Biomedicines

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13 pages, 1675 KB

Open AccessEditor’s ChoiceArticle

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 5 | Viewed by 2662

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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17 pages, 1851 KB

Open AccessEditor’s ChoiceArticle

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 Mueller Show full author list Hide full author list

Biomedicines 2024, 12(5), 1099; https://doi.org/10.3390/biomedicines12051099 - 16 May 2024

Cited by 2 | Viewed by 1973

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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10 pages, 264 KB

Open AccessEditor’s ChoiceArticle

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 4 | Viewed by 1984

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 KB

Open AccessEditor’s ChoiceArticle

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

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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 KB

Open AccessEditor’s ChoiceArticle

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 2079

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 KB

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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 5000

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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24 pages, 12805 KB

Open AccessEditor’s ChoiceArticle

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 3 | Viewed by 3214

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 (Dsg2^mt/wt) or haploinsufficient (Dsg2^0/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 Dsg2^mt/wt and Dsg2^0/wt mice and in young Dsg2^mt/wt mice exposed to endurance swim training. Cardiac structure was only occasionally affected in aged Dsg2^0/wt and Dsg2^mt/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 Dsg2^mt/wt mice but not in wild types. Dsg2^mt/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 Dsg2^mt/wt mice. Prolonged ventricular activation times in the hearts of trained Dsg2^mt/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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20 pages, 4285 KB

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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 3058

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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11 pages, 807 KB

Open AccessEditor’s ChoiceArticle

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 3114

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 KB

Open AccessEditor’s ChoiceArticle

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 4003

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 KB

Open AccessEditor’s ChoiceArticle

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 4 | Viewed by 2681

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 KB

Open AccessEditor’s ChoiceArticle

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 2 | Viewed by 2174

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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13 pages, 1289 KB

Open AccessEditor’s ChoiceArticle

by Marco Dell’Aquila, Concetta Cafiero, Alessandra Micera, Egidio Stigliano, Maria Pia Ottaiano, Giulio Benincasa, Beniamino Schiavone, Leo Guidobaldi, Luigi Santacroce, Salvatore Pisconti, Vincenzo Arena and Raffaele Palmirotta

Biomedicines 2024, 12(4), 830; https://doi.org/10.3390/biomedicines12040830 - 9 Apr 2024

Cited by 3 | Viewed by 1841

Abstract

Background: The COVID-19 pandemic has been a health emergency with a significant impact on the world due to its high infectiousness. The disease, primarily identified in the lower respiratory tract, develops with numerous clinical symptoms affecting multiple organs and displays a clinical finding [...] Read more.

Background: The COVID-19 pandemic has been a health emergency with a significant impact on the world due to its high infectiousness. The disease, primarily identified in the lower respiratory tract, develops with numerous clinical symptoms affecting multiple organs and displays a clinical finding of anosmia. Several authors have investigated the pathogenetic mechanisms of the olfactory disturbances caused by SARS-CoV-2 infection, proposing different hypotheses and showing contradictory results. Since uncertainties remain about possible virus neurotropism and direct damage to the olfactory bulb, we investigated the expression of SARS-CoV-2 as well as ACE2 receptor transcripts in autoptic lung and olfactory bulb tissues, with respect to the histopathological features. Methods: Twenty-five COVID-19 olfactory bulbs and lung tissues were randomly collected from 200 initial autopsies performed during the COVID-19 pandemic. Routine diagnosis was based on clinical and radiological findings and were confirmed with post-mortem swabs. Real-time RT-PCR for SARS-CoV-2 and ACE2 receptor RNA was carried out on autoptic FFPE lung and olfactory bulb tissues. Histological staining was performed on tissue specimens and compared with the molecular data. Results: While real-time RT-PCR for SARS-CoV-2 was positive in 23 out of 25 lung samples, the viral RNA expression was absent in olfactory bulbs. ACE2-receptor RNA was present in all tissues examined, being highly expressed in lung samples than olfactory bulbs. Conclusions: Our finding suggests that COVID-19 anosmia is not only due to neurotropism and the direct action of SARS-CoV-2 entering the olfactory bulb. The mechanism of SARS-CoV-2 neuropathogenesis in the olfactory bulb requires a better elucidation and further research studies to mitigate the olfactory bulb damage associated with virus action. Full article

(This article belongs to the Special Issue The End of the COVID-19 Pandemic—What Is Currently Known and What Could Have Been Useful Four Years Ago?)

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10 pages, 2553 KB

Open AccessEditor’s ChoiceArticle

The Effects of Local Treatment of PTH(1-34) and Whitlockite and Hydroxyapatite Graft to the Calvarial Defect in a Rat Osteoporosis Model

by Jiwoon Jeong, Jung Hee Shim and Chan Yeong Heo

Biomedicines 2024, 12(4), 820; https://doi.org/10.3390/biomedicines12040820 - 8 Apr 2024

Cited by 5 | Viewed by 1875

Abstract

With the aging population, there is a rising incidence of senile diseases, notably osteoporosis, marked by fractures, prolonged recovery, and elevated mortality rates, underscoring the urgency for effective treatments. In this study, we applied the method of absorbing parathyroid hormone (PTH), a treatment [...] Read more.

With the aging population, there is a rising incidence of senile diseases, notably osteoporosis, marked by fractures, prolonged recovery, and elevated mortality rates, underscoring the urgency for effective treatments. In this study, we applied the method of absorbing parathyroid hormone (PTH), a treatment for osteoporosis, into graft materials. Two types of graft materials with different properties, whitlockite (WH) and hydroxyapatite (HAP), were used. After forming calvarial defects in osteoporotic rats, WH and HAP grafts were implanted, with PTH applied directly to the graft sites. Micro-CT analysis was employed to assess bone regeneration, while tissue sections were stained to elucidate the regeneration process and bone cell dynamics. The results showed that bone regeneration was higher in the grafts that were actively degraded by osteoclasts in the early stage of regeneration. When PTH was applied, osteoclast activity increased, leading to enhanced bone regeneration. Furthermore, the activation of osteoclasts resulted in the penetration and formation of new bone within the degraded graft, which exhibited higher osseointegration. Therefore, for osteoporotic bone defects, bone grafts that can be easily degraded by osteoclasts are more suitable. Additionally, treatment with PTH can activate osteoclasts around the bone graft in the early stages of regeneration, inducing higher bone regeneration and improving osseointegration. Full article

(This article belongs to the Special Issue Osteoclast and Osteoblast: Current Status and Future Prospects)

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11 pages, 627 KB

Open AccessEditor’s ChoiceArticle

Elevated NET, Calprotectin, and Neopterin Levels Discriminate between Disease Activity in COVID-19, as Evidenced by Need for Hospitalization among Patients in Northern Italy

by Geir Hetland, Magne Kristoffer Fagerhol, Mohammad Reza Mirlashari, Lise Sofie Haug Nissen-Meyer, Stefania Croci, Paola Adele Lonati, Martina Bonacini, Carlo Salvarani, Chiara Marvisi, Caterina Bodio, Francesco Muratore, Maria Orietta Borghi and Pier Luigi Meroni

Biomedicines 2024, 12(4), 766; https://doi.org/10.3390/biomedicines12040766 - 30 Mar 2024

Cited by 2 | Viewed by 1801

Abstract

Coronavirus disease 2019 (COVID-19) displays clinical heterogeneity, but little information is available for patients with mild or very early disease. We aimed to characterize biomarkers that are useful for discriminating the hospitalization risk in a COVID-19 cohort from Northern Italy during the first [...] Read more.

Coronavirus disease 2019 (COVID-19) displays clinical heterogeneity, but little information is available for patients with mild or very early disease. We aimed to characterize biomarkers that are useful for discriminating the hospitalization risk in a COVID-19 cohort from Northern Italy during the first pandemic wave. We enrolled and followed for four weeks 76 symptomatic SARS-CoV-2 positive patients and age/sex-matched healthy controls. Patients with mild disease were discharged (n.42), and the remaining patients were hospitalized (n.34). Blood was collected before any anti-inflammatory/immunosuppressive therapy and assessed for soluble C5b-9/C5a, H3-neutrophil extracellular traps (NETs), calprotectin, and DNase plasma levels via ELISA and a panel of proinflammatory cytokines via ELLA. Calprotectin and NET levels discriminate between hospitalized and non-hospitalized patients, while DNase negatively correlates with NET levels; there are positive correlations between calprotectin and both NET and neopterin levels. Neopterin levels increase in patients at the beginning of the disease and do so more in hospitalized than non-hospitalized patients. C5a and sC5b-9, and other acute phase proteins, correlate with neopterin, calprotectin, and DNase. Both NET and neopterin levels negatively correlate with platelet count. We show that calprotectin, NETs, and neopterin are important proinflammatory parameters potentially useful for discriminating between COVID-19 patients at risk of hospitalization. Full article

(This article belongs to the Special Issue Editorial Board Members' Collection Series: Cell Biology and Pathology)

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17 pages, 1762 KB

Open AccessEditor’s ChoiceArticle

GDF-15 Levels and Other Laboratory Findings as Predictors of COVID-19 Severity and Mortality: A Pilot Study

by Luka Švitek, Dubravka Lišnjić, Barbara Grubišić, Mihaela Zlosa, Ema Schönberger, Nika Vlahović Vlašić, Petra Smajić, Dario Sabadi, Tara Rolić, Kristina Kralik and Sanja Mandić

Biomedicines 2024, 12(4), 757; https://doi.org/10.3390/biomedicines12040757 - 29 Mar 2024

Cited by 1 | Viewed by 2113

Abstract

Growth differentiation factor 15 (GDF-15) is a stress-induced cytokine associated with acute and chronic inflammatory states. This prospective observational study aimed to investigate the prognostic roles of GDF-15 and routine clinical laboratory parameters in COVID-19 patients. Upon the admission of 95 adult hospitalized [...] Read more.

Growth differentiation factor 15 (GDF-15) is a stress-induced cytokine associated with acute and chronic inflammatory states. This prospective observational study aimed to investigate the prognostic roles of GDF-15 and routine clinical laboratory parameters in COVID-19 patients. Upon the admission of 95 adult hospitalized COVID-19 patients in Croatia, blood analysis was performed, and medical data were collected. The patients were categorized based on survival, ICU admission, and hospitalization duration. Logistic regression and ROC curve methods were employed for the statistical analysis. Logistic regression revealed two independent predictors of negative outcomes: CURB-65 score (OR = 2.55) and LDH (OR = 1.005); one predictor of ICU admission: LDH (OR = 1.004); and one predictor of prolonged hospitalization: the need for a high-flow nasal cannula (HFNC) upon admission (OR = 4.75). The ROC curve showed diagnostic indicators of negative outcomes: age, CURB-65 score, LDH, and GDF-15. The largest area under the curve (AUC = 0.767, specificity = 65.6, sensitivity = 83.9) was represented by GDF-15, with a cutoff value of 3528 pg/mL. For ICU admission, significant diagnostic indicators were LDH, CRP, and IL-6. Significant diagnostic indicators of prolonged hospitalization were CK, GGT, and oxygenation with an HFNC upon admission. This study reaffirms the significance of the commonly used laboratory parameters and clinical scores in evaluating COVID-19. Additionally, it introduces the potential for a new diagnostic approach and research concerning GDF-15 levels in this widespread disease. Full article

(This article belongs to the Special Issue The End of the COVID-19 Pandemic—What Is Currently Known and What Could Have Been Useful Four Years Ago?)

