Biomedicines

23 pages, 699 KiB

Open AccessEditor’s ChoiceReview

Osteoporosis, Osteoarthritis, and Subchondral Insufficiency Fracture: Recent Insights

by Shunichi Yokota, Hotaka Ishizu, Takuji Miyazaki, Daisuke Takahashi, Norimasa Iwasaki and Tomohiro Shimizu

Biomedicines 2024, 12(4), 843; https://doi.org/10.3390/biomedicines12040843 - 11 Apr 2024

Cited by 13 | Viewed by 3974

Abstract

The increased incidence of osteoarthritis (OA), particularly knee and hip OA, and osteoporosis (OP), owing to population aging, have escalated the medical expense burden. Osteoarthritis is more prevalent in older women, and the involvement of subchondral bone fragility spotlights its association with OP. [...] Read more.

The increased incidence of osteoarthritis (OA), particularly knee and hip OA, and osteoporosis (OP), owing to population aging, have escalated the medical expense burden. Osteoarthritis is more prevalent in older women, and the involvement of subchondral bone fragility spotlights its association with OP. Notably, subchondral insufficiency fracture (SIF) may represent a more pronounced condition of OA pathophysiology. This review summarizes the relationship between OA and OP, incorporating recent insights into SIF. Progressive SIF leads to joint collapse and secondary OA and is associated with OP. Furthermore, the thinning and fragility of subchondral bone in early-stage OA suggest that SIF may be a subtype of OA (osteoporosis-related OA, OPOA) characterized by significant subchondral bone damage. The high bone mineral density observed in OA may be overestimated due to osteophytes and sclerosis and can potentially contribute to OPOA. The incidence of OPOA is expected to increase along with population aging. Therefore, prioritizing OP screening, early interventions for patients with early-stage OA, and fracture prevention measures such as rehabilitation, fracture liaison services, nutritional management, and medication guidance are essential. Full article

(This article belongs to the Special Issue Current Concepts of Osteoarthritis—from Pathogenesis and Prevention to Diagnosis and Treatment)

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13 pages, 1289 KiB

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 1 | Viewed by 1526

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 KiB

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 3 | Viewed by 1534

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 KiB

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 1 | Viewed by 1501

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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16 pages, 1925 KiB

Open AccessEditor’s ChoiceReview

Tumor-Infiltrating Lymphocytes (TILs) in Breast Cancer: Prognostic and Predictive Significance across Molecular Subtypes

by Aleksandra Ciarka, Michał Piątek, Rafał Pęksa, Michał Kunc and Elżbieta Senkus

Biomedicines 2024, 12(4), 763; https://doi.org/10.3390/biomedicines12040763 - 29 Mar 2024

Cited by 14 | Viewed by 9892

Abstract

Tumor-infiltrating lymphocytes (TILs) are pivotal in the immune response against breast cancer (BC), with their prognostic and predictive significance varying across BC subtypes. In triple-negative BC (TNBC), higher TIL levels correlate with improved prognosis and treatment response, guiding therapeutic strategies and potentially offering [...] Read more.

Tumor-infiltrating lymphocytes (TILs) are pivotal in the immune response against breast cancer (BC), with their prognostic and predictive significance varying across BC subtypes. In triple-negative BC (TNBC), higher TIL levels correlate with improved prognosis and treatment response, guiding therapeutic strategies and potentially offering avenues for treatment de-escalation. In metastatic TNBC, TILs identify patients with enhanced immunotherapy response. HER2+ BC, similar to TNBC, exhibits positive correlations between TILs and treatment response, especially in neoadjuvant settings. Luminal BC generally has low TILs, with limited prognostic impact. Single hormone receptor-positive BCs show distinct TIL associations, emphasizing subtype-specific considerations. TILs in ductal carcinoma in situ (DCIS) display ambiguous prognostic significance, necessitating further investigation. Standardizing TIL assessment methods is crucial for unlocking their full potential as biomarkers, guiding treatment decisions, and enhancing patient care in BC. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: The Multiple Impacts of Tumor Microenvironment)

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17 pages, 1762 KiB

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 1588

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 KiB

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 2069

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 KiB

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

Viewed by 1747

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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14 pages, 310 KiB

