the current literature on these diseases, explain where appropriate potential reasons why anti-IL-5 treatments are ineffective, and then point out possible future directions for further research. Full article
(This article belongs to the Special Issue Allergic Diseases and Asthma: Molecular Diagnosis and Precision Medicine)
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15 pages, 837 KiB  
Article
CYP21A2 Intron 2 Genetic Variants Might Be Associated with the Clinical Characteristics of Women with PCOS
by Ralitsa Robeva, Silvia Andonova, Tihomir Todorov, Aylin Feyzullova, Atanaska Elenkova, Georgi Kirilov, Alexey Savov, Sabina Zacharieva and Albena Todorova
Biomedicines 2024, 12(7), 1528; https://doi.org/10.3390/biomedicines12071528 - 9 Jul 2024
Viewed by 1784
Abstract
Aims: Pathogenic variants in the CYP21A2 gene are related to the classic and non-classic forms of congenital adrenal hyperplasia (CAH). However, the role of CAH carrier status in the clinical presentation of polycystic ovarian syndrome (PCOS) is still unclear. Moreover, the possible associations [...] Read more.
Aims: Pathogenic variants in the CYP21A2 gene are related to the classic and non-classic forms of congenital adrenal hyperplasia (CAH). However, the role of CAH carrier status in the clinical presentation of polycystic ovarian syndrome (PCOS) is still unclear. Moreover, the possible associations of different CYP21A2 gene polymorphisms with metabolic and reproductive abnormalities in PCOS have not been investigated. Therefore, the present study aims to examine the prevalence of the most common CYP21A2 pathogenic variant IVS2-13A/C>G (c.293-13A/C>G) in Eastern European women with PCOS and to evaluate the associations between common intron 2 genetic polymorphisms and the clinical symptoms of the patients. Methods: Sixty consecutively recruited women with PCOS were genotyped for the CYP21A2 intron 2 IVS2-13A/C>G genetic variant. Additionally, CYP21A2 intron 2 polymorphic variants rs6453 (c.293-44G>T), rs6451 (c.293-67C>A/G), rs369651496 (c.293-104del), and rs6474 (c.308G>A/p.R103L) were tested and described. The clinical and hormonal characteristics were compared in women with PCOS and with polymorphic and wild-type genotypes. Results: The heterozygous CYP21A2 pathogenic variant IVS2-13A/C>G was found in one of the investigated PCOS patients (1.67%) with a non-hyperandrogenic type of PCOS. The presence of the rs6453 (c.293-44G>T) T-allele was associated with increased levels of DHEAS (15.18 vs. 9.14 µmol/L, p = 0.003) compared to the wild-type genotype in the investigated group. The rs6451 (c.293-67C>A/G) minor alleles were associated with an earlier age of menarche in the patients (12.0 vs. 13.0 years, p = 0.007). The polymorphic rs369651496 minor 6G allele was related to a better lipid profile in the women with PCOS, while the rs6474 variant modulated the blood pressure of the patients. Conclusions: The presence of CYP21A2 genetic minor alleles of rs6467 (IVS2-13A/C, c.293-13A/C), rs6453 (c.293-44G>T), rs6451 (c.293-67C>A/G), rs369651496 (c.293-104del), and rs6474 (c.308G>A/p.R103L) might modulate the adrenal androgens, age of menarche, and metabolic features in women with PCOS. Further studies on 21-hydroxylase genetic variants (pathogenic and polymorphisms) in different ethnic groups might help reveal the influence of adrenal steroidogenesis on PCOS development, clinical manifestations, and lifelong cardiovascular risks. Full article
(This article belongs to the Special Issue Advances in Polycystic Ovary Syndrome Research: From Molecular Mechanisms to Therapeutic Strategies)
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11 pages, 538 KiB  
Article
Impact of SGLT2 Inhibitors on Very Elderly Population with Heart Failure with Reduce Ejection Fraction: Real Life Data
by Jorge Balaguer Germán, Marcelino Cortés García, Carlos Rodríguez López, Jose María Romero Otero, Jose Antonio Esteban Chapel, Antonio José Bollas Becerra, Luis Nieto Roca, Mikel Taibo Urquía, Ana María Pello Lázaro and José Tuñón Fernández
Biomedicines 2024, 12(7), 1507; https://doi.org/10.3390/biomedicines12071507 - 7 Jul 2024
Cited by 6 | Viewed by 1401
Abstract
(1) Background: The validation of new lines of therapy for the elderly is required due to the progressive ageing of the world population and scarce evidence in elderly patients with HF with reduced ejection fraction (HFrEF). The purpose of our study is to [...] Read more.
(1) Background: The validation of new lines of therapy for the elderly is required due to the progressive ageing of the world population and scarce evidence in elderly patients with HF with reduced ejection fraction (HFrEF). The purpose of our study is to analyze the effect of SGLT2 inhibitors (SGLT2i) in this subgroup of patients. (2) Methods: A single-center, real-world observational study was performed. We consecutively enrolled all patients aged ≥ 75 years diagnosed with HFrEF and for treatment with SGLT2i, and considered the theoretical indications. (3) Results: A total of 364 patients were recruited, with a mean age of 84.1 years. At inclusion, the mean LVEF was 29.8%. Median follow-up was 33 months, and there were 122 deaths. A total of 55 patients were under SGLT2i treatment. A multivariate Cox logistic regression test for all-cause mortality was performed, and only SGLT2i (HR 0.39 [0.19–0.82]) and glomerular filtration rate (HR 0.98 [0.98–0.99]) proved to be protective factors. In parallel, we conducted a propensity-score-matched analysis, where a significant reduction in all-cause mortality was associated with the use of SGLT2i treatment (HR 0.39, [0.16–0.97]). (4) Conclusions: Treatment with SGLT2i in elderly patients with HFrEF was associated with a lower rate of all-cause mortality. Our data show that SGLT2i therapy could improve prognosis in the elderly with HFrEF in a real-world study. Full article
(This article belongs to the Special Issue Genetics, Obesity, Diabetes and Metabolic Syndrome)
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26 pages, 13803 KiB  
Article
Restoration of T and B Cell Differentiation after RAG1 Gene Transfer in Human RAG1 Defective Hematopoietic Stem Cells
by Nataël Sorel, Francisco Díaz-Pascual, Boris Bessot, Hanem Sadek, Chloé Mollet, Myriam Chouteau, Marco Zahn, Irene Gil-Farina, Parisa Tajer, Marja van Eggermond, Dagmar Berghuis, Arjan C. Lankester, Isabelle André, Richard Gabriel, Marina Cavazzana, Kasrin Pike-Overzet, Frank J. T. Staal and Chantal Lagresle-Peyrou
Biomedicines 2024, 12(7), 1495; https://doi.org/10.3390/biomedicines12071495 - 5 Jul 2024
Cited by 3 | Viewed by 2651
Abstract
Recombinase-activating gene (RAG)-deficient SCID patients lack B and T lymphocytes due to the inability to rearrange immunoglobulin and T cell receptor genes. The two RAG genes act as a required dimer to initiate gene recombination. Gene therapy is a valid treatment alternative for [...] Read more.
Recombinase-activating gene (RAG)-deficient SCID patients lack B and T lymphocytes due to the inability to rearrange immunoglobulin and T cell receptor genes. The two RAG genes act as a required dimer to initiate gene recombination. Gene therapy is a valid treatment alternative for RAG-SCID patients who lack a suitable bone marrow donor, but developing such therapy for RAG1/2 has proven challenging. Using a clinically approved lentiviral vector with a codon-optimized RAG1 gene, we report here preclinical studies using CD34+ cells from four RAG1-SCID patients. We used in vitro T cell developmental assays and in vivo assays in xenografted NSG mice. The RAG1-SCID patient CD34+ cells transduced with the RAG1 vector and transplanted into NSG mice led to restored human B and T cell development. Together with favorable safety data on integration sites, these results substantiate an ongoing phase I/II clinical trial for RAG1-SCID. Full article
(This article belongs to the Collection Feature Papers in Gene and Cell Therapy)
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16 pages, 1041 KiB  
Review
Genetic Insights into Age-Related Macular Degeneration
by Bhumika, Nalini S. Bora and Puran S. Bora
Biomedicines 2024, 12(7), 1479; https://doi.org/10.3390/biomedicines12071479 - 4 Jul 2024
Cited by 11 | Viewed by 4080
Abstract
One of the major causes of vision impairment among elderly people in developed nations is age-related macular degeneration (AMD). The distinctive features of AMD are the accumulation of extracellular deposits called drusen and the gradual deterioration of photoreceptors and nearby tissues in the [...] Read more.
One of the major causes of vision impairment among elderly people in developed nations is age-related macular degeneration (AMD). The distinctive features of AMD are the accumulation of extracellular deposits called drusen and the gradual deterioration of photoreceptors and nearby tissues in the macula. AMD is a complex and multifaceted disease influenced by several factors such as aging, environmental risk factors, and a person’s genetic susceptibility to the condition. The interaction among these factors leads to the initiation and advancement of AMD, where genetic predisposition plays a crucial role. With the advent of high-throughput genotyping technologies, many novel genetic loci associated with AMD have been identified, enhancing our knowledge of its genetic architecture. The common genetic variants linked to AMD are found on chromosome 1q32 (in the complement factor H gene) and 10q26 (age-related maculopathy susceptibility 2 and high-temperature requirement A serine peptidase 1 genes) loci, along with several other risk variants. This review summarizes the common genetic variants of complement pathways, lipid metabolism, and extracellular matrix proteins associated with AMD risk, highlighting the intricate pathways contributing to AMD pathogenesis. Knowledge of the genetic underpinnings of AMD will allow for the future development of personalized diagnostics and targeted therapeutic interventions, paving the way for more effective management of AMD and improved outcomes for affected individuals. Full article
(This article belongs to the Special Issue Advanced Research in Metabolic Syndrome)
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14 pages, 3251 KiB  
Article
Enhancing Liver Transplant Outcomes through Liver Precooling to Mitigate Inflammatory Response and Protect Mitochondrial Function
by Minh H. Tran, Jie Gao, Xinzhe Wang, Ruisheng Liu, Colby L. Parris, Carlos Esquivel, Yingxiang Fan and Lei Wang
Biomedicines 2024, 12(7), 1475; https://doi.org/10.3390/biomedicines12071475 - 4 Jul 2024
Viewed by 1591
Abstract
Transplanted organs experience several episodes of ischemia and ischemia-reperfusion. The graft injury resulting from ischemia-reperfusion (IRI) remains a significant obstacle to the successful survival of transplanted grafts. Temperature significantly influences cellular metabolic rates because biochemical reactions are highly sensitive to temperature changes. Consequently, [...] Read more.