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18 pages, 1677 KB

Open AccessEditor’s ChoiceArticle

USP7 Deregulation Impairs S Phase Specific DNA Repair after Irradiation in Breast Cancer Cells

by Marie Vogt, Sandra Classen, Ann Kristin Krause, Nadja-Juanita Peter, Cordula Petersen, Kai Rothkamm, Kerstin Borgmann and Felix Meyer

Biomedicines 2024, 12(4), 762; https://doi.org/10.3390/biomedicines12040762 - 29 Mar 2024

Cited by 1 | Viewed by 2565

Abstract

The ubiquitin specific protease 7 (USP7) is a deubiquitinating enzyme with numerous substrates. Aberrant expression of USP7 is associated with tumor progression. This study aims to investigate how a deregulated USP7 expression affects chromosomal instability and prognosis of breast cancer patients in silico [...] Read more.

The ubiquitin specific protease 7 (USP7) is a deubiquitinating enzyme with numerous substrates. Aberrant expression of USP7 is associated with tumor progression. This study aims to investigate how a deregulated USP7 expression affects chromosomal instability and prognosis of breast cancer patients in silico and radiosensitivity and DNA repair in breast cancer cells in vitro. The investigations in silico were performed using overall survival and USP7 mRNA expression data of breast cancer patients. The results showed that a high USP7 expression was associated with increased chromosomal instability and decreased overall survival. The in vitro experiments were performed in a luminal and a triple-negative breast cancer cell line. Proliferation, DNA repair, DNA replication stress, and survival after USP7 overexpression or inhibition and irradiation were analyzed. Both, USP7 inhibition and overexpression resulted in decreased cellular survival, distinct radiosensitization and an increased number of residual DNA double-strand breaks in the S phase following irradiation. RAD51 recruitment and base incorporation were decreased after USP7 inhibition plus irradiation and more single-stranded DNA was detected. The results show that deregulation of USP7 activity disrupts DNA repair in the S phase by increasing DNA replication stress and presents USP7 as a promising target to overcome the radioresistance of breast tumors. Full article

(This article belongs to the Special Issue Editorial Board Members' Collection Series: Cell Biology and Pathology)

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14 pages, 1143 KB

Open AccessEditor’s ChoiceArticle

The Expression Patterns of Immune Checkpoint Molecules in Colorectal Cancer: An Analysis Based on Microsatellite Status

by Sanghyun An, Wanlu Li, Hyejin Do, Hye Youn Kwon, Bora Kim, Kwangmin Kim, Youngwan Kim and Mee-Yon Cho

Biomedicines 2024, 12(4), 752; https://doi.org/10.3390/biomedicines12040752 - 28 Mar 2024

Cited by 2 | Viewed by 2128

Abstract

Recently, immunotherapy has arisen as a novel treatment approach for patients with colorectal cancer (CRC), but the effectiveness of immunotherapy varies in these patients. We hypothesized that immune checkpoint molecules (ICMs), which are the targets of immunotherapy, are often exhibited concomitantly. Our objective [...] Read more.

Recently, immunotherapy has arisen as a novel treatment approach for patients with colorectal cancer (CRC), but the effectiveness of immunotherapy varies in these patients. We hypothesized that immune checkpoint molecules (ICMs), which are the targets of immunotherapy, are often exhibited concomitantly. Our objective was to investigate the patterns of ICM expression in patients with CRC and the differences in ICM expression based on microsatellite instability status. The immunohistochemical expression of programmed cell death protein 1 (PD-1), programmed cell death ligand 1 (PD-L1), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), and lymphocyte-activation gene 3 (LAG-3) in the tumor center and periphery was assessed in patients with non-metastatic colorectal cancer. We enrolled 83 patients with CRC: a total of 40 microsatellite-stable (MSS) and 43 microsatellite-instability-high (MSI-H) cancer patients. PD-L1 was more frequently expressed in the tumor center in the MSI-H patients with than that in the MSS patients (18 [41.9%] vs. 3 [7.5%], respectively; p < 0.001), and the same trend was observed for TIM-3 expression (30 [69.8%] vs. 19 [47.5%], respectively; p = 0.047). The concomitant expression of two or more ICMs was more frequently observed than no expression or the expression of a single molecule in both the MSS and MSI-H groups; a total of 34 (79.7%) patients with MSI-H cancer and 23 (57.5%) with MSS cancer showed ICM expression at the tumor center, whereas 34 (79.7%) patients with MSI-H cancer and 22 (55%) with MSS cancer showed expression at the tumor periphery. Patients with the genetic characteristics of MSI-H cancer showed higher expression levels of ICMs than those in patients with MSS cancer, and predominantly, two or more ICMs were concurrently expressed. Our findings highlight the potential efficacy of the dual-blockade approach in immunotherapy, particularly in patients with MSI-H CRC. Full article

(This article belongs to the Section Immunology and Immunotherapy)

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17 pages, 1076 KB

Open AccessEditor’s ChoiceArticle

Association of NT-proBNP and sST2 with Left Ventricular Ejection Fraction and Oxidative Stress in Patients with Stable Dilated Cardiomyopathy

by Elżbieta Lazar-Poloczek, Ewa Romuk, Wojciech Jacheć, Karolina Wróbel-Nowicka, Agata Świętek and Celina Wojciechowska

Biomedicines 2024, 12(4), 707; https://doi.org/10.3390/biomedicines12040707 - 22 Mar 2024

Cited by 1 | Viewed by 2326

Abstract

The aim of this study was to analyze the relationship between levels of sST2, NT-proBNP and oxidative stress markers in patients with reduced ejection fraction (HFrEF) due to non-ischemic cardiomyopathy. A total of 88 patients with HFrEF were divided into four groups based [...] Read more.

The aim of this study was to analyze the relationship between levels of sST2, NT-proBNP and oxidative stress markers in patients with reduced ejection fraction (HFrEF) due to non-ischemic cardiomyopathy. A total of 88 patients with HFrEF were divided into four groups based on left ventricular ejection fraction (≤25% and >25%) and NYHA functional class (group 1—LVEF > 25% and NYHA class I or II; group 2—LVEF > 25% and NYHA class III or IV; group III—LVEF ≤ 25% and NYHA class I or II; group IV—LVEF ≤ 25% and NYHA class III or IV). In 39 (44.32%) patients LVEF was reduced below 25%, and 22 of them (56.41%) were in NYHA functional class III/IV. Of the 49 (55.68%) patients with LVEF ≥ 25%, only 18.37% were in NYHA functional class III/IV (p < 0.001). Patients with LVEF ≥ 25% had lower levels of NT-proBNP, total oxidant status (TOS), total antioxidant capacity (TAC), and oxidative stress index (OSI). The levels of NT-proBNP but not sST-2 correlated positively with NYHA functional class (p < 0.001) and negatively with LVEF (p < 0.001). The levels of sST-2 were associated with increased TAC (p = 0.009) and uric acid (p = 0.040). These findings indicate that only NT-proBNP was related to the severity of heart failure, whereas sST2 correlated with total antioxidant capacity. Therefore, in stable patients with HFrEF due to dilated cardiomyopathy, sST2 may be an additional biomarker reflecting the redox status, but not the severity of heart failure. Full article

(This article belongs to the Special Issue Oxidative Stress Markers in Cardiomyopathy)

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15 pages, 3121 KB

Open AccessEditor’s ChoiceArticle

Repurposing of the Cardiovascular Drug Statin for the Treatment of Cancers: Efficacy of Statin–Dipyridamole Combination Treatment in Melanoma Cell Lines

by Nanami Irie, Kana Mizoguchi, Tomoko Warita, Mirai Nakano, Kasuga Sasaki, Jiro Tashiro, Tomohiro Osaki, Takuro Ishikawa, Zoltán N. Oltvai and Katsuhiko Warita

Biomedicines 2024, 12(3), 698; https://doi.org/10.3390/biomedicines12030698 - 21 Mar 2024

Cited by 6 | Viewed by 4573

Abstract

Metastatic melanoma has a very poor prognosis. Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) inhibitors, are cholesterol-lowering agents with a potential for cancer treatment. The inhibition of HMGCR by statins, however, induces feedback, which paradoxically upregulates HMGCR expression via sterol regulatory element-binding protein-2 (SREBP2). Dipyridamole, [...] Read more.

Metastatic melanoma has a very poor prognosis. Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) inhibitors, are cholesterol-lowering agents with a potential for cancer treatment. The inhibition of HMGCR by statins, however, induces feedback, which paradoxically upregulates HMGCR expression via sterol regulatory element-binding protein-2 (SREBP2). Dipyridamole, an antiplatelet agent, is known to inhibit SREBP2 upregulation. We aimed to demonstrate the efficacy of statin–dipyridamole combination treatment in both human and spontaneously occurring canine melanoma cell lines. The half maximal inhibitory concentration (IC₅₀) of atorvastatin showed a 68–92% reduction when combined with dipyridamole, compared with that of atorvastatin alone. In some melanoma cell lines, cell proliferation was suppressed to almost zero by the combination treatment (≥3 μM atorvastatin). Finally, the BRAF inhibitor, vemurafenib, further potentiated the effects of the combined statin–dipyridamole treatment in BRAF V600E mutation-bearing human melanoma cell lines. In conclusion, the inexpensive and frequently prescribed statin–dipyridamole combination therapy may lead to new developments in the treatment of melanoma and may potentiate the effects of vemurafenib for the targeted therapy of BRAF V600E-mutation bearing melanoma patients. The concordance between the data from canine and human melanoma cell lines reinforces this possibility. 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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18 pages, 2379 KB

Open AccessEditor’s ChoiceArticle

Comparing the Efficacy of Two Generations of EGFR-TKIs: An Integrated Drug–Disease Mechanistic Model Approach in EGFR-Mutated Lung Adenocarcinoma

by Hippolyte Darré, Perrine Masson, Arnaud Nativel, Laura Villain, Diane Lefaudeux, Claire Couty, Bastien Martin, Evgueni Jacob, Michaël Duruisseaux, Jean-Louis Palgen, Claudio Monteiro and Adèle L’Hostis

Biomedicines 2024, 12(3), 704; https://doi.org/10.3390/biomedicines12030704 - 21 Mar 2024

Cited by 2 | Viewed by 3463

Abstract

Mutationsin epidermal growth factor receptor (EGFR) are found in approximately 48% of Asian and 19% of Western patients with lung adenocarcinoma (LUAD), leading to aggressive tumor growth. While tyrosine kinase inhibitors (TKIs) like gefitinib and osimertinib target this mutation, treatments often face challenges [...] Read more.