Open AccessEditor’s ChoiceReview

Intestinal Dysbiosis: Microbial Imbalance Impacts on Colorectal Cancer Initiation, Progression and Disease Mitigation

by Mary Garvey

Biomedicines 2024, 12(4), 740; https://doi.org/10.3390/biomedicines12040740 - 26 Mar 2024

Cited by 9 | Viewed by 3774

Abstract

The human gastrointestinal tract houses a diverse range of microbial species that play an integral part in many biological functions. Several preclinical studies using germ-free mice models have demonstrated that the gut microbiome profoundly influences carcinogenesis and progression. Colorectal cancer appears to be [...] Read more.

The human gastrointestinal tract houses a diverse range of microbial species that play an integral part in many biological functions. Several preclinical studies using germ-free mice models have demonstrated that the gut microbiome profoundly influences carcinogenesis and progression. Colorectal cancer appears to be associated with microbial dysbiosis involving certain bacterial species, including F. nucleatum, pks+ E. coli, and B. fragilis, with virome commensals also disrupted in patients. A dysbiosis toward these pro-carcinogenic species increases significantly in CRC patients, with reduced numbers of the preventative species Clostridium butyicum, Roseburia, and Bifidobacterium evident. There is also a correlation between Clostridium infection and CRC. F. nucleatum, in particular, is strongly associated with CRC where it is associated with therapeutic resistance and poor outcomes in patients. The carcinogenic mode of action of pathogenic bacteria in CRC is a result of genotoxicity, epigenetic alterations, ROS generation, and pro-inflammatory activity. The aim of this review is to discuss the microbial species and their impact on colorectal cancer in terms of disease initiation, progression, and metastasis. The potential of anticancer peptides as anticancer agents or adjuvants is also discussed, as novel treatment options are required to combat the high levels of resistance to current pharmaceutical options. Full article

(This article belongs to the Special Issue Gut Microbiota, Diet, and Immunity: Investigating the Connections and Implications for Disease Development)

17 pages, 1076 KiB

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

Viewed by 1881

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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18 pages, 2379 KiB

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 2908

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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15 pages, 3121 KiB

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 5 | Viewed by 3068

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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28 pages, 7874 KiB

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 1995

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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16 pages, 1546 KiB

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 2 | Viewed by 2181

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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22 pages, 3532 KiB

Open AccessEditor’s ChoiceReview

The Role of Cytokines and Molecular Pathways in Lung Fibrosis Following SARS-CoV-2 Infection: A Physiopathologic (Re)view

by Mihai Lazar, Mihai Sandulescu, Ecaterina Constanta Barbu, Cristina Emilia Chitu-Tisu, Darie Ioan Andreescu, Andreea Nicoleta Anton, Teodora Maria Erculescu, Alexandru Mihai Petre, George Theodor Duca, Vladimir Simion, Isabela Felicia Padiu, Cosmina Georgiana Pacurar, Ruxandra Rosca, Teodor Mihai Simian, Constantin Adrian Oprea and Daniela Adriana Ion

Biomedicines 2024, 12(3), 639; https://doi.org/10.3390/biomedicines12030639 - 13 Mar 2024

Cited by 9 | Viewed by 3515

Abstract

SARS-CoV-2 infection is a significant health concern that needs to be addressed not only during the initial phase of infection but also after hospitalization. This is the consequence of the various pathologies associated with long COVID-19, which are still being studied and researched. [...] Read more.