Transplanted organs experience several episodes of ischemia and ischemia-reperfusion. The graft injury resulting from ischemia-reperfusion (IRI) remains a significant obstacle to the successful survival of transplanted grafts. Temperature significantly influences cellular metabolic rates because biochemical reactions are highly sensitive to temperature changes. Consequently, lowering the temperature could reduce the degradative reactions triggered by ischemia. In mitigating IRI in liver grafts, the potential protective effect of localized hypothermia on the liver prior to blood flow obstruction has yet to be explored. In this study, we applied local hypothermia to mouse donor livers for a specific duration before stopping blood flow to liver lobes, a procedure called “liver precooling”. Mouse donor liver temperature in control groups was controlled at 37 °C. Subsequently, the liver donors were preserved in cold University of Wisconsin solution for various durations followed by orthotopic liver transplantation. Liver graft injury, function and inflammation were assessed at 1 and 2 days post-transplantation. Liver precooling exhibited a significant improvement in graft function, revealing more than a 47% decrease in plasma aspartate transaminase (AST) and alanine aminotransferase (ALT) levels, coupled with a remarkable reduction of approximately 50% in liver graft histological damage compared to the control group. The protective effects of liver precooling were associated with the preservation of mitochondrial function, a substantial reduction in hepatocyte cell death, and a significantly attenuated inflammatory response. Taken together, reducing the cellular metabolism and enzymatic activity to a minimum level before ischemia protects against IRI during transplantation. Full article
(This article belongs to the Section Immunology and Immunotherapy)
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19 pages, 1063 KiB  
Review
Extracellular Vesicles and Immune System Function: Exploring Novel Approaches to Colorectal Cancer Immunotherapy
by Antonio Biondi, Marco Vacante, Roberta Catania and Giuseppe Sangiorgio
Biomedicines 2024, 12(7), 1473; https://doi.org/10.3390/biomedicines12071473 - 3 Jul 2024
Cited by 4 | Viewed by 1681
Abstract
This review explores the emerging role of extracellular vesicles (EVs) in modulating immune system function and their application in novel cancer immunotherapy strategies, with a focus on colorectal cancer (CRC). EVs, as carriers of bioactive molecules, have shown potential in enhancing immune responses [...] Read more.
This review explores the emerging role of extracellular vesicles (EVs) in modulating immune system function and their application in novel cancer immunotherapy strategies, with a focus on colorectal cancer (CRC). EVs, as carriers of bioactive molecules, have shown potential in enhancing immune responses and overcoming the limitations of traditional therapies. We discuss the biogenesis, types, and functional roles of immune cell-derived EVs, their interactions with cancer cells, and their implications in antitumor immunity. Challenges such as tumor heterogeneity and immune evasion are addressed, alongside the promising therapeutic prospects of EV-based strategies. This comprehensive analysis underscores the transformative potential of EVs in cancer treatment paradigms. Full article
(This article belongs to the Special Issue Recent Advances in Immunotherapy for Solid Tumors)
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23 pages, 2073 KiB  
Review
p53 Genetics and Biology in Lung Carcinomas: Insights, Implications and Clinical Applications
by Dixan A. Benitez, Guadalupe Cumplido-Laso, Marcos Olivera-Gómez, Nuria Del Valle-Del Pino, Alba Díaz-Pizarro, Sonia Mulero-Navarro, Angel Román-García and Jose Maria Carvajal-Gonzalez
Biomedicines 2024, 12(7), 1453; https://doi.org/10.3390/biomedicines12071453 - 29 Jun 2024
Cited by 3 | Viewed by 2529
Abstract
The TP53 gene is renowned as a tumor suppressor, playing a pivotal role in overseeing the cell cycle, apoptosis, and maintaining genomic stability. Dysregulation of p53 often contributes to the initiation and progression of various cancers, including lung cancer (LC) subtypes. The review [...] Read more.
The TP53 gene is renowned as a tumor suppressor, playing a pivotal role in overseeing the cell cycle, apoptosis, and maintaining genomic stability. Dysregulation of p53 often contributes to the initiation and progression of various cancers, including lung cancer (LC) subtypes. The review explores the intricate relationship between p53 and its role in the development and progression of LC. p53, a crucial tumor suppressor protein, exists in various isoforms, and understanding their distinct functions in LC is essential for advancing our knowledge of this deadly disease. This review aims to provide a comprehensive literature overview of p53, its relevance to LC, and potential clinical applications. Full article
(This article belongs to the Section Cell Biology and Pathology)
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20 pages, 19900 KiB  
Article
Suppressing Pro-Apoptotic Proteins by siRNA in Corneal Endothelial Cells Protects against Cell Death
by Susanne Staehlke, Siddharth Mahajan, Daniel Thieme, Peter Trosan and Thomas A. Fuchsluger
Biomedicines 2024, 12(7), 1439; https://doi.org/10.3390/biomedicines12071439 - 27 Jun 2024
Viewed by 1701
Abstract
Corneal endothelial cells (CE) are critical for the cornea’s transparency. For severe corneal damage, corneal tissue transplantation is the most promising option for restoring vision. However, CE apoptotic cell death occurs during the storage of donor corneas for transplantation. This study used small [...] Read more.
Corneal endothelial cells (CE) are critical for the cornea’s transparency. For severe corneal damage, corneal tissue transplantation is the most promising option for restoring vision. However, CE apoptotic cell death occurs during the storage of donor corneas for transplantation. This study used small interfering (si)RNA-mediated silencing of pro-apoptotic proteins as a novel strategy to protect CE against apoptosis. Therefore, the pro-apoptotic proteins Bax and Bak were silenced in the human corneal endothelial cell line (HCEC-12) by transfection with Accell™siRNA without any adverse effects on cell viability. When apoptosis was induced, e.g., etoposide, the caspase-3 activity and Annexin V-FITC/PI assay indicated a significantly reduced apoptosis rate in Bax+Bak-siRNA transfected HCECs compared to control (w/o siRNA). TUNEL assay in HCECs exposed also significantly lower cell death in Bax+Bak-siRNA (7.5%) compared to control (w/o siRNA: 32.8%). In ex vivo donor corneas, a significant reduction of TUNEL-positive CEs in Bax+Bak-siRNA corneas (8.1%) was detectable compared to control-treated corneas (w/o siRNA: 27.9%). In this study, we demonstrated that suppressing pro-apoptotic siRNA leads to inhibiting CE apoptosis. Gene therapy with siRNA may open a new translational approach for corneal tissue treatment in the eye bank before transplantation, leading to graft protection and prolonged graft survival. Full article
(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Ophthalmology Disorders)
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31 pages, 3419 KiB  
Review
Novel Therapeutics for Type 2 Diabetes Mellitus—A Look at the Past Decade and a Glimpse into the Future
by Ying Jie Chee and Rinkoo Dalan
Biomedicines 2024, 12(7), 1386; https://doi.org/10.3390/biomedicines12071386 - 21 Jun 2024
Cited by 3 | Viewed by 3434
Abstract
Cardiovascular disease (CVD) and kidney disease are the main causes of morbidity and mortality in type 2 diabetes mellitus (T2DM). Globally, the incidence of T2DM continues to rise. A substantial increase in the burden of CVD and renal disease, alongside the socioeconomic implications, [...] Read more.
Cardiovascular disease (CVD) and kidney disease are the main causes of morbidity and mortality in type 2 diabetes mellitus (T2DM). Globally, the incidence of T2DM continues to rise. A substantial increase in the burden of CVD and renal disease, alongside the socioeconomic implications, would be anticipated. Adopting a purely glucose-centric approach focusing only on glycemic targets is no longer adequate to mitigate the cardiovascular risks in T2DM. In the past decade, significant advancement has been achieved in expanding the pharmaceutical options for T2DM, with novel agents such as the sodium-glucose cotransporter type 2 (SGLT2) inhibitors and glucagon-like peptide receptor agonists (GLP-1 RAs) demonstrating robust evidence in cardiorenal protection. Combinatorial approaches comprising multiple pharmacotherapies combined in a single agent are an emerging and promising way to not only enhance patient adherence and improve glycemic control but also to achieve the potential synergistic effects for greater cardiorenal protection. In this review, we provide an update on the novel antidiabetic agents in the past decade, with an appraisal of the mechanisms contributing to cardiorenal protection. Additionally, we offer a glimpse into the landscape of T2DM management in the near future by providing a comprehensive summary of upcoming agents in early-phase trials. Full article
(This article belongs to the Special Issue New Advance in Cardiovascular Drugs: In Celebration of the 90th Birthday of Professor Akira Endo)
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19 pages, 3479 KiB  
Article
Chronic Lymphocytic Leukemia (CLL)-Derived Extracellular Vesicles Educate Endothelial Cells to Become IL-6-Producing, CLL-Supportive Cells
by Orit Uziel, Lian Lipshtein, Zinab Sarsor, Einat Beery, Shaked Bogen, Meir Lahav, Alon Regev, Vitali Kliminski, Roded Sharan, Asia Gervits, Lorenzo Federico Signorini, Shai Shimony, Pia Raanani and Uri Rozovski
Biomedicines 2024, 12(7), 1381; https://doi.org/10.3390/biomedicines12071381 - 21 Jun 2024
Cited by 3 | Viewed by 1724
Abstract
We hypothesized that via extracellular vesicles (EVs), chronic lymphocytic leukemia (CLL) cells turn endothelial cells into CLL-supportive cells. To test this, we treated vein-derived (HUVECs) and artery-derived (HAOECs) endothelial cells with EVs isolated from the peripheral blood of 45 treatment-naïve patients. Endothelial cells [...] Read more.