Mutationsin epidermal growth factor receptor (EGFR) are found in approximately 48% of Asian and 19% of Western patients with lung adenocarcinoma (LUAD), leading to aggressive tumor growth. While tyrosine kinase inhibitors (TKIs) like gefitinib and osimertinib target this mutation, treatments often face challenges such as metastasis and resistance. To address this, we developed physiologically based pharmacokinetic (PBPK) models for both drugs, simulating their distribution within the primary tumor and metastases following oral administration. These models, combined with a mechanistic knowledge-based disease model of EGFR-mutated LUAD, allow us to predict the tumor’s behavior under treatment considering the diversity within the tumor cells due to different mutations. The combined model reproduces the drugs’ distribution within the body, as well as the effects of both gefitinib and osimertinib on EGFR-activation-induced signaling pathways. In addition, the disease model encapsulates the heterogeneity within the tumor through the representation of various subclones. Each subclone is characterized by unique mutation profiles, allowing the model to accurately reproduce clinical outcomes, including patients’ progression, aligning with RECIST criteria guidelines (version 1.1). Datasets used for calibration came from NEJ002 and FLAURA clinical trials. The quality of the fit was ensured with rigorous visual predictive checks and statistical tests (comparison metrics computed from bootstrapped, weighted log-rank tests: 98.4% (NEJ002) and 99.9% (FLAURA) similarity). In addition, the model was able to predict outcomes from an independent retrospective study comparing gefitinib and osimertinib which had not been used within the model development phase. This output validation underscores mechanistic models’ potential in guiding future clinical trials by comparing treatment efficacies and identifying patients who would benefit most from specific TKIs. Our work is a step towards the design of a powerful tool enhancing personalized treatment in LUAD. It could support treatment strategy evaluations and potentially reduce trial sizes, promising more efficient and targeted therapeutic approaches. Following its consecutive prospective validations with the FLAURA2 and MARIPOSA trials (validation metrics computed from bootstrapped, weighted log-rank tests: 94.0% and 98.1%, respectively), the model could be used to generate a synthetic control arm. Full article

(This article belongs to the Special Issue Recent Advances of Receptor Tyrosine Kinases in Solid Tumors)

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16 pages, 1546 KB

Open AccessEditor’s ChoiceArticle

MAPT Mutations V337M and N297K Alter Organelle Trafficking in Frontotemporal Dementia Patient-Specific Motor Neurons

by Christiane Hartmann, Marie Anskat, Marc Ehrlich, Jared Sterneckert, Arun Pal and Andreas Hermann

Biomedicines 2024, 12(3), 641; https://doi.org/10.3390/biomedicines12030641 - 13 Mar 2024

Cited by 3 | Viewed by 2757

Abstract

Frontotemporal dementia (FTD) is a neurodegenerative disease characterized by the progressive loss of neurons mainly in the frontal and temporal lobes of the brain. Mutations (e.g., V337M, N297K) in the microtubule-associated protein TAU (MAPT) are responsible 5–20% of familial FTD cases and have [...] Read more.

Frontotemporal dementia (FTD) is a neurodegenerative disease characterized by the progressive loss of neurons mainly in the frontal and temporal lobes of the brain. Mutations (e.g., V337M, N297K) in the microtubule-associated protein TAU (MAPT) are responsible 5–20% of familial FTD cases and have been associated with defects in organelle trafficking that plays a critical role in the proper function of cells, including transport of essential molecules and degradation of waste products. Due to the critical role of TAU mutations in microtubule stabilization and organelle transportation, it is of great interest to study these molecular mechanisms to develop effective therapeutic strategies. Therefore, herein, we analyzed mitochondrial and lysosomal trafficking in disease-specific spinal motor neurons by using live cell imaging in undirected (uncompartmentalized) and directed (compartmentalized) cell culture systems. While V337M neurons only expressed 3R TAU, the N297K mutant neurons expressed both 3R and 4R TAU. Axonal trafficking was affected differentially in V337M and N297 MAPT mutated neurons. These findings suggest that the MAPT mutations V337M and N297K impaired axon physiology differentially, which highlights the need for mutation- and/or 3R/4R TAU-specific therapeutic approaches. Full article

(This article belongs to the Special Issue Tauopathies: New Perspectives and Challenges)

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28 pages, 7874 KB

Open AccessEditor’s ChoiceArticle

Broad Epitope Coverage of Therapeutic Multi-Antibody Combinations Targeting SARS-CoV-2 Boosts In Vivo Protection and Neutralization Potency to Corner an Immune-Evading Virus

by Ilse Roodink, Maartje van Erp, Andra Li, Sheila Potter, Sander M. J. van Duijnhoven, Milou Smits, Arthur J. Kuipers, Bert Kazemier, Bob Berkeveld, Ellen van Geffen, Britte S. de Vries, Danielle Rijbroek, Bianca Boers, Sanne Meurs, Wieger Hemrika, Alexandra Thom, Barry N. Duplantis, Roland A. Romijn, Jeremy S. Houser, Jennifer L. Bath and Yasmina N. Abdiche Show full author list Hide full author list

Biomedicines 2024, 12(3), 642; https://doi.org/10.3390/biomedicines12030642 - 13 Mar 2024

Cited by 1 | Viewed by 2323

Abstract

Therapeutic antibodies (Abs) which act on a broader range of epitopes may provide more durable protection against the genetic drift of a target, typical of viruses or tumors. When these Abs exist concurrently on the targeted antigen, several mechanisms of action (MoAs) can [...] Read more.

Therapeutic antibodies (Abs) which act on a broader range of epitopes may provide more durable protection against the genetic drift of a target, typical of viruses or tumors. When these Abs exist concurrently on the targeted antigen, several mechanisms of action (MoAs) can be engaged, boosting therapeutic potency. This study selected combinations of four and five Abs with non- or partially overlapping epitopes to the SARS-CoV-2 spike glycoprotein, on or outside the crucial receptor binding domain (RBD), to offer resilience to emerging variants and trigger multiple MoAs. The combinations were derived from a pool of unique-sequence scFv Ab fragments retrieved from two SARS-CoV-2-naïve human phage display libraries. Following recombinant expression to full-length human IgG₁ candidates, a biolayer interferometric analysis mapped epitopes to bins and confirmed that up to four Abs from across the bins can exist simultaneously on the spike glycoprotein trimer. Not all the bins of Abs interfered with the spike protein binding to angiotensin converting enzyme 2 (ACE2) in competitive binding assays, nor neutralized the pseudovirus or authentic virus in vitro, but when combined in vivo, their inclusion resulted in a much stronger viral clearance in the lungs of intranasally challenged hamsters, compared to that of those treated with mono ACE2 blockers. In addition, the Ab mixtures activated in vitro reporter cells expressing Fc-gamma receptors (FcγRs) involved in antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). The best four-Ab combination neutralized seventeen variants of concern from Wuhan-Hu1 to Omicron BA.4/BA.5 in vitro. Full article

(This article belongs to the Section Drug Discovery, Development and Delivery)

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10 pages, 1519 KB

Open AccessEditor’s ChoiceArticle

Astemizole, a Second-Generation Histamine H1-Receptor Antagonist, Did Not Attenuate the Aggregation Process of α-Synuclein In Vitro

by Jung Il Choi, Hyunjo Lee, Dong Jun Kim, Eun Suk Park, Kyung Yeon Lee and Hui-Jun Yang

Biomedicines 2024, 12(3), 611; https://doi.org/10.3390/biomedicines12030611 - 8 Mar 2024

Cited by 1 | Viewed by 2458

Abstract

The antihistamine astemizole has shown disease-modifying effects in several preclinical disease models of Parkinson’s disease (PD). Astemizole also interacts with an anomalous aggregation of Alzheimer’s disease-related amyloid-β (Aβ) peptide and has inhibitory activity on the human prion protein PrP^Sc. We hypothesized [...] Read more.

The antihistamine astemizole has shown disease-modifying effects in several preclinical disease models of Parkinson’s disease (PD). Astemizole also interacts with an anomalous aggregation of Alzheimer’s disease-related amyloid-β (Aβ) peptide and has inhibitory activity on the human prion protein PrP^Sc. We hypothesized that the proposed preclinical benefits of astemizole on PD can be associated with the attenuation of pathological α-synuclein (α-syn) aggregation. We tested the effects of astemizole on the fibrillation processes of amyloid peptides using thioflavin T aggregation monitoring, Congo red spectral analysis, cell viability study, and transmission electron microscopic imaging. We found that astemizole did not inhibit α-syn aggregation in vitro even at a high molar ratio but inhibited the assembly of Aβ aggregates. Our results suggest that the inhibitory effect of astemizole on amyloid formation is target-protein selective, and the proposed beneficial effects of this compound observed in translational PD models might not be due to its ameliorating effects on α-syn aggregation. Full article

(This article belongs to the Special Issue Amyloid β, Tau, and α-Synuclein Aggregates in the Pathogenesis, Prognosis, and Therapeutics for Neurodegenerative Diseases)

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12 pages, 2486 KB

Open AccessEditor’s ChoiceArticle

Targeted Delivery of Abaloparatide to Spinal Fusion Site Accelerates Fusion Process in Rats

by Jeffery J. Nielsen, Stewart A. Low, Christopher Chen, Xinlan Li, Ephraim Mbachu, Lina Trigg, Siyuan Sun, Madeline Tremby, Rahul Hadap and Philip S. Low

Biomedicines 2024, 12(3), 612; https://doi.org/10.3390/biomedicines12030612 - 8 Mar 2024

Cited by 1 | Viewed by 2411

Abstract

Spinal fusions are performed to treat congenital skeletal malformations, spondylosis, degenerative disk diseases, and other pathologies of the vertebrae that can be resolved by reducing motion between neighboring vertebrae. Unfortunately, up to 100,000 fusion procedures fail per year in the United States, suggesting [...] Read more.

Spinal fusions are performed to treat congenital skeletal malformations, spondylosis, degenerative disk diseases, and other pathologies of the vertebrae that can be resolved by reducing motion between neighboring vertebrae. Unfortunately, up to 100,000 fusion procedures fail per year in the United States, suggesting that efforts to develop new approaches to improve spinal fusions are justified. We have explored whether the use of an osteotropic oligopeptide to target an attached bone anabolic agent to the fusion site might be exploited to both accelerate the mineralization process and improve the overall success rate of spinal fusions. The data presented below demonstrate that subcutaneous administration of a modified abaloparatide conjugated to 20 mer of D-glutamic acid not only localizes at the spinal fusion site but also outperforms the standard of care (topically applied BMP2) in both speed of mineralization (p < 0.05) and overall fusion success rate (p < 0.05) in a posterior lateral spinal fusion model in male and female rats, with no accompanying ectopic mineralization. Because the bone-localizing conjugate can be administered ad libitum post-surgery, and since the procedure appears to improve on standard of care, we conclude that administration of a bone-homing anabolic agent for improvement of spinal fusion surgeries warrants further exploration. Full article

(This article belongs to the Special Issue Development of Bone Anabolic Agents and Scaffolds for Improved Fracture Healing)

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15 pages, 3038 KB

Open AccessEditor’s ChoiceArticle

In Vivo Osteogenic and Angiogenic Properties of a 3D-Printed Isosorbide-Based Gyroid Scaffold Manufactured via Digital Light Processing

by Fiona Verisqa, Jeong-Hui Park, Nandin Mandakhbayar, Jae-Ryung Cha, Linh Nguyen, Hae-Won Kim and Jonathan C. Knowles

Biomedicines 2024, 12(3), 609; https://doi.org/10.3390/biomedicines12030609 - 7 Mar 2024

Cited by 7 | Viewed by 3990

Abstract

Introduction: Osteogenic and angiogenic properties of synthetic bone grafts play a crucial role in the restoration of bone defects. Angiogenesis is recognised for its support in bone regeneration, particularly in larger defects. The objective of this study is to evaluate the new bone [...] Read more.