SARS-CoV-2 infection is a significant health concern that needs to be addressed not only during the initial phase of infection but also after hospitalization. This is the consequence of the various pathologies associated with long COVID-19, which are still being studied and researched. Lung fibrosis is an important complication after COVID-19, found in up to 71% of patients after discharge. Our research is based on scientific articles indexed in PubMed; in the selection process, we used the following keywords: “lung fibrosis”, “fibrosis mediators”, “fibrosis predictors”, “COVID-19”, “SARS-CoV-2 infection”, and “long COVID-19”. In this narrative review, we aimed to discuss the current understanding of the mechanisms of initiation and progression of post-COVID-19 lung fibrosis (PC-19-LF) and the risk factors for its occurrence. The pathogenesis of pulmonary fibrosis involves various mediators such as TGF-β, legumain, osteopontin, IL-4, IL-6, IL-13, IL-17, TNF-α, Gal-1, Gal-3, PDGF, and FGFR-1. The key cellular effectors involved in COVID-19 lung fibrosis are macrophages, epithelial alveolar cells, neutrophils, and fibroblasts. The main fibrosis pathways in SARS-CoV-2 infection include hypoxemia-induced fibrosis, macrophage-induced fibrosis, and viral-fibroblast interaction-induced fibrosis. Full article

(This article belongs to the Special Issue The Role of Cytokines in Health and Disease: 2nd Edition)

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12 pages, 2486 KiB

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

Viewed by 1676

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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10 pages, 1519 KiB

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 1977

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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15 pages, 3038 KiB

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 4 | Viewed by 1856

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 KiB

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 7 | Viewed by 2419

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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22 pages, 3205 KiB

Open AccessEditor’s ChoiceReview

Nephrotic Syndrome: From Pathophysiology to Novel Therapeutic Approaches

by Valentina-Georgiana Frățilă, Gabriela Lupușoru, Bogdan Marian Sorohan, Bogdan Obrișcă, Valentin Mocanu, Mircea Lupușoru and Gener Ismail

Biomedicines 2024, 12(3), 569; https://doi.org/10.3390/biomedicines12030569 - 3 Mar 2024

Cited by 7 | Viewed by 17900

Abstract

Nephrotic edema stands out as one of the most common complications of nephrotic syndrome. The effective management of hypervolemia is paramount in addressing this condition. Initially, “the underfill hypothesis” suggested that proteinuria and hypoalbuminemia led to fluid extravasation into the interstitial space, causing [...] Read more.

Nephrotic edema stands out as one of the most common complications of nephrotic syndrome. The effective management of hypervolemia is paramount in addressing this condition. Initially, “the underfill hypothesis” suggested that proteinuria and hypoalbuminemia led to fluid extravasation into the interstitial space, causing the intravascular hypovolemia and activation of neurohormonal compensatory mechanisms, which increased the retention of salt and water. Consequently, the recommended management involved diuretics and human-albumin infusion. However, recent findings from human and animal studies have unveiled a kidney-limited sodium-reabsorption mechanism, attributed to the presence of various serine proteases in the tubular lumen-activating ENaC channels, thereby causing sodium reabsorption. There is currently no standardized guideline for diuretic therapy. In clinical practice, loop diuretics continue to be the preferred initial choice. It is noteworthy that patients often exhibit diuretic resistance due to various factors such as high-sodium diets, poor drug compliance, changes in pharmacokinetics or pharmacodynamics, kidney dysfunction, decreased renal flow, nephron remodeling and proteasuria. Considering these challenges, combining diuretics may be a rational approach to overcoming diuretic resistance. Despite the limited data available on diuretic treatment in nephrotic syndrome complicated by hypervolemia, ENaC blockers emerge as a potential add-on treatment for nephrotic edema. Full article

(This article belongs to the Special Issue New Insights in the Pathogenesis and Treatment of Chronic Kidney Disease and Its Complications)

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13 pages, 1859 KiB

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 1 | Viewed by 3182

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, 26225 KiB

Open AccessEditor’s ChoiceReview

100 Years since the Discovery of Insulin, from Its Discovery to the Insulins of the Future

by Carmen Lambert and Elias Delgado

Biomedicines 2024, 12(3), 533; https://doi.org/10.3390/biomedicines12030533 - 27 Feb 2024

Cited by 2 | Viewed by 4004

Abstract

The term diabetes first emerged in the 3rd century BC, in a reference by Demetrius of Apamea, who described the disease as a dropsy in which any liquid ingested is eliminated in the form of urine. However, the great discovery that revolutionized this [...] Read more.