We hypothesized that via extracellular vesicles (EVs), chronic lymphocytic leukemia (CLL) cells turn endothelial cells into CLL-supportive cells. To test this, we treated vein-derived (HUVECs) and artery-derived (HAOECs) endothelial cells with EVs isolated from the peripheral blood of 45 treatment-naïve patients. Endothelial cells took up CLL-EVs in a dose- and time-dependent manner. To test whether CLL-EVs turn endothelial cells into IL-6-producing cells, we exposed them to CLL-EVs and found a 50% increase in IL-6 levels. Subsequently, we filtered out the endothelial cells and added CLL cells to this IL-6-enriched medium. After 15 min, STAT3 became phosphorylated, and there was a 40% decrease in apoptosis rate, indicating that IL-6 activated the STAT3-dependent anti-apoptotic pathway. Phospho-proteomics analysis of CLL-EV-exposed endothelial cells revealed 23 phospho-proteins that were upregulated, and network analysis unraveled the central role of phospho-β-catenin. We transfected HUVECs with a β-catenin-containing plasmid and found by ELISA a 30% increase in the levels of IL-6 in the culture medium. By chromatin immunoprecipitation assay, we observed an increased binding of three transcription factors to the IL-6 promoter. Importantly, patients with CLL possess significantly higher levels of peripheral blood IL-6 compared to normal individuals, suggesting that the inducers of endothelial IL-6 are the neoplastic EVs derived from the CLL cells versus those of healthy people. Taken together, we found that CLL cells communicate with endothelial cells through EVs that they release. Once they are taken up by endothelial cells, they turn them into IL-6-producing cells. Full article
(This article belongs to the Special Issue Exosomes and Their Role in Diseases)
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19 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 3 | Viewed by 2257
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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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
Cited by 4 | Viewed by 7144
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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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
Cited by 4 | Viewed by 1793
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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15 pages, 2304 KiB  
Article
Effect of 5-Aminolevulinic Acid (5-ALA) in “ALADENT” Gel Formulation and Photodynamic Therapy (PDT) against Human Oral and Pancreatic Cancers
by Domenica Lucia D’Antonio, Simona Marchetti, Pamela Pignatelli, Samia Umme, Domenico De Bellis, Paola Lanuti, Adriano Piattelli and Maria Cristina Curia
Biomedicines 2024, 12(6), 1316; https://doi.org/10.3390/biomedicines12061316 - 13 Jun 2024
Cited by 2 | Viewed by 2340
Abstract
Oral squamous-cell and pancreatic carcinomas are aggressive cancers with a poor outcome. Photodynamic therapy (PDT) consists of the use of photosensitizer-induced cell and tissue damage that is activated by exposure to visible light. PDT selectively acts on cancer cells, which have an accumulation [...] Read more.
Oral squamous-cell and pancreatic carcinomas are aggressive cancers with a poor outcome. Photodynamic therapy (PDT) consists of the use of photosensitizer-induced cell and tissue damage that is activated by exposure to visible light. PDT selectively acts on cancer cells, which have an accumulation of photosensitizer superior to that of the normal surrounding tissues. 5-aminolevulinic acid (5-ALA) induces the production of protoporphyrin IX (PpIX), an endogenous photosensitizer activated in PDT. This study aimed to test the effect of a new gel containing 5% v/v 5-ALA (ALAD-PDT) on human oral CAL-27 and pancreatic CAPAN-2 cancer cell lines. The cell lines were incubated in low concentrations of ALAD-PDT (0.05%, 0.10%, 0.20%, 0.40%, 0.75%, 1.0%) for 4 h or 8 h, and then irradiated for 7 min with 630 nm RED light. The cytotoxic effects of ALAD-PDT were measured using the MTS assay. Apoptosis, cell cycle, and ROS assays were performed using flow cytometry. PpIX accumulation was measured using a spectrofluorometer after 10 min and 24 and 48 h of treatment. The viability was extremely reduced at all concentrations, at 4 h for CAPAN-2 and at 8 h for CAL-27. ALAD-PDT induced marked apoptosis rates in both oral and pancreatic cancer cells. Elevated ROS production and appreciable levels of PpIX were detected in both cell lines. The use of ALA-PDT as a topical or intralesional therapy would permit the use of very low doses to achieve effective results and minimize side effects. ALAD-PDT has the potential to play a significant role in complex oral and pancreatic anticancer therapies. Full article
(This article belongs to the Special Issue Photodynamic Therapy (3rd Edition))
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13 pages, 3486 KiB  
Article
Expression of HOXB7 in the Lung of Patients with Idiopathic Pulmonary Fibrosis: A Proof-of-Concept Study
by Anna Valeria Samarelli, Roberto Tonelli, Giulia Raineri, Ilenia Mastrolia, Matteo Costantini, Luca Fabbiani, Virginia Catani, Tiziana Petrachi, Giulia Bruzzi, Dario Andrisani, Filippo Gozzi, Alessandro Marchioni, Valentina Masciale, Beatrice Aramini, Valentina Ruggieri, Giulia Grisendi, Massimo Dominici, Stefania Cerri and Enrico Clini
Biomedicines 2024, 12(6), 1321; https://doi.org/10.3390/biomedicines12061321 - 13 Jun 2024
Cited by 1 | Viewed by 1786
Abstract
Background: The molecular pathways involved in the onset and progression of idiopathic pulmonary fibrosis (IPF) still need to be fully clarified as some are shared with lung cancer development. HOXB7, a member of the homeobox (Hox) gene family, has been found [...] Read more.
Background: The molecular pathways involved in the onset and progression of idiopathic pulmonary fibrosis (IPF) still need to be fully clarified as some are shared with lung cancer development. HOXB7, a member of the homeobox (Hox) gene family, has been found involved in various cancers. Methods: Immunohistochemical (IHC) analysis was run on lung tissue samples from surgical lung biopsy (SLB) of 19 patients with IPF, retrospectively selected from the IPF database of the University Hospital of Modena. HOXB7 expression was analyzed and compared with that of five patients with no evidence of pulmonary fibrosis as controls. Results: The semi-quantitative analysis of IHC showed that HOXB7 protein expression was higher in IPF patients compared to controls (difference between means = 6.2 ± 2.37, p = 0.0157). Further, HOXB7 expression was higher in IPF patients with a higher extent of fibrosis (50–75%)—measured with high-resolution computer tomography—compared to those with a lower extent (0–25%) (difference between means = 25.74 ± 6.72, p = 0.004). Conclusions: The expression of HOXB7 is higher in the lung of IPF patients compared to controls, and was represented in different cellular compartments within the lung niche. Further investigations are needed to clarify its role in the pathogenesis and progression of IPF. Full article
(This article belongs to the Special Issue Phenotypes and Endotypes in Interstitial Lung Diseases)
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25 pages, 2874 KiB  
Review
The Multifaceted Nature of Macrophages in Cardiovascular Disease
by Cindy X. Li and Lixia Yue
Biomedicines 2024, 12(6), 1317; https://doi.org/10.3390/biomedicines12061317 - 13 Jun 2024
Cited by 5 | Viewed by 2396
Abstract
As the leading cause of mortality worldwide, cardiovascular disease (CVD) represents a variety of heart diseases and vascular disorders, including atherosclerosis, aneurysm, ischemic injury in the heart and brain, arrythmias, and heart failure. Macrophages, a diverse population of immune cells that can promote [...] Read more.
As the leading cause of mortality worldwide, cardiovascular disease (CVD) represents a variety of heart diseases and vascular disorders, including atherosclerosis, aneurysm, ischemic injury in the heart and brain, arrythmias, and heart failure. Macrophages, a diverse population of immune cells that can promote or suppress inflammation, have been increasingly recognized as a key regulator in various processes in both healthy and disease states. In healthy conditions, these cells promote the proper clearance of cellular debris, dead and dying cells, and provide a strong innate immune barrier to foreign pathogens. However, macrophages can play a detrimental role in the progression of disease as well, particularly those inflammatory in nature. This review will focus on the current knowledge regarding the role of macrophages in cardiovascular diseases. Full article
(This article belongs to the Special Issue Macrophages in Cardio-Renal Diseases)
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20 pages, 2220 KiB  
Article
Mitochondrial Dysfunction in Sporadic Amyotrophic Lateral Sclerosis Patients: Insights from High-Resolution Respirometry
by Petra Parvanovova, Andrea Evinova, Milan Grofik, Petra Hnilicova, Zuzana Tatarkova and Monika Turcanova-Koprusakova
Biomedicines 2024, 12(6), 1294; https://doi.org/10.3390/biomedicines12061294 - 11 Jun 2024
Cited by 6 | Viewed by 2563
Abstract
Amyotrophic lateral sclerosis is a severe neurodegenerative disease whose exact cause is still unclear. Currently, research attention is turning to the mitochondrion as a critical organelle of energy metabolism. Current knowledge is sufficient to confirm the involvement of the mitochondria in the pathophysiology [...] Read more.
Amyotrophic lateral sclerosis is a severe neurodegenerative disease whose exact cause is still unclear. Currently, research attention is turning to the mitochondrion as a critical organelle of energy metabolism. Current knowledge is sufficient to confirm the involvement of the mitochondria in the pathophysiology of the disease, since the mitochondria are involved in many processes in the cell; however, the exact mechanism of involvement is still unclear. We used peripheral blood mononuclear cells isolated from whole fresh blood from patients with amyotrophic lateral sclerosis for measurement and matched an age- and sex-matched set of healthy subjects. The group of patients consisted of patients examined and diagnosed at the neurological clinic of the University Hospital Martin. The set of controls consisted of healthy individuals who were actively searched, and controls were selected on the basis of age and sex. The group consisted of 26 patients with sporadic forms of ALS (13 women, 13 men), diagnosed based on the definitive criteria of El Escorial. The average age of patients was 54 years, and the average age of healthy controls was 56 years. We used a high-resolution O2K respirometry method, Oxygraph-2k, to measure mitochondrial respiration. Basal respiration was lower in patients by 29.48%, pyruvate-stimulated respiration (respiratory chain complex I) was lower by 29.26%, and maximal respiratory capacity was lower by 28.15%. The decrease in succinate-stimulated respiration (respiratory chain complex II) was 26.91%. Our data confirm changes in mitochondrial respiration in ALS patients, manifested by the reduced function of complex I and complex II of the respiratory chain. These defects are severe enough to confirm this disease’s hypothesized mitochondrial damage. Therefore, research interest in the future should be directed towards a deeper understanding of the involvement of mitochondria and respiratory complexes in the pathophysiology of the disease. This understanding could develop new biomarkers in diagnostics and subsequent therapeutic interventions. Full article
(This article belongs to the Collection Neurodegeneration No More: Cutting-Edge Technologies and Therapies in the Evolution of Neurodegenerative Disease Management)
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16 pages, 1812 KiB  
Review
The Role of Zinc in the Development of Vascular Dementia and Parkinson’s Disease and the Potential of Carnosine as Their Therapeutic Agent
by Dai Mizuno, Masahiro Kawahara, Keiko Konoha-Mizuno, Ryoji Hama and Terumasa Ogawara
Biomedicines 2024, 12(6), 1296; https://doi.org/10.3390/biomedicines12061296 - 11 Jun 2024
Cited by 3 | Viewed by 2171
Abstract
Synaptic zinc ions (Zn2+) play an important role in the development of vascular dementia (VD) and Parkinson’s disease (PD). In this article, we reviewed the current comprehension of the Zn2+-induced neurotoxicity that leads to the pathogenesis of these neuronal [...] Read more.