Introduction: Osteogenic and angiogenic properties of synthetic bone grafts play a crucial role in the restoration of bone defects. Angiogenesis is recognised for its support in bone regeneration, particularly in larger defects. The objective of this study is to evaluate the new bone formation and neovascularisation of a 3D-printed isosorbide-based novel CSMA-2 polymer in biomimetic gyroid structures. Methods: The gyroid scaffolds were fabricated by 3D printing CSMA-2 polymers with different hydroxyapatite (HA) filler concentrations using the digital light processing (DLP) method. A small animal subcutaneous model and a rat calvaria critical-size defect model were performed to analyse tissue compatibility, angiogenesis, and new bone formation. Results: The in vivo results showed good biocompatibility of the 3D-printed gyroid scaffolds with no visible prolonged inflammatory reaction. Blood vessels were found to infiltrate the pores from day 7 of the implantation. New bone formation was confirmed with positive MT staining and BMP-2 expression, particularly on scaffolds with 10% HA. Bone volume was significantly higher in the CSMA-2 10HA group compared to the sham control group. Discussion and Conclusions: The results of the subcutaneous model demonstrated a favourable tissue response, including angiogenesis and fibrous tissue, indicative of the early wound healing process. The results from the critical-size defect model showcased new bone formation, as confirmed by micro-CT imaging and immunohistochemistry. The combination of CSMA-2 as the 3D printing material and the gyroid as the 3D structure was found to support essential events in bone healing, specifically angiogenesis and osteogenesis. Full article

(This article belongs to the Special Issue Trends in 3D Printing Processes for Biomedical Field: Opportunities and Challenges)

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12 pages, 2354 KB

Open AccessEditor’s ChoiceArticle

In Vitro Simulated Hemoperfusion on Seraph^®-100 as a Promising Strategy to Counteract Sepsis

by Antonio Lacquaniti, Antonella Smeriglio, Susanna Campo, Erminia La Camera, Giovanni Lanteri, Elena Giunta, Paolo Monardo and Domenico Trombetta

Biomedicines 2024, 12(3), 575; https://doi.org/10.3390/biomedicines12030575 - 5 Mar 2024

Cited by 8 | Viewed by 3920

Abstract

Blood purification represents a treatment option for sepsis, improving inflammation and the hyper-activated immune system. This study investigates the binding efficacy of Seraph^®-100 against 10⁸ CFU/mL of Staphylococcus aureus (S. aureus), Pseudomonas aeruginosa (P. aeruginosa), and [...] Read more.

Blood purification represents a treatment option for sepsis, improving inflammation and the hyper-activated immune system. This study investigates the binding efficacy of Seraph^®-100 against 10⁸ CFU/mL of Staphylococcus aureus (S. aureus), Pseudomonas aeruginosa (P. aeruginosa), and Escherichia coli (E. coli) during a simulated hemoperfusion treatment. The fluorescence-activated cell sorting (FACS) technique was used to evaluate the bacteria reduction, whereas kinetic analysis and cultures revealed bacterial detection and counting at established time points. At the end of the experiment, the filter was cut at three different levels, obtaining suspensions for cultures and scanning electron microscopy (SEM) analyses. The FACS technique revealed a 78.77% reduction of the total bacterial load at the end of the treatment, with maximum filter sequestration occurring in the first 30 min of the treatment. Non-linear regression analysis of kinetic experiments (T_{0–240 min}) highlighted a lower growth rate of S. aureus than the other two Gram bacteria, demonstrating a greater affinity without influencing a reduction rate of 99% for all three bacteria. The analyses of the suspension aliquots of the filter sections confirmed these data, revealing 1 × 10⁸ CFU/mL, equal to the initial bacterial charge. Furthermore, the filter head adsorbed approximately 50% of bacteria, whereas the remaining amount was equally distributed between the body and the tail, as corroborated by SEM analysis. In conclusion, Seraph^®-100 adsorbed 10⁸ CFU/mL of S. aureus, E. coli, and P. aeruginosa during an in vitro simulated hemoperfusion session. Full article

(This article belongs to the Special Issue Molecular Biomarkers and More Efficient Therapies for Sepsis)

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13 pages, 1859 KB

Open AccessEditor’s ChoiceArticle

Fibroblast Activation Protein (FAP)-Mediated Cleavage of Type III Collagen Reveals Serum Biomarker Potential in Non-Small Cell Lung Cancer and Spondyloarthritis

by Rasmus S. Pedersen, Jeppe Thorlacius-Ussing, Maria G. Raimondo, Lasse L. Langholm, Georg Schett, Andreas Ramming, Morten Karsdal and Nicholas Willumsen

Biomedicines 2024, 12(3), 545; https://doi.org/10.3390/biomedicines12030545 - 29 Feb 2024

Cited by 2 | Viewed by 3941

Abstract

Fibroblast activation protein (FAP) is a known promoter of tumor development and is associated with poor clinical outcome for various cancer types. Being specifically expressed in pathological conditions including multiple types of fibrosis and cancers, FAP is an optimal target for diagnostics and [...] Read more.

Fibroblast activation protein (FAP) is a known promoter of tumor development and is associated with poor clinical outcome for various cancer types. Being specifically expressed in pathological conditions including multiple types of fibrosis and cancers, FAP is an optimal target for diagnostics and treatment. Treatment strategies utilizing the unique proteolytic activity of FAP are emerging, thus emphasizing the importance of biomarkers to directly assess FAP activity. FAP is a type II transmembrane serine protease that has been shown to cleave collagens and other ECM components. In this study, we developed an ELISA assay (C3F) targeting a circulating type III collagen fragment derived from FAP cleavage to reflect FAP activity. We demonstrated that C3F was specific to the neoepitope of the cleavage site and that the fragment was generated through FAP cleavage of type III collagen. We measured C3F in serum from a cohort of patients with non-small cell lung cancer (NSCLC) (n = 109) matched to healthy subjects (n = 42) and a cohort of patients with spondyloarthritis (SpA) (n = 17) matched to healthy subjects (n = 19). We found that C3F was significantly elevated in patients with NSCLC and in patients with SpA compared to healthy controls (p < 0.0001 and p = 0.0015, respectively). These findings suggest that C3F is a promising non-invasive biomarker reflecting FAP activity, which may aid in understanding tumor heterogeneity and potentially FAP-targeted therapies. Full article

(This article belongs to the Topic Biomarker Development and Application)

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13 pages, 3343 KB

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Antiadhesive Hyaluronic Acid-Based Wound Dressings Promote Wound Healing by Preventing Re-Injury: An In Vivo Investigation

by Da Som Kim, Keum-Yong Seong, Hyeseon Lee, Min Jae Kim, Sung-Min An, Jea Sic Jeong, So Young Kim, Hyeon-Gu Kang, Sangsoo Jang, Dae-Youn Hwang, Sung-Baek Seo, Seong-Min Jo, Seung Yun Yang and Beum-Soo An

Biomedicines 2024, 12(3), 510; https://doi.org/10.3390/biomedicines12030510 - 23 Feb 2024

Cited by 5 | Viewed by 4080

Abstract

Wound dressings are widely used to protect wounds and promote healing. The water absorption and antifriction properties of dressings are important for regulating the moisture balance and reducing secondary damages during dressing changes. Herein, we developed a hyaluronic acid (HA)-based foam dressing prepared [...] Read more.

Wound dressings are widely used to protect wounds and promote healing. The water absorption and antifriction properties of dressings are important for regulating the moisture balance and reducing secondary damages during dressing changes. Herein, we developed a hyaluronic acid (HA)-based foam dressing prepared via the lyophilization of photocrosslinked HA hydrogels with high water absorption and antiadhesion properties. To fabricate the HA-based foam dressing (HA foam), the hydroxyl groups of the HA were modified with methacrylate groups, enabling rapid photocuring. The resulting photocured HA solution was freeze-dried to form a porous structure, enhancing its exudate absorption capacity. Compared with conventional biopolymer-based foam dressings, this HA foam exhibited superior water absorption and antifriction properties. To assess the wound-healing potential of HA foam, animal experiments involving SD rats were conducted. Full-thickness defects measuring 2 × 2 cm² were created on the skin of 36 rats, divided into four groups with 9 individuals each. The groups were treated with gauze, HA foam, CollaDerm^®, and CollaHeal^® Plus, respectively. The rats were closely monitored for a period of 24 days. In vivo testing demonstrated that the HA foam facilitated wound healing without causing inflammatory reactions and minimized secondary damages during dressing changes. This research presents a promising biocompatible foam wound dressing based on modified HA, which offers enhanced wound-healing capabilities and improved patient comfort and addresses the challenges associated with conventional dressings. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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22 pages, 7667 KB

Open AccessEditor’s ChoiceArticle

Can Combining Hyaluronic Acid and Physiotherapy in Knee Osteoarthritis Improve the Physicochemical Properties of Synovial Fluid?

by Ilie Onu, Robert Gherghel, Isabella Nacu, Florina-Daniela Cojocaru, Liliana Verestiuc, Daniela-Viorelia Matei, Dan Cascaval, Ionela Lacramioara Serban, Daniel Andrei Iordan, Alexandra Tucaliuc and Anca-Irina Galaction

Biomedicines 2024, 12(2), 449; https://doi.org/10.3390/biomedicines12020449 - 17 Feb 2024

Cited by 9 | Viewed by 7267

Abstract

Known as the degenerative disease of the knee with the highest prevalence, knee osteoarthritis (KOA) is characterized by a gradual destructive mechanism that, in severe cases, can provoke the need for total knee substitution. As the disease progresses, various enzymatic, immunological, and inflammatory [...] Read more.

Known as the degenerative disease of the knee with the highest prevalence, knee osteoarthritis (KOA) is characterized by a gradual destructive mechanism that, in severe cases, can provoke the need for total knee substitution. As the disease progresses, various enzymatic, immunological, and inflammatory processes abnormally degrade hyaluronic acid (HA), SF’s main component, and affect the concentrations of specific proteins, with the final results seriously endangering synovial fluid (SF)’s rheological and tribological features and characteristics. No effective treatments have been found to stop the progression of KOA, but the injection of HA-based viscoelastic gels has been considered (alone or combined with physiotherapy (PT)) as an alternative to symptomatic therapies. In order to evaluate the effect of viscosupplementation and PT on the characteristics of SF, SF aspirated from groups treated for KOA (HA Kombihylan^® and groups that received Kombihylan^® and complex PT) was analyzed and compared from analytical, spectrophotometrical, and rheological perspectives. In the patients treated with PT, the SF extracted 6 weeks after viscosupplementation had a superior elastic modulus (G′) and viscous moduli (G″), as well as a homogeneous distribution of proteins and polysaccharides. The viscosupplementation fluid improved the bioadhesive properties of the SF, and the use of the viscosupplementation fluid in conjunction with PT was found to be favorable for the distribution of macromolecules and phospholipids, contributing to the lubrication process and the treatment of OA-affected joints. Full article

(This article belongs to the Special Issue Osteoarthritis and Associated Pain: Molecular Research and Novel Therapeutic Approaches)

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17 pages, 3129 KB

Open AccessEditor’s ChoiceArticle

Exploring Cardiac Exosomal RNAs of Acute Myocardial Infarction

by Seung Eun Jung, Sang Woo Kim and Jung-Won Choi

Biomedicines 2024, 12(2), 430; https://doi.org/10.3390/biomedicines12020430 - 14 Feb 2024

Cited by 5 | Viewed by 4717

Abstract

Background: Myocardial infarction (MI), often a frequent symptom of coronary artery disease (CAD), is a leading cause of death and disability worldwide. Acute myocardial infarction (AMI), a major form of cardiovascular disease, necessitates a deep understanding of its complex pathophysiology to develop innovative [...] Read more.