The term diabetes first emerged in the 3rd century BC, in a reference by Demetrius of Apamea, who described the disease as a dropsy in which any liquid ingested is eliminated in the form of urine. However, the great discovery that revolutionized this field came from the Canadian doctor Frederick Banting, who together with his student and assistant Charles Best, managed to isolate insulin and treat a patient with diabetes on 23 January 1922. This patient was Leonard Thompson, and the results obtained from him were surprising. His glycosuria and ketonuria disappeared and his blood glucose returned to normal. He received daily injections and lived 13 more years. Advances in the treatment of diabetes have been numerous in the 100 years since its discovery. In this review, we recapitulate the most important events that have occurred, and where research is progressing today. Full article

(This article belongs to the Special Issue New Advances in Insulin—100 Years since Its Discovery)

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13 pages, 3343 KiB

Open AccessEditor’s ChoiceArticle

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 3 | Viewed by 3008

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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18 pages, 1614 KiB

Open AccessEditor’s ChoiceReview

Endothelin-1 and Its Role in Cancer and Potential Therapeutic Opportunities

by Madeline Harrison, Dmitry Zinovkin and Md Zahidul Islam Pranjol

Biomedicines 2024, 12(3), 511; https://doi.org/10.3390/biomedicines12030511 - 23 Feb 2024

Cited by 10 | Viewed by 2638

Abstract

Endothelin-1 (ET-1) plays a physiological role as a potent vasoconstrictor. It is implicated in an array of diseases, and its signalling is often found to be overactivated within cancers. ET-1 has been found to potentiate hallmarks of cancer progression such as cell proliferation, [...] Read more.

Endothelin-1 (ET-1) plays a physiological role as a potent vasoconstrictor. It is implicated in an array of diseases, and its signalling is often found to be overactivated within cancers. ET-1 has been found to potentiate hallmarks of cancer progression such as cell proliferation, invasion and metastasis, as well as angiogenesis. ET-1 has also been implicated in inducing the epithelial–mesenchymal transition (EMT) and promoting resistance to anticancer drugs. Many preclinical efforts have been made to target ET-1 expression within cancer, such as by using ET-1 receptor antagonists, many of which have been approved for treating pulmonary hypertension. Targeting ET-1 has been shown to improve the response to various other cancer therapeutics, highlighting the potential benefits targeting this peptide may exert. Drug repurposing is an attractive strategy, and exploration of this avenue may be promising for targeting ET-1 in cancer. There are many clinical trials which have been completed and are currently undergoing involving the repurposing of ET-1 receptor antagonists for cancer treatment. In this review, the pathways through which ET-1 potentiates cancer will be discussed, as well as where the opportunity for therapeutic intervention lies in relation to cancer. Full article

(This article belongs to the Special Issue Vascular Endothelial Functions: Insights from Molecular Perspectives)

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22 pages, 7667 KiB

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 2 | Viewed by 3793

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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18 pages, 714 KiB

Open AccessEditor’s ChoiceReview

Unraveling the Link between Ιnsulin Resistance and Bronchial Asthma

by Konstantinos Bartziokas, Andriana I. Papaioannou, Fotios Drakopanagiotakis, Evanthia Gouveri, Nikolaos Papanas and Paschalis Steiropoulos

Biomedicines 2024, 12(2), 437; https://doi.org/10.3390/biomedicines12020437 - 16 Feb 2024

Cited by 6 | Viewed by 3045

Abstract

Evidence from large epidemiological studies has shown that obesity may predispose to increased Th2 inflammation and increase the odds of developing asthma. On the other hand, there is growing evidence suggesting that metabolic dysregulation that occurs with obesity, and more specifically hyperglycemia and [...] Read more.