Synaptic zinc ions (Zn2+) play an important role in the development of vascular dementia (VD) and Parkinson’s disease (PD). In this article, we reviewed the current comprehension of the Zn2+-induced neurotoxicity that leads to the pathogenesis of these neuronal diseases. Zn2+-induced neurotoxicity was investigated by using immortalised hypothalamic neurons (GT1-7 cells). This cell line is useful for the development of a rapid and convenient screening system for investigating Zn2+-induced neurotoxicity. GT1-7 cells were also used to search for substances that prevent Zn2+-induced neurotoxicity. Among the tested substances was a protective substance in the extract of Japanese eel (Anguilla japonica), and we determined its structure to be like carnosine (β-alanylhistidine). Carnosine may be a therapeutic drug for VD and PD. Furthermore, we reviewed the molecular mechanisms that involve the role of carnosine as an endogenous protector and its protective effect against Zn2+-induced cytotoxicity and discussed the prospects for the future therapeutic applications of this dipeptide for neurodegenerative diseases and dementia. Full article
(This article belongs to the Section Neurobiology and Clinical Neuroscience)
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17 pages, 1544 KiB  
Review
Therapeutic Nonsense Suppression Modalities: From Small Molecules to Nucleic Acid-Based Approaches
by Pedro Morais, Rui Zhang and Yi-Tao Yu
Biomedicines 2024, 12(6), 1284; https://doi.org/10.3390/biomedicines12061284 - 10 Jun 2024
Cited by 4 | Viewed by 4137
Abstract
Nonsense mutations are genetic mutations that create premature termination codons (PTCs), leading to truncated, defective proteins in diseases such as cystic fibrosis, neurofibromatosis type 1, Dravet syndrome, Hurler syndrome, Beta thalassemia, inherited bone marrow failure syndromes, Duchenne muscular dystrophy, and even cancer. These [...] Read more.
Nonsense mutations are genetic mutations that create premature termination codons (PTCs), leading to truncated, defective proteins in diseases such as cystic fibrosis, neurofibromatosis type 1, Dravet syndrome, Hurler syndrome, Beta thalassemia, inherited bone marrow failure syndromes, Duchenne muscular dystrophy, and even cancer. These mutations can also trigger a cellular surveillance mechanism known as nonsense-mediated mRNA decay (NMD) that degrades the PTC-containing mRNA. The activation of NMD can attenuate the consequences of truncated, defective, and potentially toxic proteins in the cell. Since approximately 20% of all single-point mutations are disease-causing nonsense mutations, it is not surprising that this field has received significant attention, resulting in a remarkable advancement in recent years. In fact, since our last review on this topic, new examples of nonsense suppression approaches have been reported, namely new ways of promoting the translational readthrough of PTCs or inhibiting the NMD pathway. With this review, we update the state-of-the-art technologies in nonsense suppression, focusing on novel modalities with therapeutic potential, such as small molecules (readthrough agents, NMD inhibitors, and molecular glue degraders); antisense oligonucleotides; tRNA suppressors; ADAR-mediated RNA editing; targeted pseudouridylation; and gene/base editing. While these various modalities have significantly advanced in their development stage since our last review, each has advantages (e.g., ease of delivery and specificity) and disadvantages (manufacturing complexity and off-target effect potential), which we discuss here. Full article
(This article belongs to the Special Issue Epigenetic Regulation and Its Impact for Medicine)
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36 pages, 20306 KiB  
Article
The Wnt/β-catenin/TCF/Sp5/Zic4 Gene Network That Regulates Head Organizer Activity in Hydra Is Differentially Regulated in Epidermis and Gastrodermis
by Laura Iglesias Ollé, Chrystelle Perruchoud, Paul Gerald Layague Sanchez, Matthias Christian Vogg and Brigitte Galliot
Biomedicines 2024, 12(6), 1274; https://doi.org/10.3390/biomedicines12061274 - 8 Jun 2024
Cited by 4 | Viewed by 1866
Abstract
Hydra head formation depends on an organizing center in which Wnt/β-catenin signaling, that plays an inductive role, positively regulates Sp5 and Zic4, with Sp5 limiting Wnt3/β-catenin expression and Zic4 triggering tentacle formation. Using transgenic lines in which the HySp5 promoter drives eGFP [...] Read more.
Hydra head formation depends on an organizing center in which Wnt/β-catenin signaling, that plays an inductive role, positively regulates Sp5 and Zic4, with Sp5 limiting Wnt3/β-catenin expression and Zic4 triggering tentacle formation. Using transgenic lines in which the HySp5 promoter drives eGFP expression in either the epidermis or gastrodermis, we show that Sp5 promoter activity is differentially regulated in each epithelial layer. In intact animals, epidermal HySp5:GFP activity is strong apically and weak along the body column, while in the gastrodermis, it is maximal in the tentacle ring region and maintained at a high level along the upper body column. During apical regeneration, HySp5:GFP is activated early in the gastrodermis and later in the epidermis. Alsterpaullone treatment induces a shift in apical HySp5:GFP expression towards the body column where it forms transient circular figures in the epidermis. Upon β-catenin(RNAi), HySp5:GFP activity is down-regulated in the epidermis while bud-like structures expressing HySp5:GFP in the gastrodermis develop. Sp5(RNAi) reveals a negative Sp5 autoregulation in the epidermis, but not in the gastrodermis. These differential regulations in the epidermis and gastrodermis highlight the distinct architectures of the Wnt/β-catenin/TCF/Sp5/Zic4 network in the hypostome, tentacle base and body column of intact animals, as well as in the buds and apical and basal regenerating tips. Full article
(This article belongs to the Special Issue Hydra, Polyps, Medusae: Model Organisms in Biomedical Research)
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15 pages, 1167 KiB  
Article
Induction Therapies Determine the Distribution of Perforin and Granzyme B Transcripts in Kidney Transplant Recipients
by Dino Pipic, Marianne Rasmussen, Qais W. Saleh and Martin Tepel
Biomedicines 2024, 12(6), 1258; https://doi.org/10.3390/biomedicines12061258 - 5 Jun 2024
Viewed by 1179
Abstract
Peripheral blood mononuclear cells contain secretory granules with Perforin and Granzyme B for defense against pathogens. The objective of the present study was to compare the effects of immunosuppressive induction therapies on Perforin and Granzyme B transcripts in kidney transplant recipients. Transcripts were [...] Read more.
Peripheral blood mononuclear cells contain secretory granules with Perforin and Granzyme B for defense against pathogens. The objective of the present study was to compare the effects of immunosuppressive induction therapies on Perforin and Granzyme B transcripts in kidney transplant recipients. Transcripts were determined in 408 incident kidney transplant recipients eight days posttransplant using quantitative real-time PCR. Compared to 90 healthy subjects, the median Perforin transcripts were lower in kidney transplant recipients with blood-group ABO-incompatible donors (N = 52), compatible living donors (N = 130), and deceased donors (N = 226) (25.7%; IQR, 6.5% to 46.0%; 31.5%; IQR, 10.9% to 57.7%; and 35.6%; IQR, 20.6% to 60.2%; respectively; p = 0.015 by the Kruskal–Wallis test). Kidney transplant recipients who were treated with thymoglobulin (N = 64) had significantly lower Perforin as well as Granzyme B compared to all other induction therapies (N = 344) (each p < 0.001). Receiver operator characteristics analysis showed that both Perforin (area under curve, 0.919) and Granzyme B (area under curve, 0.915) indicated thyroglobulin-containing induction therapies. Regression analysis showed that both reduction in plasma creatinine and human leukocyte antigen mismatches were positively associated with elevated Perforin/Granzyme B transcript ratio posttransplant. We conclude clinical parameters and therapies affect Perforin and Granzyme B transcripts posttransplant. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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16 pages, 1592 KiB  
Review
The Role of Lipoprotein(a) in Peripheral Artery Disease
by Nicholas Pavlatos and Dinesh K. Kalra
Biomedicines 2024, 12(6), 1229; https://doi.org/10.3390/biomedicines12061229 - 1 Jun 2024
Cited by 4 | Viewed by 2347
Abstract
Lipoprotein(a) is a low-density-lipoprotein-like particle that consists of apolipoprotein(a) bound to apolipoprotein(b). It has emerged as an established causal risk factor for atherosclerotic cardiovascular disease, stroke, and aortic valve stenosis through multifactorial pathogenic mechanisms that include inflammation, atherogenesis, and thrombosis. Despite an estimated [...] Read more.
Lipoprotein(a) is a low-density-lipoprotein-like particle that consists of apolipoprotein(a) bound to apolipoprotein(b). It has emerged as an established causal risk factor for atherosclerotic cardiovascular disease, stroke, and aortic valve stenosis through multifactorial pathogenic mechanisms that include inflammation, atherogenesis, and thrombosis. Despite an estimated 20% of the global population having elevated lipoprotein(a) levels, testing remains underutilized due to poor awareness and a historical lack of effective and safe therapies. Although lipoprotein(a) has a strong association with coronary artery disease and cerebrovascular disease, its relationship with peripheral artery disease is less well established. In this article, we review the epidemiology, biology, and pathogenesis of lipoprotein(a) as it relates to peripheral artery disease. We also discuss emerging treatment options to help mitigate major adverse cardiac and limb events in this population. Full article
(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)
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15 pages, 1447 KiB  
Review
Microbubble-Enhanced Focused Ultrasound for Infiltrating Gliomas
by Alexandra A. Seas, Adarsha P. Malla, Nima Sharifai, Jeffrey A. Winkles, Graeme F. Woodworth and Pavlos Anastasiadis
Biomedicines 2024, 12(6), 1230; https://doi.org/10.3390/biomedicines12061230 - 1 Jun 2024
Cited by 7 | Viewed by 2546
Abstract
Infiltrating gliomas are challenging to treat, as the blood-brain barrier significantly impedes the success of therapeutic interventions. While some clinical trials for high-grade gliomas have shown promise, patient outcomes remain poor. Microbubble-enhanced focused ultrasound (MB-FUS) is a rapidly evolving technology with demonstrated safety [...] Read more.