Background: Myocardial infarction (MI), often a frequent symptom of coronary artery disease (CAD), is a leading cause of death and disability worldwide. Acute myocardial infarction (AMI), a major form of cardiovascular disease, necessitates a deep understanding of its complex pathophysiology to develop innovative therapeutic strategies. Exosomal RNAs (exoRNA), particularly microRNAs (miRNAs) within cardiac tissues, play a critical role in intercellular communication and pathophysiological processes of AMI. Methods: This study aimed to delineate the exoRNA landscape, focusing especially on miRNAs in animal models using high-throughput sequencing. The approach included sequencing analysis to identify significant miRNAs in AMI, followed by validation of the functions of selected miRNAs through in vitro studies involving primary cardiomyocytes and fibroblasts. Results: Numerous differentially expressed miRNAs in AMI were identified using five mice per group. The functions of 20 selected miRNAs were validated through in vitro studies with primary cardiomyocytes and fibroblasts. Conclusions: This research enhances understanding of post-AMI molecular changes in cardiac tissues and investigates the potential of exoRNAs as biomarkers or therapeutic targets. These findings offer new insights into the molecular mechanisms of AMIs, paving the way for RNA-based diagnostics and therapeutics and therapies and contributing to the advancement of cardiovascular medicine. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions 2.0)

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16 pages, 1982 KB

Open AccessEditor’s ChoiceArticle

Natural Killer Cells as a Further Insight into the Course of Chronic Obstructive Pulmonary Disease

by Beata Brajer-Luftmann, Tomasz Trafas, Marta Stelmach-Mardas, Weronika Bendowska, Tomasz Piorunek, Marcin Grabicki and Mariusz Kaczmarek

Biomedicines 2024, 12(2), 419; https://doi.org/10.3390/biomedicines12020419 - 11 Feb 2024

Cited by 3 | Viewed by 2298

Abstract

The role of natural killer (NK) cells in chronic obstructive pulmonary disease (COPD) pathogenesis has been discussed but is not yet clearly understood. This current study aimed to evaluate the associations between immunophenotypes, degrees of maturity, and the expression level of functional receptors [...] Read more.

The role of natural killer (NK) cells in chronic obstructive pulmonary disease (COPD) pathogenesis has been discussed but is not yet clearly understood. This current study aimed to evaluate the associations between immunophenotypes, degrees of maturity, and the expression level of functional receptors of NK cells in the lung environment present in bronchoalveolar lavage fluid (BALF), and an attempt was made to determine their relationship in the course and progression of COPD. A total of 15 COPD patients and 14 healthy smokers were included. The clinical parameters of COPD were evaluated. In both groups, NK cells using monoclonal antibodies directly conjugated with fluorochromes in flow cytometry were assessed in the peripheral blood. Additionally, NK cells using the same method were assessed in BALF in the COPD subgroup. The blood’s NK cells differed from the estimated group’s maturity and receptor expression. Functional receptors CD158b+, CD314+, and CD336+ expressed by NK cells were significantly interlinked with age, RV, TLC, 6MWT, smoking, and the number of exacerbations. These results confirm the essential role of NK cells in COPD pathogenesis. Additionally, the relationship between clinical parameters and NK cell expression may indicate its participation in the disease progression and exacerbation and allow for a better understanding of NK cell biology in COPD. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular and Translational Medicine in Poland: Volume II)

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11 pages, 1391 KB

Open AccessEditor’s ChoiceArticle

Dupilumab Efficacy on Asthma Functional, Inflammatory, and Patient-Reported Outcomes across Different Disease Phenotypes and Severity: A Real-Life Perspective

by Marco Caminati, Matteo Maule, Roberto Benoni, Diego Bagnasco, Bianca Beghè, Fulvio Braido, Luisa Brussino, Paolo Cameli, Maria Giulia Candeliere, Giovanna Elisiana Carpagnano, Giulia Costanzo, Claudia Crimi, Mariella D’Amato, Stefano Del Giacco, Gabriella Guarnieri, Mona-Rita Yacoub, Claudio Micheletto, Stefania Nicola, Bianca Olivieri, Laura Pini, Michele Schiappoli, Rachele Vaia, Andrea Vianello, Dina Visca, Antonio Spanevello and Gianenrico Senna Show full author list Hide full author list

Biomedicines 2024, 12(2), 390; https://doi.org/10.3390/biomedicines12020390 - 8 Feb 2024

Cited by 9 | Viewed by 4657

Abstract

Dupilumab is currently approved for the treatment of Type 2 severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). Few studies have specifically reported on dupilumab efficacy on asthma outcomes as a primary objective in a real-life setting, in patients with and without [...] Read more.

Dupilumab is currently approved for the treatment of Type 2 severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). Few studies have specifically reported on dupilumab efficacy on asthma outcomes as a primary objective in a real-life setting, in patients with and without CRSwNP. Our study aimed to explore the efficacy of dupilumab on functional, inflammatory, and patient-reported outcomes in asthma patients across different disease phenotypes and severity, including mild-to-moderate asthma coexisting with CRSwNP. Data from 3, 6, and 12 months follow-up were analyzed. Asthma (FEV1%, Tiffeneau%, ACT, FeNO, oral steroid use, exacerbation rate, and blood eosinophilia) and polyposis (SNOT22, VAS, NPS) outcomes showed a rapid (3 months) and sustained (6 and 12 months) significant change from baseline, despite most of the patients achieving oral steroid withdrawal. According to the sensitivity analysis, the improvement was not conditioned by either the presence of polyposis or severity of asthma at baseline. Of note, even in the case of milder asthma forms, a significant further improvement was recorded during dupilumab treatment course. Our report provides short-, medium-, and long-term follow-up data on asthma outcomes across different diseases phenotypes and severity, contributing to the real-world evidence related to dupilumab efficacy on upper and lower airways T2 inflammation. Full article

(This article belongs to the Special Issue Allergic Diseases and Asthma: Molecular Diagnosis and Precision Medicine)

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13 pages, 1247 KB

Open AccessEditor’s ChoiceArticle

Intermediate Repeat Expansion in the ATXN2 Gene as a Risk Factor in the ALS and FTD Spanish Population

by Daniel Borrego-Hernández, Juan Francisco Vázquez-Costa, Raúl Domínguez-Rubio, Laura Expósito-Blázquez, Elena Aller, Ariadna Padró-Miquel, Pilar García-Casanova, María J. Colomina, Cristina Martín-Arriscado, Rosario Osta, Pilar Cordero-Vázquez, Jesús Esteban-Pérez, Mónica Povedano-Panadés and Alberto García-Redondo

Biomedicines 2024, 12(2), 356; https://doi.org/10.3390/biomedicines12020356 - 2 Feb 2024

Cited by 7 | Viewed by 3005

Abstract

Intermediate CAG expansions in the gene ataxin-2 (ATXN2) are a known risk factor for ALS, but little is known about their role in FTD risk. Moreover, their contribution to the risk and phenotype of patients might vary in populations with different [...] Read more.

Intermediate CAG expansions in the gene ataxin-2 (ATXN2) are a known risk factor for ALS, but little is known about their role in FTD risk. Moreover, their contribution to the risk and phenotype of patients might vary in populations with different genetic backgrounds. The aim of this study was to assess the relationship of intermediate CAG expansions in ATXN2 with the risk and phenotype of ALS and FTD in the Spanish population. Repeat-primed PCR was performed in 620 ALS and 137 FTD patients in three referral centers in Spain to determine the exact number of CAG repeats. In our cohort, ≥27 CAG repeats in ATXN2 were associated with a higher risk of developing ALS (odds ratio [OR] = 2.666 [1.471–4.882]; p = 0.0013) but not FTD (odds ratio [OR] = 1.446 [0.558–3.574]; p = 0.44). Moreover, ALS patients with ≥27 CAG repeats in ATXN2 showed a shorter survival rate compared to those with <27 repeats (hazard ratio [HR] 1.74 [1.18, 2.56], p = 0.005), more frequent limb onset (odds ratio [OR] = 2.34 [1.093–4.936]; p = 0.028) and a family history of ALS (odds ratio [OR] = 2.538 [1.375–4.634]; p = 0.002). Intermediate CAG expansions of ≥27 repeats in ATXN2 are associated with ALS risk but not with FTD in the Spanish population. ALS patients carrying an intermediate expansion in ATXN2 show more frequent limb onset but a worse prognosis than those without expansions. In patients carrying C9orf72 expansions, the intermediate ATXN2 expansion might increase the penetrance and modify the phenotype. Full article

(This article belongs to the Special Issue Mechanisms Leading to Neurodegeneration in the ALS and FTD Spectrum)

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14 pages, 588 KB

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Placental mRNA Expression of Neurokinin B Is Increased in PCOS Pregnancies with Female Offspring

by Georgios K. Markantes, Evangelia Panagodimou, Vasiliki Koika, Irene Mamali, Apostolos Kaponis, George Adonakis and Neoklis A. Georgopoulos

Biomedicines 2024, 12(2), 334; https://doi.org/10.3390/biomedicines12020334 - 1 Feb 2024

Viewed by 1998

Abstract

Current research suggests that polycystic ovary syndrome (PCOS) might originate in utero and implicates the placenta in its pathogenesis. Kisspeptin (KISS1) and neurokinin B (NKB) are produced by the placenta in high amounts, and they have been implicated in several pregnancy complications associated [...] Read more.

Current research suggests that polycystic ovary syndrome (PCOS) might originate in utero and implicates the placenta in its pathogenesis. Kisspeptin (KISS1) and neurokinin B (NKB) are produced by the placenta in high amounts, and they have been implicated in several pregnancy complications associated with placental dysfunction. However, their placental expression has not been studied in PCOS. We isolated mRNA after delivery from the placentae of 31 PCOS and 37 control women with term, uncomplicated, singleton pregnancies. The expression of KISS1, NKB, and neurokinin receptors 1, 2, and 3 was analyzed with real-time polymerase chain reaction, using β-actin as the reference gene. Maternal serum and umbilical cord levels of total testosterone, sex hormone-binding globulin (SHBG), free androgen index (FAI), androstenedione, dehydroepiandrosterone sulfate (DHEAS), Anti-Mullerian hormone (AMH), and estradiol were also assessed. NKB placental mRNA expression was higher in PCOS women versus controls in pregnancies with female offspring. NKB expression depended on fetal gender, being higher in pregnancies with male fetuses, regardless of PCOS. NKB was positively correlated with umbilical cord FAI and AMH, and KISS1 was positively correlated with cord testosterone and FAI; there was also a strong positive correlation between NKB and KISS1 expression. Women with PCOS had higher serum AMH and FAI and lower SHBG than controls. Our findings indicate that NKB might be involved in the PCOS-related placental dysfunction and warrant further investigation. Studies assessing the placental expression of NKB should take fetal gender into consideration. Full article

(This article belongs to the Special Issue Molecular Research on Polycystic Ovary Syndrome (PCOS) 2.0)

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17 pages, 1780 KB

Open AccessEditor’s ChoiceArticle

Structural Progression in Patients with Definite and Non-Definite Arrhythmogenic Right Ventricular Cardiomyopathy and Risk of Major Adverse Cardiac Events

by Areej Aljehani, Shanat Baig, Tania Kew, Manish Kalla, Laura C. Sommerfeld, Vaishnavi Ameya Murukutla, Larissa Fabritz and Richard P. Steeds

Biomedicines 2024, 12(2), 328; https://doi.org/10.3390/biomedicines12020328 - 31 Jan 2024