Evidence from large epidemiological studies has shown that obesity may predispose to increased Th2 inflammation and increase the odds of developing asthma. On the other hand, there is growing evidence suggesting that metabolic dysregulation that occurs with obesity, and more specifically hyperglycemia and insulin resistance, may modify immune cell function and in some degree systemic inflammation. Insulin resistance seldom occurs on its own, and in most cases constitutes a clinical component of metabolic syndrome, along with central obesity and dyslipidemia. Despite that, in some cases, hyperinsulinemia associated with insulin resistance has proven to be a stronger risk factor than body mass in developing asthma. This finding has been supported by recent experimental studies showing that insulin resistance may contribute to airway remodeling, promotion of airway smooth muscle (ASM) contractility and proliferation, increase of airway hyper-responsiveness and release of pro-inflammatory mediators from adipose tissue. All these effects indicate the potential impact of hyperinsulinemia on airway structure and function, suggesting the presence of a specific asthma phenotype with insulin resistance. Epidemiologic studies have found that individuals with severe and uncontrolled asthma have a higher prevalence of glycemic dysfunction, whereas longitudinal studies have linked glycemic dysfunction to an increased risk of asthma exacerbations. Since the components of metabolic syndrome interact with one another so much, it is challenging to identify each one’s specific role in asthma. This is why, over the last decade, additional studies have been conducted to determine whether treatment of type 2 diabetes mellitus affects comorbid asthma as shown by the incidence of asthma, asthma control and asthma-related exacerbations. The purpose of this review is to present the mechanism of action, and existing preclinical and clinical data, regarding the effect of insulin resistance in asthma. Full article

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

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17 pages, 3129 KiB

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 3 | Viewed by 1728

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 KiB

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 2 | Viewed by 1849

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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20 pages, 382 KiB

Open AccessEditor’s ChoiceReview

Current and Emerging Diagnostic, Prognostic, and Predictive Biomarkers in Head and Neck Cancer

by Hänel W. Eberly, Bao Y. Sciscent, F. Jeffrey Lorenz, Eleni M. Rettig and Neerav Goyal

Biomedicines 2024, 12(2), 415; https://doi.org/10.3390/biomedicines12020415 - 10 Feb 2024

Cited by 9 | Viewed by 4627

Abstract

Head and neck cancers (HNC) are a biologically diverse set of cancers that are responsible for over 660,000 new diagnoses each year. Current therapies for HNC require a comprehensive, multimodal approach encompassing resection, radiation therapy, and systemic therapy. With an increased understanding of [...] Read more.

Head and neck cancers (HNC) are a biologically diverse set of cancers that are responsible for over 660,000 new diagnoses each year. Current therapies for HNC require a comprehensive, multimodal approach encompassing resection, radiation therapy, and systemic therapy. With an increased understanding of the mechanisms behind HNC, there has been growing interest in more accurate prognostic indicators of disease, effective post-treatment surveillance, and individualized treatments. This chapter will highlight the commonly used and studied biomarkers in head and neck squamous cell carcinoma. Full article

(This article belongs to the Special Issue Feature Reviews in Cancer Biomarkers)

11 pages, 1391 KiB

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 4 | Viewed by 2910

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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28 pages, 1848 KiB

Open AccessEditor’s ChoiceReview

Exploring the Multifaceted Landscape of MASLD: A Comprehensive Synthesis of Recent Studies, from Pathophysiology to Organoids and Beyond

by Allison Soto, Colby Spongberg, Alessandro Martinino and Francesco Giovinazzo

Biomedicines 2024, 12(2), 397; https://doi.org/10.3390/biomedicines12020397 - 8 Feb 2024

Cited by 22 | Viewed by 5886

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a widespread contributor to chronic liver disease globally. A recent consensus on renaming liver disease was established, and metabolic dysfunction-associated steatotic liver disease, MASLD, was chosen as the replacement for NAFLD. The disease’s range extends from the [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is a widespread contributor to chronic liver disease globally. A recent consensus on renaming liver disease was established, and metabolic dysfunction-associated steatotic liver disease, MASLD, was chosen as the replacement for NAFLD. The disease’s range extends from the less severe MASLD, previously known as non-alcoholic fatty liver (NAFL), to the more intense metabolic dysfunction-associated steatohepatitis (MASH), previously known as non-alcoholic steatohepatitis (NASH), characterized by inflammation and apoptosis. This research project endeavors to comprehensively synthesize the most recent studies on MASLD, encompassing a wide spectrum of topics such as pathophysiology, risk factors, dietary influences, lifestyle management, genetics, epigenetics, therapeutic approaches, and the prospective trajectory of MASLD, particularly exploring its connection with organoids. Full article