Infiltrating gliomas are challenging to treat, as the blood-brain barrier significantly impedes the success of therapeutic interventions. While some clinical trials for high-grade gliomas have shown promise, patient outcomes remain poor. Microbubble-enhanced focused ultrasound (MB-FUS) is a rapidly evolving technology with demonstrated safety and efficacy in opening the blood-brain barrier across various disease models, including infiltrating gliomas. Initially recognized for its role in augmenting drug delivery, the potential of MB-FUS to augment liquid biopsy and immunotherapy is gaining research momentum. In this review, we will highlight recent advancements in preclinical and clinical studies that utilize focused ultrasound to treat gliomas and discuss the potential future uses of image-guided precision therapy using focused ultrasound. Full article
(This article belongs to the Special Issue Gliomas: Signaling Pathways, Molecular Mechanisms and Novel Therapies)
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12 pages, 1304 KiB  
Article
Number of Premature Ventricular Complexes Predicts Long-Term Outcomes in Patients with Persistent Atrial Fibrillation
by Kun-Chi Yen, Yi-Hsin Chan and Chun-Li Wang
Biomedicines 2024, 12(6), 1149; https://doi.org/10.3390/biomedicines12061149 - 23 May 2024
Cited by 1 | Viewed by 2376
Abstract
Background: Premature ventricular complexes (PVCs) are common electrocardiographic abnormalities and may be a prognosticator in predicting mortality in patients with structurally normal hearts or chronic heart diseases. Whether PVC burden was associated with mortality in patients with chronic atrial fibrillation (AF) remained unknown. [...] Read more.
Background: Premature ventricular complexes (PVCs) are common electrocardiographic abnormalities and may be a prognosticator in predicting mortality in patients with structurally normal hearts or chronic heart diseases. Whether PVC burden was associated with mortality in patients with chronic atrial fibrillation (AF) remained unknown. We investigated the prognostic value of PVC burden in patients with persistent AF. Methods: A retrospective analysis of 24 h Holter recordings of 1767 patients with persistent AF was conducted. Clinical characteristics, 24 h average heart rate (HR), and PVC measures, including 24 h PVC burden and the presence of consecutive PVCs (including any PVC couplet, triplet, or non-sustained ventricular tachycardia) were examined for the prediction of all-cause and cardiovascular mortality using the Cox proportional hazards model. Results: After a median follow-up time of 30 months, 286 (16%) patients died and 1481 (84%) patients survived. Multivariate analysis revealed that age, heart failure, stroke, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, beta-blocker, digoxin, oral anticoagulant use, and estimated glomerular filtration rate were significant baseline predictors of all-cause mortality and cardiovascular mortality. Twenty-four-hour PVC burden and the presence of consecutive PVCs were significantly associated with all-cause and cardiovascular mortality after adjusting for significant clinical factors. When compared to the first quartile of PVC burden (<0.003%/day), the highest quartile (>0.3%/day) was significantly associated with an increased risk of all-cause mortality (hazard ratio, 2.46; 95% CI, 1.77–3.42) and cardiovascular mortality (hazard ratio: 2.67; 95% CI, 1.76–4.06). Conclusions: Twenty-four-hour PVC burden is independently associated with all-cause and cardiovascular mortality in patients with persistent AF. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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22 pages, 4133 KiB  
Article
An Assessment of Semaglutide Safety Based on Real World Data: From Popularity to Spontaneous Reporting in EudraVigilance Database
by Anca Butuca, Carmen Maximiliana Dobrea, Anca Maria Arseniu, Adina Frum, Adriana Aurelia Chis, Luca Liviu Rus, Steliana Ghibu, Anca Maria Juncan, Andrei Catalin Muntean, Antonina Evelina Lazăr, Felicia Gabriela Gligor, Claudiu Morgovan and Andreea Loredana Vonica-Tincu
Biomedicines 2024, 12(5), 1124; https://doi.org/10.3390/biomedicines12051124 - 18 May 2024
Cited by 4 | Viewed by 5600
Abstract
Some glucagon-like peptide-1 receptor agonists (GLP-1 RAs), first used in the treatment of type 2 diabetes mellitus (T2DM), have been approved for the treatment of obesity in patients with or without T2DM (liraglutide—LIR, semaglutide—SEM, and tirzepatide—TIR). Social media had an important influence on [...] Read more.
Some glucagon-like peptide-1 receptor agonists (GLP-1 RAs), first used in the treatment of type 2 diabetes mellitus (T2DM), have been approved for the treatment of obesity in patients with or without T2DM (liraglutide—LIR, semaglutide—SEM, and tirzepatide—TIR). Social media had an important influence on the off-label use of GLP-1 RAs for obesity, especially for SEM. We analyzed the Google queries related to SEM to assess people’s interest in this drug. We also investigated the occurrence of adverse drug reactions (ADRs) by searching the EudraVigilance database (EV) for Individual Case Safety Reports (ICSRs) that reported SEM as the suspected drug and performed a descriptive and a disproportionality analysis. The data obtained for SEM were compared to other GLP-1 RAs. SEM had the highest proportions of searches on Google associated with the term “weight loss” and presented the lowest number of severe ADRs, but it also had the highest number of ICSRs reported in EV. Even though no unexpected safety issues have been reported for it until now, SEM has a hi3gh tendency for overdose reports. The most frequent off-label use was reported for SEM and TIR. In order to lower the risks of ADRs, the off-label use should be reduced and carefully monitored. Full article
(This article belongs to the Special Issue Diabetes: Comorbidities, Therapeutics and Insights)
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13 pages, 1675 KiB  
Article
IFN-γ, IL-17A, IL-4, and IL-13: Potential Biomarkers for Prediction of the Effectiveness of Biologics in Psoriasis Patients
by Ching-Liang Hsieh, Sheng-Jie Yu, Kuo-Lung Lai, Wei-Ting Chao and Chung-Yang Yen
Biomedicines 2024, 12(5), 1115; https://doi.org/10.3390/biomedicines12051115 - 17 May 2024
Cited by 4 | Viewed by 2350
Abstract
Biologics are widely used to treat moderate-to-severe psoriasis. However, we have unmet needs for predicting individual patient responses to biologics before starting psoriasis treatment. We investigate a reliable platform and biomarkers for predicting individual patient responses to biologics. In a cohort study between [...] Read more.
Biologics are widely used to treat moderate-to-severe psoriasis. However, we have unmet needs for predicting individual patient responses to biologics before starting psoriasis treatment. We investigate a reliable platform and biomarkers for predicting individual patient responses to biologics. In a cohort study between 2018 and 2023 from a referral center in Taiwan, twenty psoriasis patients with or without psoriatic arthritis who had ever experienced two or more biologics were enrolled. Peripheral blood mononuclear cells obtained from these patients were treated with Streptococcus pyogenes and different biologics. The PASI reduction rate was strongly correlated with the reduction rate in the IL-13 level (p = 0.001) and the ratios of IFN-γ to IL-13 (p < 0.001), IFN-γ to IL-4 (p = 0.019), and IL-17A to IL-13 (p = 0.001). The PASI reduction difference was strongly correlated with the difference in the IFN-γ level (p = 0.002), the difference in the ratios of IFN-γ to IL-4 (p = 0.041), the difference in the ratios of IFN-γ to IL-13 (p = 0.006), the difference in the ratios of IL-17A to IL-4 (p = 0.011), and the difference in the ratios of IL-17A to IL-13 (p = 0.029). The biomarkers IFN-γ, IL-13, IFN-γ/IL4, IFN-γ/IL13, IL-17A/IL-4, and IL-17A/IL-13 are representative of the effectiveness of psoriasis treatment. Full article
(This article belongs to the Special Issue Disease Biomarkers in the Precision Medicine Era: A Comprehensive Multi-Omics Analysis)
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11 pages, 2592 KiB  
Article
The Impact of Frailty Components and Preoperative Mechanical Cardiac Support Changes with Time after Heart Transplantation
by Rita Szentgróti, Dmitry Khochanskiy, Balázs Szécsi, Flóra Németh, András Szabó, Kinga Koritsánszky, Alexandra Vereb, Zsuzsanna Cserép, Balázs Sax, Béla Merkely and Andrea Székely
Biomedicines 2024, 12(5), 1114; https://doi.org/10.3390/biomedicines12051114 - 17 May 2024
Viewed by 1465
Abstract
Background: Frailty has been proven to be associated with mortality after orthotopic heart transplantation (OHT). The aim of our study was to determine the impact of frailty on mortality in the current era using pretransplant mechanical cardiac support (MCS). Methods: We retrospectively calculated [...] Read more.