Cited by 2 | Viewed by 2414

Abstract

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare inherited disease characterised by early arrhythmias and structural changes. Still, there are limited echocardiography data on its structural progression. We studied structural progression and its impact on the occurrence of major adverse cardiovascular events (MACE). [...] Read more.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare inherited disease characterised by early arrhythmias and structural changes. Still, there are limited echocardiography data on its structural progression. We studied structural progression and its impact on the occurrence of major adverse cardiovascular events (MACE). In this single-centre observational cohort study, structural progression was defined as the development of new major or minor imaging 2010 Task Force Criteria during follow-up. Of 101 patients, a definite diagnosis of ARVC was made in 51 patients, while non-definite ‘early’ disease was diagnosed in 50 patients. During 4 years of follow-up (IQR: 2–6), 23 (45%) patients with a definite diagnosis developed structural progression while only 1 patient in the non-definite (early) group gained minor imaging Task Force Criteria. Male gender was strongly associated with structural progression (62% of males progressed structurally, while 88% of females remained stable). Patients with structural progression were at higher risk of MACE (64% of patients with MACE had structural progression). Therefore, the rate of structural progression is an essential factor to be considered in ARVC studies. Full article

(This article belongs to the Special Issue Advanced Research in Arrhythmogenic Cardiomyopathy)

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14 pages, 854 KB

Open AccessEditor’s ChoiceArticle

Short- and Long-Term Outcomes of Patients with Postoperative Arrhythmia after Liver Surgery

by Felix Rühlmann, Deborah Engelhardt, Alma Franziska Mackert, Mara Sophie Hedicke, Tobias Tichelbäcker, Andreas Leha, Markus Bernhardt, Michael Ghadimi, Thorsten Perl, Azadeh Azizian and Jochen Gaedcke

Biomedicines 2024, 12(2), 271; https://doi.org/10.3390/biomedicines12020271 - 25 Jan 2024

Viewed by 1517

Abstract

Background: New-onset postoperative arrhythmia (PA) has previously been described as a pivotal risk factor for postoperative morbidity and mortality after visceral surgery. However, there is a lack of data concerning liver surgery. The incidence and impact of new-onset postoperative arrhythmia after liver surgery [...] Read more.

Background: New-onset postoperative arrhythmia (PA) has previously been described as a pivotal risk factor for postoperative morbidity and mortality after visceral surgery. However, there is a lack of data concerning liver surgery. The incidence and impact of new-onset postoperative arrhythmia after liver surgery was, therefore, analyzed in a monocentric study. Methods: In total, n = 460 patients (221 female, 239 male) who underwent liver surgery between January 2012 and April 2020 without any prior arrhythmia in their medical history were included in this retrospective analysis. Clinical monitoring started with the induction of anesthesia and was terminated with discharge from the intensive care unit (ICU) or intermediate care unit (IMC). Follow-up included documentation of complications during the hospital stay, as well as long-term survival analysis. Results: Postoperative arrhythmia after liver surgery was observed in 25 patients, corresponding to an incidence of 5.4%. The occurrence of arrhythmia was significantly associated with intraoperative complications (p < 0.05), liver fibrosis/cirrhosis (p < 0.05), bile fistula/bile leakage/bilioma (p < 0.05), and organ failure (p < 0.01). Survival analysis showed a significantly poorer overall survival of patients who developed postoperative arrhythmia after liver surgery (p < 0.001). Conclusions: New-onset postoperative arrhythmia after liver surgery has an incidence of only 5.4% but is significantly associated with higher postoperative morbidity and poorer overall survival. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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15 pages, 3879 KB

Open AccessEditor’s ChoiceArticle

Differential Expression of NOTCH-1 and Its Molecular Targets in Response to Metronomic Followed by Conventional Therapy in a Patient with Advanced Triple-Negative Breast Cancer

by Alice Ilari, Viola Cogliati, Noorhan Sherif, Emanuela Grassilli, Daniele Ramazzotti, Nicoletta Cordani, Giorgio Cazzaniga, Camillo Di Bella, Marialuisa Lavitrano, Marina Elena Cazzaniga and Maria Grazia Cerrito

Biomedicines 2024, 12(2), 272; https://doi.org/10.3390/biomedicines12020272 - 25 Jan 2024

Cited by 3 | Viewed by 2112

Abstract

A group of 27 patients diagnosed with metastatic triple-negative breast cancer (mTNBC) was randomly distributed into two groups and underwent different lines of metronomic treatment (mCHT). The former group (N 14) received first-line mCHT and showed a higher overall survival rate than the [...] Read more.

A group of 27 patients diagnosed with metastatic triple-negative breast cancer (mTNBC) was randomly distributed into two groups and underwent different lines of metronomic treatment (mCHT). The former group (N 14) received first-line mCHT and showed a higher overall survival rate than the second group (N 13), which underwent second-line mCHT. Analysis of one patient still alive from the first group, diagnosed with mTNBC in 2019, showed a complete metabolic response (CMR) after a composite approach implicating first-line mCHT followed by second-line epirubicin and third-line nab-paclitaxel, and was chosen for subsequent molecular characterization. We found altered expression in the cancer stemness-associated gene NOTCH-1 and its corresponding protein. Additionally, we found changes in the expression of oncogenes, such as MYC and AKT, along with their respective proteins. Overall, our data suggest that a first-line treatment with mCHT followed by MTD might be effective by negatively regulating stemness traits usually associated with the emergence of drug resistance. Full article

(This article belongs to the Special Issue Molecular Research of Triple-Negative Breast Cancer)

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14 pages, 5975 KB

Open AccessEditor’s ChoiceArticle

A Platform for Testing the Biocompatibility of Implants: Silicone Induces a Proinflammatory Response in a 3D Skin Equivalent

by Rima Nuwayhid, Torsten Schulz, Frank Siemers, Jeannine Schreiter, Philipp Kobbe, Gunther Hofmann, Stefan Langer and Olga Kurow

Biomedicines 2024, 12(1), 224; https://doi.org/10.3390/biomedicines12010224 - 19 Jan 2024

Cited by 5 | Viewed by 3272

Abstract

Biocompatibility testing of materials is carried out in 2D cell cultures or animal models despite serious limitations. 3D skin equivalents are advanced in vitro models for human skin. Silicone has been shown to be noncytotoxic but capable of eliciting an immune response. Our [...] Read more.

Biocompatibility testing of materials is carried out in 2D cell cultures or animal models despite serious limitations. 3D skin equivalents are advanced in vitro models for human skin. Silicone has been shown to be noncytotoxic but capable of eliciting an immune response. Our aim was to (1) establish a 3D skin equivalent to (2) assess the proinflammatory properties of silicone. We developed a coculture of keratinocytes and fibroblasts resulting in a 3D skin equivalent with an implant using samples from a breast implant. Samples with and without the silicone implant were studied histologically and immunohistochemically in comparison to native human skin samples. Cytotoxicity was assessed via LDH-assay, and cytokine response was assessed via ELISA. Histologically, our 3D skin equivalents had a four-layered epidermal and a dermal component. The presence of tight junctions was demonstrated in immunofluorescence. The only difference in 3D skin equivalents with implants was an epidermal thinning. Implanting the silicone samples did not cause more cell death, however, an inflammatory cytokine response was triggered. We were able to establish an organotypical 3D skin equivalent with an implant, which can be utilised for studies on biocompatibility of materials. This first integration of silicone into a 3D skin equivalent confirmed previous findings on silicone being non-cell-toxic but capable of exerting a proinflammatory effect. Full article

(This article belongs to the Special Issue Applications of 3D Cell Culture in Biomedicines)

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16 pages, 2832 KB

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Upregulation of Anti-Angiogenic miR-106b-3p Correlates Negatively with IGF-1 and Vascular Health Parameters in a Model of Subclinical Cardiovascular Disease: Study with Metformin Therapy

by Sherin Bakhashab, Josie O’Neill, Rosie Barber, Catherine Arden and Jolanta U. Weaver

Biomedicines 2024, 12(1), 171; https://doi.org/10.3390/biomedicines12010171 - 12 Jan 2024

Cited by 4 | Viewed by 1832

Abstract

Well-controlled type 1 diabetes mellitus (T1DM) is regarded as a model of subclinical cardiovascular disease (CVD), characterized by inflammation and adverse vascular health. However, the underlying mechanisms are not fully understood. We investigated insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) levels, their [...] Read more.

Well-controlled type 1 diabetes mellitus (T1DM) is regarded as a model of subclinical cardiovascular disease (CVD), characterized by inflammation and adverse vascular health. However, the underlying mechanisms are not fully understood. We investigated insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) levels, their correlation to miR-106b-3p expression in a subclinical CVD model, and the cardioprotective effect of metformin. A total of 20 controls and 29 well-controlled T1DM subjects were studied. Plasma IGF-1, IGFBP-3 levels, and miR-106b-3p expression in colony-forming unit-Hills were analyzed and compared with vascular markers. miR-106b-3p was upregulated in T1DM (p < 0.05) and negatively correlated with pro-angiogenic markers CD34+/100-lymphocytes (p < 0.05) and IGF-1 (p < 0.05). IGF-1 was downregulated in T1DM (p < 0.01), which was associated with increased inflammatory markers TNF-α, CRP, and IL-10 and reduced CD34+/100-lymphocytes. IGFBP-3 had no significant results. Metformin had no effect on IGF-1 but significantly reduced miR-106b-3p (p < 0.0001). An Ingenuity Pathway analysis predicted miR-106b-3p to inhibit PDGFA, PIK3CG, GDNF, and ADAMTS13, which activated CVD. Metformin was predicted to be cardioprotective by inhibiting miR-106b-3p. In conclusion: Subclinical CVD is characterized by a cardio-adverse profile of low IGF-1 and upregulated miR-106b-3p. We demonstrated that the cardioprotective effect of metformin may be via downregulation of upregulated miR-106b-3p and its effect on downstream targets. Full article

(This article belongs to the Special Issue Adult Stem Cells and Endothelial Progenitor Cells in Diseases)

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12 pages, 1229 KB

Open AccessEditor’s ChoiceArticle

TAS2R38 Bitter Taste Receptor Polymorphisms in Patients with Chronic Rhinosinusitis with Nasal Polyps Preliminary Data in Polish Population

by Joanna Jeruzal-Świątecka, Edyta Marta Borkowska, Martyna Borkowska and Wioletta Pietruszewska

Biomedicines 2024, 12(1), 168; https://doi.org/10.3390/biomedicines12010168 - 12 Jan 2024

Cited by 6 | Viewed by 4746

Abstract

Chronic rhinosinusitis (CRS) affects 5–12% of the general population, and the most challenging patients are those with nasal polyposis (CRSwNP). Its complexity, unpredictability, and difficulties in selecting a treatment plan individually for each patient prompted scientists to look for possible genetic causes of [...] Read more.