(This article belongs to the Special Issue Metabolic- and Genetic-Associated Fatty Liver Diseases Volume II)

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13 pages, 1247 KiB

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 6 | Viewed by 2279

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 KiB

Open AccessEditor’s ChoiceArticle

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 1645

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 KiB

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 1984

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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15 pages, 1558 KiB

Open AccessEditor’s ChoiceReview

Wnt Signaling in Atherosclerosis: Mechanisms to Therapeutic Implications

by Rizwana Afroz and Julie E. Goodwin

Biomedicines 2024, 12(2), 276; https://doi.org/10.3390/biomedicines12020276 - 25 Jan 2024

Cited by 1 | Viewed by 2334

Abstract

Atherosclerosis is a vascular disease in which inflammation plays a pivotal role. Receptor-mediated signaling pathways regulate vascular inflammation and the pathophysiology of atherosclerosis. Emerging evidence has revealed the role of the Wnt pathway in atherosclerosis progression. The Wnt pathway influences almost all stages [...] Read more.

Atherosclerosis is a vascular disease in which inflammation plays a pivotal role. Receptor-mediated signaling pathways regulate vascular inflammation and the pathophysiology of atherosclerosis. Emerging evidence has revealed the role of the Wnt pathway in atherosclerosis progression. The Wnt pathway influences almost all stages of atherosclerosis progression, including endothelial dysfunction, monocyte infiltration, smooth muscle cell proliferation and migration, and plaque formation. Targeting the Wnt pathway to treat atherosclerosis represents a promising therapeutic approach that remains understudied. Blocking Wnt signaling utilizing small molecule inhibitors, recombinant proteins, and/or neutralizing antibodies ameliorates atherosclerosis in preclinical models. The Wnt pathway can be potentially manipulated through targeting Wnt ligands, receptors, co-receptors, and downstream signaling molecules. However, there are challenges associated with developing a real world therapeutic compound that targets the Wnt pathway. This review focuses on the role of Wnt signaling in atherosclerosis development, and the rationale for targeting this pathway for the treatment of atherosclerosis. Full article

(This article belongs to the Special Issue Role of Endothelial Cells in Cardiovascular Disease)

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14 pages, 854 KiB

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 1253

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 KiB

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 2 | Viewed by 1807

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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15 pages, 913 KiB

Open AccessEditor’s ChoiceReview

The Role of Chaperone-Mediated Autophagy in Tissue Homeostasis and Disease Pathogenesis

by Rut Valdor and Marta Martinez-Vicente

Biomedicines 2024, 12(2), 257; https://doi.org/10.3390/biomedicines12020257 - 23 Jan 2024

Cited by 13 | Viewed by 3525

Abstract

Chaperone-mediated autophagy (CMA) is a selective proteolytic pathway in the lysosomes. Proteins are recognized one by one through the detection of a KFERQ motif or, at least, a KFERQ-like motif, by a heat shock cognate protein 70 (Hsc70), a molecular chaperone. CMA substrates [...] Read more.

Chaperone-mediated autophagy (CMA) is a selective proteolytic pathway in the lysosomes. Proteins are recognized one by one through the detection of a KFERQ motif or, at least, a KFERQ-like motif, by a heat shock cognate protein 70 (Hsc70), a molecular chaperone. CMA substrates are recognized and delivered to a lysosomal CMA receptor, lysosome-associated membrane protein 2A (LAMP-2A), the only limiting component of this pathway, and transported to the lysosomal lumen with the help of another resident chaperone HSp90. Since approximately 75% of proteins are reported to have canonical, phosphorylation-generated, or acetylation-generated KFERQ motifs, CMA maintains intracellular protein homeostasis and regulates specific functions in the cells in different tissues. CMA also regulates physiologic functions in different organs, and is then implicated in disease pathogenesis related to aging, cancer, and the central nervous and immune systems. In this minireview, we have summarized the most important findings on the role of CMA in tissue homeostasis and disease pathogenesis, updating the recent advances for this Special Issue. Full article

(This article belongs to the Special Issue The Role of Chaperone-Mediated Autophagy in Tissue Homeostasis and Disease Pathogenesis)