Background: Frailty has been proven to be associated with mortality after orthotopic heart transplantation (OHT). The aim of our study was to determine the impact of frailty on mortality in the current era using pretransplant mechanical cardiac support (MCS). Methods: We retrospectively calculated the frailty scores of 471 patients undergoing OHT in a single institution between January 2012 and August 2022. The outcome was all-cause mortality. Results: The median survival time was 1987 days (IQR: 1487 days) for all patients. In total, 266 (56.5%) patients were categorized as nonfrail, 179 (38.0%) as prefrail, and 26 (5.5%) as frail. The survival rates were 0.73, 0.54, and 0.28 for nonfrail, prefrail, and frail patients, respectively. The frailty score was associated with mortality [HR: 1.34 (95% CI: 1.22–1.47, p < 0.001)]. Among the components of the frailty score, age above 50 years, creatinine ≥ 3.0 mg/dL or prior dialysis, and hospitalization before OHT were independently associated with mortality. Continuous-flow left ventricular assist devices (CF-LVAD) were associated with an increased risk for all-cause mortality [AHR: 1.80 (95% CI: 1.01–3.24, p = 0.047)]. Conclusions: The components of the frailty score were not equally associated with mortality. Frailty and pretransplant MCS should be included in the risk estimation. Full article
(This article belongs to the Special Issue Heart Failure: New Diagnostic and Therapeutic Approaches)
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17 pages, 1851 KiB  
Article
Quantifying Hemodynamic Cardiac Stress and Cardiomyocyte Injury in Normotensive and Hypertensive Acute Heart Failure
by Nikola Kozhuharov, Eleni Michou, Desiree Wussler, Maria Belkin, Corinna Heinisch, Johan Lassus, Krista Siirilä-Waris, Harjola Veli-Pekka, Nisha Arenja, Thenral Socrates, Albina Nowak, Samyut Shrestha, Julie Valerie Willi, Ivo Strebel, Danielle M. Gualandro, Katharina Rentsch, Micha T. Maeder, Thomas Münzel, Mucio Tavares de Oliveira Junior, Arnold von Eckardstein, Tobias Breidthardt and Christian Muelleradd Show full author list remove Hide full author list
Biomedicines 2024, 12(5), 1099; https://doi.org/10.3390/biomedicines12051099 - 16 May 2024
Cited by 2 | Viewed by 1826
Abstract
Background: The characterization of the different pathophysiological mechanisms involved in normotensive versus hypertensive acute heart failure (AHF) might help to develop individualized treatments. Methods: The extent of hemodynamic cardiac stress and cardiomyocyte injury was quantified by measuring the B-type natriuretic peptide (BNP), N-terminal [...] Read more.
Background: The characterization of the different pathophysiological mechanisms involved in normotensive versus hypertensive acute heart failure (AHF) might help to develop individualized treatments. Methods: The extent of hemodynamic cardiac stress and cardiomyocyte injury was quantified by measuring the B-type natriuretic peptide (BNP), N-terminal proBNP (NT-proBNP), and high-sensitivity cardiac troponin T (hs-cTnT) concentrations in 1152 patients presenting with centrally adjudicated AHF to the emergency department (ED) (derivation cohort). AHF was classified as normotensive with a systolic blood pressure (SBP) of 90–140 mmHg and hypertensive with SBP > 140 mmHg at presentation to the ED. Findings were externally validated in an independent AHF cohort (n = 324). Results: In the derivation cohort, with a median age of 79 years, 43% being women, 667 (58%) patients had normotensive and 485 (42%) patients hypertensive AHF. Hemodynamic cardiac stress, as quantified by the BNP and NT-proBNP, was significantly higher in normotensive as compared to hypertensive AHF [1105 (611–1956) versus 827 (448–1419) pg/mL, and 5890 (2959–12,162) versus 4068 (1986–8118) pg/mL, both p < 0.001, respectively]. Similarly, the extent of cardiomyocyte injury, as quantified by hs-cTnT, was significantly higher in normotensive AHF as compared to hypertensive AHF [41 (24–71) versus 33 (19–59) ng/L, p < 0.001]. A total of 313 (28%) patients died during 360 days of follow-up. All-cause mortality was higher in patients with normotensive AHF vs. patients with hypertensive AHF (hazard ratio 1.66, 95%CI 1.31–2.10; p < 0.001). Normotensive patients with a high BNP, NT-proBNP, or hs-cTnT had the highest mortality. The findings were confirmed in the validation cohort. Conclusion: Biomarker profiling revealed a higher extent of hemodynamic stress and cardiomyocyte injury in patients with normotensive versus hypertensive AHF. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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16 pages, 4036 KiB  
Review
Molecular Role of Protein Phosphatases in Alzheimer’s and Other Neurodegenerative Diseases
by Mubashir Hassan, Muhammad Yasir, Saba Shahzadi, Wanjoo Chun and Andrzej Kloczkowski
Biomedicines 2024, 12(5), 1097; https://doi.org/10.3390/biomedicines12051097 - 15 May 2024
Cited by 6 | Viewed by 2718
Abstract
Alzheimer’s disease (AD) is distinguished by the gradual loss of cognitive function, which is associated with neuronal loss and death. Accumulating evidence supports that protein phosphatases (PPs; PP1, PP2A, PP2B, PP4, PP5, PP6, and PP7) are directly linked with amyloid beta (Aβ) as [...] Read more.
Alzheimer’s disease (AD) is distinguished by the gradual loss of cognitive function, which is associated with neuronal loss and death. Accumulating evidence supports that protein phosphatases (PPs; PP1, PP2A, PP2B, PP4, PP5, PP6, and PP7) are directly linked with amyloid beta (Aβ) as well as the formation of the neurofibrillary tangles (NFTs) causing AD. Published data reported lower PP1 and PP2A activity in both gray and white matters in AD brains than in the controls, which clearly shows that dysfunctional phosphatases play a significant role in AD. Moreover, PP2A is also a major causing factor of AD through the deregulation of the tau protein. Here, we review recent advances on the role of protein phosphatases in the pathology of AD and other neurodegenerative diseases. A better understanding of this problem may lead to the development of phosphatase-targeted therapies for neurodegenerative disorders in the near future. Full article
(This article belongs to the Special Issue Molecular Basis of Neurodegenerative Diseases)
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14 pages, 983 KiB  
Review
Polymerase I as a Target for Treating Neurodegenerative Disorders
by Mark S. LeDoux
Biomedicines 2024, 12(5), 1092; https://doi.org/10.3390/biomedicines12051092 - 15 May 2024
Viewed by 2189
Abstract
Polymerase I (Pol I) is at the epicenter of ribosomal RNA (rRNA) synthesis. Pol I is a target for the treatment of cancer. Given the many cellular commonalities between cancer and neurodegeneration (i.e., different faces of the same coin), it seems rational to [...] Read more.
Polymerase I (Pol I) is at the epicenter of ribosomal RNA (rRNA) synthesis. Pol I is a target for the treatment of cancer. Given the many cellular commonalities between cancer and neurodegeneration (i.e., different faces of the same coin), it seems rational to consider targeting Pol I or, more generally, rRNA synthesis for the treatment of disorders associated with the death of terminally differentiated neurons. Principally, ribosomes synthesize proteins, and, accordingly, Pol I can be considered the starting point for protein synthesis. Given that cellular accumulation of abnormal proteins such as α-synuclein and tau is an essential feature of neurodegenerative disorders such as Parkinson disease and fronto-temporal dementia, reduction of protein production is now considered a viable target for treatment of these and closely related neurodegenerative disorders. Abnormalities in polymerase I activity and rRNA production may also be associated with nuclear and nucleolar stress, DNA damage, and childhood-onset neuronal death, as is the case for the UBTF E210K neuroregression syndrome. Moreover, restraining the activity of Pol I may be a viable strategy to slow aging. Before starting down the road of Pol I inhibition for treating non-cancerous disorders of the nervous system, many questions must be answered. First, how much Pol I inhibition can neurons tolerate, and for how long? Should inhibition of Pol I be continuous or pulsed? Will cells compensate for Pol I inhibition by upregulating the number of active rDNAs? At present, we have no effective and safe disease modulatory treatments for Alzheimer disease, α-synucleinopathies, or tauopathies, and novel therapeutic targets and approaches must be explored. Full article
(This article belongs to the Special Issue Therapeutic Targeting of RNA Polymerase I Transcription, Ribosome Biogenesis and Function)
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10 pages, 264 KiB  
Article
First Report of the Prevalence at Baseline and after 1-Year Follow-Up of Treatable Traits in Interstitial Lung Diseases
by Francesco Amati, Anna Stainer, Giacomo Maruca, Maria De Santis, Giuseppe Mangiameli, Chiara Torrisi, Paola Bossi, Veronica Polelli, Francesco Blasi, Carlo Selmi, Giuseppe Marulli, Luca Balzarini, Luigi Maria Terracciano, Roberto Gatti and Stefano Aliberti
Biomedicines 2024, 12(5), 1047; https://doi.org/10.3390/biomedicines12051047 - 9 May 2024
Cited by 3 | Viewed by 1752
Abstract
Different factors, not limited to the lung, influence the progression of ILDs. A “treatable trait” strategy was recently proposed for ILD patients as a precision model of care to improve outcomes. However, no data have been published so far on the prevalence of [...] Read more.
Different factors, not limited to the lung, influence the progression of ILDs. A “treatable trait” strategy was recently proposed for ILD patients as a precision model of care to improve outcomes. However, no data have been published so far on the prevalence of TTs in ILD. A prospective, observational, cohort study was conducted within the ILD Program at the IRCCS Humanitas Research Hospital (Milan, Italy) between November 2021 and November 2023. TTs were selected according to recent literature and assigned during multidisciplinary discussion (MDD) to one of the following categories: pulmonary, etiological, comorbidities, and lifestyle. Patients were further divided into four groups according to their post-MDD diagnosis: idiopathic ILD, sarcoidosis, connective tissue disease–ILD, and other ILD. The primary study outcome was the prevalence of each TT in the study population. A total of 116 patients with ILD [63.9% male; median (IQR) age: 69 (54–78) years] were included in the study. All the TTs identified in the literature were found in our cohort, except for intractable chronic cough. We also recognized differences in TTs across the ILD groups, with less TTs in patients with sarcoidosis. This analysis provides the first ancillary characterization of TTs in ILD patients in a real setting to date. Full article
(This article belongs to the Special Issue Phenotypes and Endotypes in Interstitial Lung Diseases)
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10 pages, 592 KiB  
Article
The Urine Light Chain/eGFR Quotient as a Tool to Rule out Cast Nephropathy in Myeloma-Associated Kidney Failure
by David Klank, Christian Löffler, Julian Friedrich, Martin Hoffmann, Peter Paschka and Raoul Bergner
Biomedicines 2024, 12(5), 1032; https://doi.org/10.3390/biomedicines12051032 - 8 May 2024
Viewed by 1367
Abstract
Kidney involvement with resulting kidney failure leads to increased mortality in patients with multiple myeloma (MM). Cast nephropathy (CN), in particular, if left untreated, quickly leads to kidney failure requiring dialysis and has a very poor prognosis for the affected patient. The gold [...] Read more.