Chronic rhinosinusitis (CRS) affects 5–12% of the general population, and the most challenging patients are those with nasal polyposis (CRSwNP). Its complexity, unpredictability, and difficulties in selecting a treatment plan individually for each patient prompted scientists to look for possible genetic causes of this disease. It was proven that single nucleotide polymorphisms (SNPs) in the TAS2R38 gene may affect the mobility and the activity of the ciliated epithelium of the upper respiratory tract what can contribute to individual differences in susceptibility to CRS. There are two common haplotypes: a “protective” type (PAV), and a “non-protective” type (AVI). CRS patients who are homozygous PAV/PAV are considered as less susceptible to the severe course of the disease, whereas patients with AVI/AVI haplotype are more vulnerable. The aim of this study was to examine TAS2R38 gene polymorphisms among CRSwNP patients and control group (N = 544) with the evaluation of the association between the distribution of studied polymorphic variants and the incidence as well as severity of CRSwNP in the study group. Whole blood samples from CRSwNP patients (N = 106) and the control group (N = 438) were analyzed for alleles of the TAS2R38 gene using real-time PCR single nucleotide polymorphism genotyping assays for rs713598, rs1726866, and rs10246939. PAV (SG: 41%; CG: 49%) and AVI (SG: 59%; CG: 51%) haplotypes were the only ones detected in the study. The AVI haplotypes were 1.5 times more frequent in the study group than in the control group (p = 0.0204; OR = 1.43). AVI/AVI individuals tended to have more severe symptoms in the VAS scale, less QoL in the SNOT-22 test, and a bigger nasal obstruction upon endoscopic examination. Patients with PAV/PAV were twice more likely to have minor changes in preoperative CT scans (p = 0.0158; OR = 2.1; Fi = 0.24). Our study confirmed that the PAV/PAV diplotype might have some protective properties and carrying the AVI haplotype might predispose to the development of CRSwNP. Full article

(This article belongs to the Special Issue Recent Advances in Chronic Rhinosinusitis and Asthma)

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20 pages, 4692 KB

Open AccessEditor’s ChoiceArticle

Mice Generated with Induced Pluripotent Stem Cells Derived from Mucosal-Associated Invariant T Cells

by Chie Sugimoto, Hiroyoshi Fujita and Hiroshi Wakao

Biomedicines 2024, 12(1), 137; https://doi.org/10.3390/biomedicines12010137 - 9 Jan 2024

Cited by 4 | Viewed by 2214

Abstract

The function of mucosal-associated invariant T (MAIT) cells, a burgeoning member of innate-like T cells abundant in humans and implicated in many diseases, remains obscure. To explore this, mice with a rearranged T cell receptor (TCR) α or β locus, specific for MAIT [...] Read more.

The function of mucosal-associated invariant T (MAIT) cells, a burgeoning member of innate-like T cells abundant in humans and implicated in many diseases, remains obscure. To explore this, mice with a rearranged T cell receptor (TCR) α or β locus, specific for MAIT cells, were generated via induced pluripotent stem cells derived from MAIT cells and were designated Vα19 and Vβ8 mice, respectively. Both groups of mice expressed large numbers of MAIT cells. The MAIT cells from these mice were activated by cytokines and an agonist to produce IFN-γ and IL-17. While Vβ8 mice showed resistance in a cancer metastasis model, Vα19 mice did not. Adoptive transfer of MAIT cells from the latter into the control mice, however, recapitulated the resistance. These mice present an implication for understanding the role of MAIT cells in health and disease and in developing treatments for the plethora of diseases in which MAIT cells are implicated. Full article

(This article belongs to the Special Issue Roles of T Cells in Immunotherapy)

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25 pages, 4204 KB

Open AccessEditor’s ChoiceArticle

Chemokine Receptor Antagonists Prevent and Reverse Cofilin-Actin Rod Pathology and Protect Synapses in Cultured Rodent and Human iPSC-Derived Neurons

by Thomas B. Kuhn, Laurie S. Minamide, Lubna H. Tahtamouni, Sydney A. Alderfer, Keifer P. Walsh, Alisa E. Shaw, Omar Yanouri, Henry J. Haigler, Michael R. Ruff and James R. Bamburg

Biomedicines 2024, 12(1), 93; https://doi.org/10.3390/biomedicines12010093 - 1 Jan 2024

Cited by 2 | Viewed by 4453

Abstract

Synapse loss is the principal cause of cognitive decline in Alzheimer’s disease (AD) and related disorders (ADRD). Synapse development depends on the intricate dynamics of the neuronal cytoskeleton. Cofilin, the major protein regulating actin dynamics, can be sequestered into cofilactin rods, intra-neurite bundles [...] Read more.

Synapse loss is the principal cause of cognitive decline in Alzheimer’s disease (AD) and related disorders (ADRD). Synapse development depends on the intricate dynamics of the neuronal cytoskeleton. Cofilin, the major protein regulating actin dynamics, can be sequestered into cofilactin rods, intra-neurite bundles of cofilin-saturated actin filaments that can disrupt vesicular trafficking and cause synaptic loss. Rods are a brain pathology in human AD and mouse models of AD and ADRD. Eliminating rods is the focus of this paper. One pathway for rod formation is triggered in ~20% of rodent hippocampal neurons by disease-related factors (e.g., soluble oligomers of Amyloid-β (Aβ)) and requires cellular prion protein (PrP^C), active NADPH oxidase (NOX), and cytokine/chemokine receptors (CCRs). FDA-approved antagonists of CXCR4 and CCR5 inhibit Aβ-induced rods in both rodent and human neurons with effective concentrations for 50% rod reduction (EC₅₀) of 1–10 nM. Remarkably, two D-amino acid receptor-active peptides (RAP-103 and RAP-310) inhibit Aβ-induced rods with an EC₅₀ of ~1 pM in mouse neurons and ~0.1 pM in human neurons. These peptides are analogs of D-Ala-Peptide T-Amide (DAPTA) and share a pentapeptide sequence (TTNYT) antagonistic to several CCR-dependent responses. RAP-103 does not inhibit neuritogenesis or outgrowth even at 1 µM, >10⁶-fold above its EC₅₀. N-terminal methylation, or D-Thr to D-Ser substitution, decreases the rod-inhibiting potency of RAP-103 by 10³-fold, suggesting high target specificity. Neither RAP peptide inhibits neuronal rod formation induced by excitotoxic glutamate, but both inhibit rods induced in human neurons by several PrP^C/NOX pathway activators (Aβ, HIV-gp120 protein, and IL-6). Significantly, RAP-103 completely protects against Aβ-induced loss of mature and developing synapses and, at 0.1 nM, reverses rods in both rodent and human neurons (T_½ ~ 3 h) even in the continuous presence of Aβ. Thus, this orally available, brain-permeable peptide should be highly effective in reducing rod pathology in multifactorial neurological diseases with mixed proteinopathies acting through PrP^C/NOX. Full article

(This article belongs to the Special Issue New Perspectives on Neuronal Cytoskeletal Dysregulation in Health and Disease)

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21 pages, 6168 KB

Open AccessEditor’s ChoiceArticle

Cell-Free Genic Extrachromosomal Circular DNA Profiles of DNase Knockouts Associated with Systemic Lupus Erythematosus and Relation with Common Fragile Sites

by Daniela Gerovska, Patricia Fernández Moreno, Aitor Zabala and Marcos J. Araúzo-Bravo

Biomedicines 2024, 12(1), 80; https://doi.org/10.3390/biomedicines12010080 - 28 Dec 2023

Cited by 2 | Viewed by 2812

Abstract

Cell-free extrachromosomal circular DNA (cf-eccDNA) has been proposed as a promising early biomarker for disease diagnosis, progression and drug response. Its established biomarker features are changes in the number and length distribution of cf-eccDNA. Another novel promising biomarker is a set of eccDNA [...] Read more.

Cell-free extrachromosomal circular DNA (cf-eccDNA) has been proposed as a promising early biomarker for disease diagnosis, progression and drug response. Its established biomarker features are changes in the number and length distribution of cf-eccDNA. Another novel promising biomarker is a set of eccDNA excised from a panel of genes specific to a condition compared to a control. Deficiencies in two endonucleases that specifically target DNA, Dnase1 and Dnase1l3, are associated with systemic lupus erythematosus (SLE). To study the genic eccDNA profiles in the case of their deficiencies, we mapped sequenced eccDNA data from plasma, liver and buffy coat from Dnase1 and Dnase1l3 knockouts (KOs), and wild type controls in mouse. Next, we performed an eccDNA differential analysis between KO and control groups using our DifCir algorithm. We found a specific genic cf-eccDNA fingerprint of the Dnase1l3 group compared to the wild type controls involving 131 genes; 26% of them were associated with human chromosomal fragile sites (CFSs) and with a statistically significant enrichment of CFS-associated genes. We found six genes in common with the genic cf-eccDNA profile of SLE patients with DNASE1L3 deficiency, namely Rorb, Mvb12b, Osbpl10, Fto, Tnik and Arhgap10; all of them were specific and present in all human plasma samples, and none of them were associated with CFSs. A not so distinctive genic cf-eccDNA difference involving only seven genes was observed in the case of the Dnase1 group compared to the wild type. In tissue—liver and buffy coat—we did not detect the same genic eccDNA difference observed in the plasma samples. These results point to a specific role of a set of genic eccDNA in plasma from DNase KOs, as well as a relation with CFS genes, confirming the promise of the genic cf-eccDNA in studying diseases and the need for further research on the relationship between eccDNA and CFSs. Full article

(This article belongs to the Special Issue Systemic Lupus Erythematosus: From Molecular Mechanisms to Therapies)

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11 pages, 1485 KB

Open AccessEditor’s ChoiceArticle

Luteinizing Hormone Surge-Induced Krüppel-like Factor 4 Inhibits Cyp17A1 Expression in Preovulatory Granulosa Cells

by Yuri Choi, Okto Lee, Kiyoung Ryu and Jaesook Roh

Biomedicines 2024, 12(1), 71; https://doi.org/10.3390/biomedicines12010071 - 27 Dec 2023

Cited by 2 | Viewed by 2067

Abstract

Previous in vivo and in vitro studies have demonstrated a dramatic up-regulation of Krüppel-like factor 4 (Klf4) in rat preovulatory granulosa cells (GCs) after LH/hCG treatment and its role in regulating Cyp19A1 expression during the luteal shift in steroidogenesis. In this [...] Read more.

Previous in vivo and in vitro studies have demonstrated a dramatic up-regulation of Krüppel-like factor 4 (Klf4) in rat preovulatory granulosa cells (GCs) after LH/hCG treatment and its role in regulating Cyp19A1 expression during the luteal shift in steroidogenesis. In this study, we examined whether Klf4 also mediates the LH-induced repression of Cyp17A1 expression in primary rat preovulatory GCs. In response to LH treatment of GCs in vitro, Cyp17A1 expression declined to less than half of its initial value by 1 h, remaining low for 24 h of culture. Overexpression of Klf4 decreased basal and Sf1-induced Cyp17A1 expressions and increased progesterone secretion. Reduction of endogenous Klf4 by siRNA elevated basal Cyp17A1 expression but did not affect LH-stimulated progesterone production. Overexpression of Klf4 also significantly attenuated Sf1-induced Cyp17A1 promoter activity. On the other hand, mutation of the conserved Sp1/Klf binding motif in the promoter revealed that this motif is not required for Klf4-mediated repression. Taken together, these data indicate that the Cyp17A1 gene may be one of the downstream targets of Klf4, which is induced by LH in preovulatory GCs. This information may help in identifying potential targets for preventing the molecular changes occurring in hyperandrogenic disorders. Full article

(This article belongs to the Special Issue Reproductive Medicine: Focus on Cell and Molecule 2.0)

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11 pages, 1208 KB

Open AccessEditor’s ChoiceArticle

Predicting Histologic Grade of Meningiomas Using a Combined Model of Radiomic and Clinical Imaging Features from Preoperative MRI

by Jae Hyun Park, Le Thanh Quang, Woong Yoon, Byung Hyun Baek, Ilwoo Park and Seul Kee Kim

Biomedicines 2023, 11(12), 3268; https://doi.org/10.3390/biomedicines11123268 - 10 Dec 2023

Cited by 10 | Viewed by 4234

Abstract

Meningiomas are common primary brain tumors, and their accurate preoperative grading is crucial for treatment planning. This study aimed to evaluate the value of radiomics and clinical imaging features in predicting the histologic grade of meningiomas from preoperative MRI. We retrospectively reviewed patients [...] Read more.