Kidney involvement with resulting kidney failure leads to increased mortality in patients with multiple myeloma (MM). Cast nephropathy (CN), in particular, if left untreated, quickly leads to kidney failure requiring dialysis and has a very poor prognosis for the affected patient. The gold standard for diagnosing kidney involvement is a kidney biopsy. However, due to bleeding risk, this cannot be done in every patient. We recently reported that a quotient of urine light chain (LCurine) to glomerular filtration rate (eGFR) is a non-invasive diagnostic tool for patients with kidney involvement in MM. But this quotient has not yet been tested in everyday clinical practice. In this study, our LCurine/eGFR ratio was tested on 67 patients in two centers. Enrollment took place between January 2019 and September 2023. A total of 18 of the 67 patients had CN. With the threshold defined in our initial paper, we were able to show a sensitivity of 100% with a specificity of 85.7% for CN in patients with MM. As a result, the LCurine/eGFR quotient recognizes 100% of all CN and can therefore detect this group, which has a very poor prognosis, without the need for a kidney biopsy. Full article
(This article belongs to the Special Issue Nephrotic Syndrome: Pathomechanism, Diagnostics and Novel Treatment Options)
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18 pages, 2585 KiB  
Article
Unveiling the Novel Benefits of Co-Administering Butyrate and Active Vitamin D3 in Mice Subjected to Chemotherapy-Induced Gut-Derived Pseudomonas aeruginosa Sepsis
by Fu-Chen Huang and Shun-Chen Huang
Biomedicines 2024, 12(5), 1026; https://doi.org/10.3390/biomedicines12051026 - 7 May 2024
Cited by 2 | Viewed by 1798
Abstract
Cancer patients face increased susceptibility to invasive infections, primarily due to ulcerative lesions on mucosal surfaces and immune suppression resulting from chemotherapy. Pseudomonas aeruginosa (P. aeruginosa) bacteremia is notorious for its rapid progression into fatal sepsis, posing a significant threat to [...] Read more.
Cancer patients face increased susceptibility to invasive infections, primarily due to ulcerative lesions on mucosal surfaces and immune suppression resulting from chemotherapy. Pseudomonas aeruginosa (P. aeruginosa) bacteremia is notorious for its rapid progression into fatal sepsis, posing a significant threat to cancer patients, particularly those experiencing chemotherapy-induced neutropenia. This bacterial infection contributes significantly to morbidity and mortality rates among such individuals. Our latest report showed the mutually beneficial effects of postbiotic butyrate on 1,25-dihydroxyvitamin D3 (1,25D3)-controlled innate immunity during Salmonella colitis. Hence, we investigated the impact of butyrate and 1,25D3 on chemotherapy-induced gut-derived P. aeruginosa sepsis in mice. The chemotherapy-induced gut-derived P. aeruginosa sepsis model was established through oral administration of 1 × 107 CFU of the P. aeruginosa wild-type strain PAO1 in C57BL/6 mice undergoing chemotherapy. Throughout the infection process, mice were orally administered butyrate and/or 1,25D3. Our observations revealed that the combined action of butyrate and 1,25D3 led to a reduction in the severity of colitis and the invasion of P. aeruginosa into the liver and spleen of the mice. This reduction was attributed to an enhancement in the expression of defensive cytokines and antimicrobial peptides within the cecum, coupled with decreased levels of zonulin and claudin-2 proteins in the mucosal lining. These effects were notably more pronounced when compared to treatments administered individually. This study unveils a promising alternative therapy that involves combining postbiotics and 1,25D3 for treating chemotherapy-induced gut-derived P. aeruginosa sepsis. Full article
(This article belongs to the Special Issue Aryl Hydrocarbon Receptor in Human Diseases)
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22 pages, 10465 KiB  
Article
Inhibition of NF-κB with an Analog of Withaferin-A Restores TDP-43 Homeostasis and Proteome Profiles in a Model of Sporadic ALS
by Pooja Shree Mishra, Daniel Phaneuf, Hejer Boutej, Vincent Picher-Martel, Nicolas Dupre, Jasna Kriz and Jean-Pierre Julien
Biomedicines 2024, 12(5), 1017; https://doi.org/10.3390/biomedicines12051017 - 5 May 2024
Cited by 1 | Viewed by 4751
Abstract
The current knowledge on pathogenic mechanisms in amyotrophic lateral sclerosis (ALS) has widely been derived from studies with cell and animal models bearing ALS-linked genetic mutations. However, it remains unclear to what extent these disease models are of relevance to sporadic ALS. Few [...] Read more.
The current knowledge on pathogenic mechanisms in amyotrophic lateral sclerosis (ALS) has widely been derived from studies with cell and animal models bearing ALS-linked genetic mutations. However, it remains unclear to what extent these disease models are of relevance to sporadic ALS. Few years ago, we reported that the cerebrospinal fluid (CSF) from sporadic ALS patients contains toxic factors for disease transmission in mice via chronic intracerebroventricular (i.c.v.) infusion. Thus a 14-day i.c.v. infusion of pooled CSF samples from ALS cases in mice provoked motor impairment as well as ALS-like pathological features. This offers a unique paradigm to test therapeutics in the context of sporadic ALS disease. Here, we tested a new Withaferin-A analog (IMS-088) inhibitor of NF-κB that was found recently to mitigate disease phenotypes in mouse models of familial disease expressing TDP-43 mutant. Our results show that oral intake of IMS-088 ameliorated motor performance of mice infused with ALS-CSF and it alleviated pathological changes including TDP-43 proteinopathy, neurofilament disorganization, and neuroinflammation. Moreover, CSF infusion experiments were carried out with transgenic mice having neuronal expression of tagged ribosomal protein (hNfL-RFP mice), which allowed immunoprecipitation of neuronal ribosomes for analysis by mass spectrometry of the translational peptide signatures. The results indicate that treatment with IMS-088 prevented many proteomic alterations associated with exposure to ALS-CSF involving pathways related to cytoskeletal changes, inflammation, metabolic dysfunction, mitochondria, UPS, and autophagy dysfunction. The effective disease-modifying effects of this drug in a mouse model based on i.c.v. infusion of ALS-CSF suggest that the NF-κB signaling pathway represents a compelling therapeutic target for sporadic ALS. Full article
(This article belongs to the Special Issue New Insights into Motor Neuron Diseases)
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20 pages, 4285 KiB  
Article
Characterization of a Clinically and Biologically Defined Subgroup of Patients with Autism Spectrum Disorder and Identification of a Tailored Combination Treatment
by Laura Pérez-Cano, Luigi Boccuto, Francesco Sirci, Jose Manuel Hidalgo, Samuel Valentini, Mattia Bosio, Xavier Liogier D’Ardhuy, Cindy Skinner, Lauren Cascio, Sujata Srikanth, Kelly Jones, Caroline B. Buchanan, Steven A. Skinner, Baltazar Gomez-Mancilla, Jean-Marc Hyvelin, Emre Guney and Lynn Durham
Biomedicines 2024, 12(5), 991; https://doi.org/10.3390/biomedicines12050991 - 30 Apr 2024
Cited by 3 | Viewed by 2740
Abstract
Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders (NDDs) with a high unmet medical need. The diagnosis of ASD is currently based on behavior criteria, which overlooks the diversity of genetic, neurophysiological, and clinical manifestations. Failure to acknowledge such heterogeneity [...] Read more.
Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders (NDDs) with a high unmet medical need. The diagnosis of ASD is currently based on behavior criteria, which overlooks the diversity of genetic, neurophysiological, and clinical manifestations. Failure to acknowledge such heterogeneity has hindered the development of efficient drug treatments for ASD and other NDDs. DEPI® (Databased Endophenotyping Patient Identification) is a systems biology, multi-omics, and machine learning-driven platform enabling the identification of subgroups of patients with NDDs and the development of patient-tailored treatments. In this study, we provide evidence for the validation of a first clinically and biologically defined subgroup of patients with ASD identified by DEPI, ASD Phenotype 1 (ASD-Phen1). Among 313 screened patients with idiopathic ASD, the prevalence of ASD-Phen1 was observed to be ~24% in 84 patients who qualified to be enrolled in the study. Metabolic and transcriptomic alterations differentiating patients with ASD-Phen1 were consistent with an over-activation of NF-κB and NRF2 transcription factors, as predicted by DEPI. Finally, the suitability of STP1 combination treatment to revert such observed molecular alterations in patients with ASD-Phen1 was determined. Overall, our results support the development of precision medicine-based treatments for patients diagnosed with ASD. Full article
(This article belongs to the Special Issue Diagnostic Biomarkers and Novel Therapeutics Targets for Fragile X Syndrome, Autism Spectrum Disorders and Genetic Neurodevelopmental Diseases: Advances and Challenges)
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24 pages, 12805 KiB  
Article
Endurance Training Provokes Arrhythmogenic Right Ventricular Cardiomyopathy Phenotype in Heterozygous Desmoglein-2 Mutants: Alleviation by Preload Reduction
by Larissa Fabritz, Lisa Fortmueller, Katja Gehmlich, Sebastian Kant, Marcel Kemper, Dana Kucerova, Fahima Syeda, Cornelius Faber, Rudolf E. Leube, Paulus Kirchhof and Claudia A. Krusche
Biomedicines 2024, 12(5), 985; https://doi.org/10.3390/biomedicines12050985 - 30 Apr 2024
Cited by 2 | Viewed by 2796
Abstract
Desmoglein-2 mutations are detected in 5–10% of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). Endurance training accelerates the development of the ARVC phenotype, leading to earlier arrhythmic events. Homozygous Dsg2 mutant mice develop a severe ARVC-like phenotype. The phenotype of heterozygous mutant ( [...] Read more.