Meningiomas are common primary brain tumors, and their accurate preoperative grading is crucial for treatment planning. This study aimed to evaluate the value of radiomics and clinical imaging features in predicting the histologic grade of meningiomas from preoperative MRI. We retrospectively reviewed patients with intracranial meningiomas from two hospitals. Preoperative MRIs were analyzed for tumor and edema volumes, enhancement patterns, margins, and tumor–brain interfaces. Radiomics features were extracted, and machine learning models were employed to predict meningioma grades. A total of 212 patients were included. In the training group (Hospital 1), significant differences were observed between low-grade and high-grade meningiomas in terms of tumor volume (p = 0.012), edema volume (p = 0.004), enhancement (p = 0.001), margin (p < 0.001), and tumor–brain interface (p < 0.001). Five radiomics features were selected for model development. The prediction model for radiomics features demonstrated an average validation accuracy of 0.74, while the model for clinical imaging features showed an average validation accuracy of 0.69. When applied to external test data (Hospital 2), the radiomics model achieved an area under the receiver operating characteristics curve (AUC) of 0.72 and accuracy of 0.69, while the clinical imaging model achieved an AUC of 0.82 and accuracy of 0.81. An improved performance was obtained from the model constructed by combining radiomics and clinical imaging features. In the combined model, the AUC and accuracy for meningioma grading were 0.86 and 0.73, respectively. In conclusion, this study demonstrates the potential value of radiomics and clinical imaging features in predicting the histologic grade of meningiomas. The combination of both radiomics and clinical imaging features achieved the highest AUC among the models. Therefore, the combined model of radiomics and clinical imaging features may offer a more effective tool for predicting clinical outcomes in meningioma patients. Full article

(This article belongs to the Special Issue Artificial Intelligence in Neurobiology and Neurologic Diseases)

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17 pages, 5016 KB

Open AccessEditor’s ChoiceArticle

The Na/K-ATPase α1/Src Signaling Axis Regulates Mitochondrial Metabolic Function and Redox Signaling in Human iPSC-Derived Cardiomyocytes

by Liquan Cai, Marco T. Pessoa, Yingnyu Gao, Sidney Strause, Moumita Banerjee, Jiang Tian, Zijian Xie and Sandrine V. Pierre

Biomedicines 2023, 11(12), 3207; https://doi.org/10.3390/biomedicines11123207 - 2 Dec 2023

Cited by 4 | Viewed by 2839

Abstract

Na/K-ATPase (NKA)-mediated regulation of Src kinase, which involves defined amino acid sequences of the NKA α1 polypeptide, has emerged as a novel regulatory mechanism of mitochondrial function in metazoans. Mitochondrial metabolism ensures adequate myocardial performance and adaptation to physiological demand. It is also [...] Read more.

Na/K-ATPase (NKA)-mediated regulation of Src kinase, which involves defined amino acid sequences of the NKA α1 polypeptide, has emerged as a novel regulatory mechanism of mitochondrial function in metazoans. Mitochondrial metabolism ensures adequate myocardial performance and adaptation to physiological demand. It is also a critical cellular determinant of cardiac repair and remodeling. To assess the impact of the proposed NKA/Src regulatory axis on cardiac mitochondrial metabolic function, we used a gene targeting approach in human cardiac myocytes. Human induced pluripotent stem cells (hiPSC) expressing an Src-signaling null mutant (A420P) form of the NKA α1 polypeptide were generated using CRISPR/Cas9-mediated genome editing. Total cellular Na/K-ATPase activity remained unchanged in A420P compared to the wild type (WT) hiPSC, but baseline phosphorylation levels of Src and ERK1/2 were drastically reduced. Both WT and A420P mutant hiPSC readily differentiated into cardiac myocytes (iCM), as evidenced by marker gene expression, spontaneous cell contraction, and subcellular striations. Total NKA α1-3 protein expression was comparable in WT and A420P iCM. However, live cell metabolism assessed functionally by Seahorse extracellular flux analysis revealed significant reductions in both basal and maximal rates of mitochondrial respiration, spare respiratory capacity, ATP production, and coupling efficiency. A significant reduction in ROS production was detected by fluorescence imaging in live cells, and confirmed by decreased cellular protein carbonylation levels in A420P iCM. Taken together, these data provide genetic evidence for a role of NKA α1/Src in the tonic stimulation of basal mitochondrial metabolism and ROS production in human cardiac myocytes. This signaling axis in cardiac myocytes may provide a new approach to counteract mitochondrial dysfunction in cardiometabolic diseases. Full article

(This article belongs to the Special Issue The Role of Na,K-ATPase in Human Health: From Structure to Function)

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10 pages, 1777 KB

Open AccessEditor’s ChoiceArticle

Application of a Receptor-Binding-Domain-Based Simple Immunoassay for Assessing Humoral Immunity against Emerging SARS-CoV-2 Virus Variants

by Orsolya Mózner, Judit Moldvay, Kata Sára Szabó, Dorottya Vaskó, Júlia Domján, Dorottya Ács, Zoltán Ligeti, Csaba Fehér, Edit Hirsch, László Puskás, Cordula Stahl, Manfred Frey and Balázs Sarkadi

Biomedicines 2023, 11(12), 3193; https://doi.org/10.3390/biomedicines11123193 - 1 Dec 2023

Cited by 1 | Viewed by 2155

Abstract

We have developed a simple, rapid, high-throughput RBD-based ELISA to assess the humoral immunity against emerging SARS-CoV-2 virus variants. The cDNAs of the His-tagged RBD proteins of the virus variants were stably engineered into HEK cells secreting the protein into the supernatant, and [...] Read more.

We have developed a simple, rapid, high-throughput RBD-based ELISA to assess the humoral immunity against emerging SARS-CoV-2 virus variants. The cDNAs of the His-tagged RBD proteins of the virus variants were stably engineered into HEK cells secreting the protein into the supernatant, and RBD purification was performed by Ni-chromatography and buffer exchange by membrane filtration. The simplified assay uses single dilutions of sera from finger-pricked native blood samples, purified RBD in 96-well plates, and a chromogenic dye for development. The results of this RBD-ELISA were confirmed to correlate with those of a commercial immunoassay measuring antibodies against the Wuhan strain, as well as direct virus neutralization assays assessing the cellular effects of the Wuhan and the Omicron (BA.5) variants. Here, we document the applicability of this ELISA to assess the variant-specific humoral immunity in vaccinated and convalescent patients, as well as to follow the time course of selective vaccination response. This simple and rapid assay, easily modified to detect humoral immunity against emerging SARS-CoV-2 virus variants, may help to assess the level of antiviral protection after vaccination or infection. Full article

(This article belongs to the Special Issue The End of the COVID-19 Pandemic—What Is Currently Known and What Could Have Been Useful Four Years Ago?)

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15 pages, 2120 KB

Open AccessEditor’s ChoiceArticle

Whole Genome Expression Profiling of Semitendinosus Tendons from Children with Diplegic and Tetraplegic Cerebral Palsy

by Simona Nemska, Simone Serio, Veronica Larcher, Giulia Beltrame, Nicola Marcello Portinaro and Marie-Louise Bang

Biomedicines 2023, 11(11), 2918; https://doi.org/10.3390/biomedicines11112918 - 28 Oct 2023

Cited by 3 | Viewed by 2338

Abstract

Cerebral palsy (CP) is the most common movement disorder in children, with a prevalence ranging from 1.5 to 4 per 1000 live births. CP is caused by a non-progressive lesion of the developing brain, leading to progressive alterations of the musculoskeletal system, including [...] Read more.

Cerebral palsy (CP) is the most common movement disorder in children, with a prevalence ranging from 1.5 to 4 per 1000 live births. CP is caused by a non-progressive lesion of the developing brain, leading to progressive alterations of the musculoskeletal system, including spasticity, often leading to the development of fixed contractures, necessitating tendon lengthening surgery. Total RNA-sequencing analysis was performed on semitendinosus tendons from diplegic and tetraplegic CP patients subjected to tendon lengthening surgery compared to control patients undergoing anterior cruciate ligament reconstructive surgery. Tetraplegic CP patients showed increased expression of genes implicated in collagen synthesis and extracellular matrix (ECM) turnover, while only minor changes were observed in diplegic CP patients. In addition, tendons from tetraplegic CP patients showed an enrichment for upregulated genes involved in vesicle-mediated transport and downregulated genes involved in cytokine and apoptotic signaling. Overall, our results indicate increased ECM turnover with increased net synthesis of collagen in tetraplegic CP patients without activation of inflammatory and apoptotic pathways, similar to observations in athletes where ECM remodeling results in increased tendon stiffness and tensile strength. Nevertheless, the resulting increased tendon stiffness is an important issue in clinical practice, where surgery is often required to restore joint mobility. Full article

(This article belongs to the Special Issue From Pathophysiology to Novel Therapeutic Approaches in Musculoskeletal System 2.0)

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14 pages, 3822 KB

Open AccessEditor’s ChoiceArticle

Role of Pericytes in Cardiomyopathy-Associated Myocardial Infarction Revealed by Multiple Single-Cell Sequencing Analysis

by Yanqiao Lu, Huanhuan Huo, Feng Liang, Jieyuan Xue, Liang Fang, Yutong Miao, Lan Shen and Ben He

Biomedicines 2023, 11(11), 2896; https://doi.org/10.3390/biomedicines11112896 - 26 Oct 2023

Cited by 4 | Viewed by 2596

Abstract

Acute myocardial infarction (AMI) is one of the leading causes of cardiovascular death worldwide. AMI with cardiomyopathy is accompanied by a poor long-term prognosis. However, limited studies have focused on the mechanism of cardiomyopathy associated with AMI. Pericytes are important to the microvascular [...] Read more.

Acute myocardial infarction (AMI) is one of the leading causes of cardiovascular death worldwide. AMI with cardiomyopathy is accompanied by a poor long-term prognosis. However, limited studies have focused on the mechanism of cardiomyopathy associated with AMI. Pericytes are important to the microvascular function in the heart, yet little attention has been paid to their function in myocardial infarction until now. In this study, we integrated single-cell data from individuals with cardiomyopathy and myocardial infarction (MI) GWAS data to reveal the potential function of pericytes in cardiomyopathy-associated MI. We found that pericytes were concentrated in the left atrium and left ventricle tissues. DLC1/GUCY1A2/EGFLAM were the top three uniquely expressed genes in pericytes (p < 0.05). The marker genes of pericytes were enriched in renin secretion, vascular smooth muscle contraction, gap junction, purine metabolism, and diabetic cardiomyopathy pathways (p < 0.05). Among these pathways, the renin secretion and purine metabolism pathways were also found in the process of MI. In cardiomyopathy patients, the biosynthesis of collagen, modulating enzymes, and collagen formation were uniquely negatively regulated in pericytes compared to other cell types (p < 0.05). COL4A2/COL4A1/SMAD3 were the hub genes in pericyte function involved in cardiomyopathy and AMI. In conclusion, this study provides new evidence about the importance of pericytes in the pathogenesis of cardiomyopathy-associated MI. DLC1/GUCY1A2/EGFLAM were highly expressed in pericytes. The hub genes COL4A2/COL4A1/SMAD3 may be potential research targets for cardiomyopathy-associated MI. Full article

(This article belongs to the Special Issue Acute and Chronic Heart Failure: Pathophysiology and New Therapeutic Developments)

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