Desmoglein-2 mutations are detected in 5–10% of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). Endurance training accelerates the development of the ARVC phenotype, leading to earlier arrhythmic events. Homozygous Dsg2 mutant mice develop a severe ARVC-like phenotype. The phenotype of heterozygous mutant (Dsg2mt/wt) or haploinsufficient (Dsg20/wt) mice is still not well understood. To assess the effects of age and endurance swim training, we studied cardiac morphology and function in sedentary one-year-old Dsg2mt/wt and Dsg20/wt mice and in young Dsg2mt/wt mice exposed to endurance swim training. Cardiac structure was only occasionally affected in aged Dsg20/wt and Dsg2mt/wt mice manifesting as small fibrotic foci and displacement of Connexin 43. Endurance swim training increased the right ventricular (RV) diameter and decreased RV function in Dsg2mt/wt mice but not in wild types. Dsg2mt/wt hearts showed increased ventricular activation times and pacing-induced ventricular arrhythmia without obvious fibrosis or inflammation. Preload-reducing therapy during training prevented RV enlargement and alleviated the electrophysiological phenotype. Taken together, endurance swim training induced features of ARVC in young adult Dsg2mt/wt mice. Prolonged ventricular activation times in the hearts of trained Dsg2mt/wt mice are therefore a potential mechanism for increased arrhythmia risk. Preload-reducing therapy prevented training-induced ARVC phenotype pointing to beneficial treatment options in human patients. Full article
(This article belongs to the Special Issue Advanced Research in Arrhythmogenic Cardiomyopathy)
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Graphical abstract

11 pages, 807 KiB  
Article
Relationship of Hematological Profiles with the Serum Complement System in Patients with Systemic Lupus Erythematosus
by Yolanda Fernández-Cladera, María García-González, Marta Hernández-Díaz, Fuensanta Gómez-Bernal, Juan C. Quevedo-Abeledo, Agustín F. González-Rivero, Antonia de Vera-González, Cristina Gómez-Moreno, Miguel Á. González-Gay and Iván Ferraz-Amaro
Biomedicines 2024, 12(5), 967; https://doi.org/10.3390/biomedicines12050967 - 27 Apr 2024
Cited by 1 | Viewed by 2523
Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder identified by hematological abnormalities including anemia, leukopenia, and thrombocytopenia. Complement system disturbance is implicated in the pathogenesis of SLE. In this work, we aim to study how a full assessment of the complement system, [...] Read more.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder identified by hematological abnormalities including anemia, leukopenia, and thrombocytopenia. Complement system disturbance is implicated in the pathogenesis of SLE. In this work, we aim to study how a full assessment of the complement system, which includes the evaluation of its three pathways, relates to blood cell counts in a population of patients with SLE. New-generation functional assays of the classical, alternative, and lectin pathways of the complement system were conducted in 284 patients with SLE. Additionally, serum levels of inactive molecules (C1q, C2, C3, C4, factor D) and activated molecules (C3a), as well as regulators (C1-inhibitor and factor H), were evaluated. Complete blood cell counts were analyzed. Multivariable linear regression analysis was performed to study the relationship of hematological profiles with this full characterization of the complement system. After multivariable adjustments that included age, sex, SLICC-DI (damage), and SLEDAI (activity) scores, as well as the use of aspirin, prednisone, methotrexate, azathioprine, and mycophenolate mofetil, several relationships were observed between the C pathways and the individual products and blood cells profile. Lower values of C1q and C2 were associated with lower hemoglobin levels. Lower leukocyte counts showed significantly lower values of C4, C1 inhibitor, C3, factor D, and alternative pathway functional levels. Neutrophil counts showed significant negative relationships only with the alternative pathway and C1-inh. In the case of lymphocytes, associations were found, especially with functional tests of the classical and alternative pathways, as well as with C2, C4, C3, and C3a. On the contrary, for platelets, significance was only observed, after multivariable adjustment, with lower C2 concentrations. In conclusion, the serum complement system and hematological profile in SLE are independently linked, after adjustment for disease activity and damage. These relationships are basically negative and are predominantly found in lymphocytes. Full article
(This article belongs to the Special Issue Musculoskeletal Diseases: From Molecular Basis to Therapy (Volume II))
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18 pages, 4058 KiB  
Article
Combined Metabolic Activators with Different NAD+ Precursors Improve Metabolic Functions in the Animal Models of Neurodegenerative Diseases
by Ozlem Altay, Hong Yang, Serkan Yildirim, Cemil Bayram, Ismail Bolat, Sena Oner, Ozlem Ozdemir Tozlu, Mehmet Enes Arslan, Ahmet Hacimuftuoglu, Saeed Shoaie, Cheng Zhang, Jan Borén, Mathias Uhlén, Hasan Turkez and Adil Mardinoglu
Biomedicines 2024, 12(4), 927; https://doi.org/10.3390/biomedicines12040927 - 22 Apr 2024
Cited by 7 | Viewed by 3687
Abstract
Background: Mitochondrial dysfunction and metabolic abnormalities are acknowledged as significant factors in the onset of neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). Our research has demonstrated that the use of combined metabolic activators (CMA) may alleviate metabolic dysfunctions and [...] Read more.
Background: Mitochondrial dysfunction and metabolic abnormalities are acknowledged as significant factors in the onset of neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). Our research has demonstrated that the use of combined metabolic activators (CMA) may alleviate metabolic dysfunctions and stimulate mitochondrial metabolism. Therefore, the use of CMA could potentially be an effective therapeutic strategy to slow down or halt the progression of PD and AD. CMAs include substances such as the glutathione precursors (L-serine and N-acetyl cysteine), the NAD+ precursor (nicotinamide riboside), and L-carnitine tartrate. Methods: Here, we tested the effect of two different formulations, including CMA1 (nicotinamide riboside, L-serine, N-acetyl cysteine, L-carnitine tartrate), and CMA2 (nicotinamide, L-serine, N-acetyl cysteine, L-carnitine tartrate), as well as their individual components, on the animal models of AD and PD. We assessed the brain and liver tissues for pathological changes and immunohistochemical markers. Additionally, in the case of PD, we performed behavioral tests and measured responses to apomorphine-induced rotations. Findings: Histological analysis showed that the administration of both CMA1 and CMA2 formulations led to improvements in hyperemia, degeneration, and necrosis in neurons for both AD and PD models. Moreover, the administration of CMA2 showed a superior effect compared to CMA1. This was further corroborated by immunohistochemical data, which indicated a reduction in immunoreactivity in the neurons. Additionally, notable metabolic enhancements in liver tissues were observed using both formulations. In PD rat models, the administration of both formulations positively influenced the behavioral functions of the animals. Interpretation: Our findings suggest that the administration of both CMA1 and CMA2 markedly enhanced metabolic and behavioral outcomes, aligning with neuro-histological observations. These findings underscore the promise of CMA2 administration as an effective therapeutic strategy for enhancing metabolic parameters and cognitive function in AD and PD patients. Full article
(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Neurodegenerative Diseases)
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14 pages, 3124 KiB  
Article
Metabolomic Approach to Identify Potential Biomarkers in KRAS-Mutant Pancreatic Cancer Cells
by Boyun Kim and Jewon Jung
Biomedicines 2024, 12(4), 865; https://doi.org/10.3390/biomedicines12040865 - 15 Apr 2024
Cited by 3 | Viewed by 2316
Abstract
Pancreatic cancer is characterized by its high mortality rate and limited treatment options, often driven by oncogenic RAS mutations. In this study, we investigated the metabolomic profiles of pancreatic cancer cells based on their KRAS genetic status. Utilizing both KRAS-wildtype BxPC3 and KRAS-mutant [...] Read more.
Pancreatic cancer is characterized by its high mortality rate and limited treatment options, often driven by oncogenic RAS mutations. In this study, we investigated the metabolomic profiles of pancreatic cancer cells based on their KRAS genetic status. Utilizing both KRAS-wildtype BxPC3 and KRAS-mutant PANC1 cell lines, we identified 195 metabolites differentially altered by KRAS status through untargeted metabolomics. Principal component analysis and hierarchical condition trees revealed distinct separation between KRAS-wildtype and KRAS-mutant cells. Metabolite set enrichment analysis highlighted significant pathways such as homocysteine degradation and taurine and hypotaurine metabolism. Additionally, lipid enrichment analysis identified pathways including fatty acyl glycosides and sphingoid bases. Mapping of identified metabolites to KEGG pathways identified nine significant metabolic pathways associated with KRAS status, indicating diverse metabolic alterations in pancreatic cancer cells. Furthermore, we explored the impact of TRPML1 inhibition on the metabolomic profile of KRAS-mutant pancreatic cancer cells. TRPML1 inhibition using ML-SI1 significantly altered the metabolomic profile, leading to distinct separation between vehicle-treated and ML-SI1-treated PANC1 cells. Metabolite set enrichment analysis revealed enriched pathways such as arginine and proline metabolism, and mapping to KEGG pathways identified 17 significant metabolic pathways associated with TRPML1 inhibition. Interestingly, some metabolites identified in PANC1 compared to BxPC3 were oppositely regulated by TRPML1 inhibition, suggesting their potential as biomarkers for KRAS-mutant cancer cells. Overall, our findings shed light on the distinct metabolite changes induced by both KRAS status and TRPML1 inhibition in pancreatic cancer cells, providing insights into potential therapeutic targets and biomarkers for this deadly disease. Full article
(This article belongs to the Special Issue Advanced Cancer Diagnosis and Treatment)
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21 pages, 12760 KiB  
Article
Significant Genes Associated with Mortality and Disease Progression in Grade II and III Glioma
by Bo Mi Choi, Jin Hwan Cheong, Je Il Ryu, Yu Deok Won, Kyueng-Whan Min and Myung-Hoon Han
Biomedicines 2024, 12(4), 858; https://doi.org/10.3390/biomedicines12040858 - 12 Apr 2024
Cited by 1 | Viewed by 1986
Abstract
Background: The Wnt/β-catenin pathway plays a critical role in the tumorigenesis and maintenance of glioma stem cells. This study aimed to evaluate significant genes associated with the Wnt/β-catenin pathway involved in mortality and disease progression in patients with grade II and III glioma, [...] Read more.
Background: The Wnt/β-catenin pathway plays a critical role in the tumorigenesis and maintenance of glioma stem cells. This study aimed to evaluate significant genes associated with the Wnt/β-catenin pathway involved in mortality and disease progression in patients with grade II and III glioma, using the Cancer Genome Atlas (TCGA) database. Methods: We obtained clinicopathological information and mRNA expression data from 515 patients with grade II and III gliomas from the TCGA database. We performed a multivariate Cox regression analysis to identify genes independently associated with glioma prognosis. Results: The analysis of 34 genes involved in Wnt/β-catenin signaling demonstrated that four genes (CER1, FRAT1, FSTL1, and RPSA) related to the Wnt/β-catenin pathway were significantly associated with mortality and disease progression in patients with grade II and III glioma. We also identified additional genes related to the four significant genes of the Wnt/β-catenin pathway mentioned above. The higher expression of BMP2, RPL18A, RPL19, and RPS12 is associated with better outcomes in patients with glioma. Conclusions: Using a large-scale open database, we identified significant genes related to the Wnt/β-catenin signaling pathway associated with mortality and disease progression in patients with grade II and III gliomas. Full article
(This article belongs to the Special Issue Gliomas: Signaling Pathways, Molecular Mechanisms and Novel Therapies)
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