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14 pages, 818 KiB

Open AccessEditor’s ChoiceReview

Silent Myocardial Ischemia: From Pathophysiology to Diagnosis and Treatment

by Panagiotis Theofilis, Alexios S. Antonopoulos, Marios Sagris, Aggelos Papanikolaou, Evangelos Oikonomou, Konstantinos Tsioufis and Dimitris Tousoulis

Biomedicines 2024, 12(2), 259; https://doi.org/10.3390/biomedicines12020259 - 23 Jan 2024

Cited by 9 | Viewed by 6603

Abstract

Silent myocardial ischemia (SMI), characterized by a lack of overt symptoms despite an inadequate blood supply to the myocardium, remains a challenging entity in cardiovascular medicine. The pathogenesis involves intricate interactions of vascular, neurohormonal, and metabolic factors, contributing to perfusion deficits without the [...] Read more.

Silent myocardial ischemia (SMI), characterized by a lack of overt symptoms despite an inadequate blood supply to the myocardium, remains a challenging entity in cardiovascular medicine. The pathogenesis involves intricate interactions of vascular, neurohormonal, and metabolic factors, contributing to perfusion deficits without the characteristic chest pain. Understanding these mechanisms is pivotal for recognizing diverse clinical presentations and designing targeted interventions. Diagnostic strategies for SMI have evolved from traditional electrocardiography to advanced imaging modalities, including stress echocardiography, single-photon emission computed tomography (SPECT), positron emission tomography (PET), and cardiac magnetic resonance imaging (MRI). Treating SMI is a matter of ongoing debate, as the available evidence on the role of invasive versus medical management is controversial. This comprehensive review synthesizes current knowledge of silent myocardial ischemia, addressing its pathophysiology, diagnostic modalities, and therapeutic interventions. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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14 pages, 1622 KiB

Open AccessEditor’s ChoiceReview

In Utero Origins of Acute Leukemia in Children

by Adam J. de Smith and Logan G. Spector

Biomedicines 2024, 12(1), 236; https://doi.org/10.3390/biomedicines12010236 - 19 Jan 2024

Cited by 4 | Viewed by 3789

Abstract

Acute leukemias, mainly consisting of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), comprise a major diagnostic group among hematologic cancers. Due to the early age at onset of ALL, particularly, it has long been suspected that acute leukemias of childhood may [...] Read more.

Acute leukemias, mainly consisting of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), comprise a major diagnostic group among hematologic cancers. Due to the early age at onset of ALL, particularly, it has long been suspected that acute leukemias of childhood may have an in utero origin. This supposition has motivated many investigations seeking direct proof of prenatal leukemogenesis, in particular, twin and “backtracking studies”. The suspected in utero origin has also focused on gestation as a critical window of risk, resulting in a rich literature on prenatal risk factors for pediatric acute leukemias. In this narrative review, we recount the circumstantial and direct evidence for an in utero origin of childhood acute leukemias. Full article

(This article belongs to the Special Issue Pathogenesis and Novel Therapies of Acute Leukemias)

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14 pages, 5975 KiB

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 4 | Viewed by 2417

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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42 pages, 1151 KiB

Open AccessEditor’s ChoiceReview

Microbiota Implications in Endocrine-Related Diseases: From Development to Novel Therapeutic Approaches

by Vicente Javier Clemente-Suárez, Laura Redondo-Flórez, Alejandro Rubio-Zarapuz, Alexandra Martín-Rodríguez and José Francisco Tornero-Aguilera

Biomedicines 2024, 12(1), 221; https://doi.org/10.3390/biomedicines12010221 - 18 Jan 2024

Cited by 14 | Viewed by 5348

Abstract

This comprehensive review article delves into the critical role of the human microbiota in the development and management of endocrine-related diseases. We explore the complex interactions between the microbiota and the endocrine system, emphasizing the implications of microbiota dysbiosis for the onset and [...] Read more.

This comprehensive review article delves into the critical role of the human microbiota in the development and management of endocrine-related diseases. We explore the complex interactions between the microbiota and the endocrine system, emphasizing the implications of microbiota dysbiosis for the onset and progression of various endocrine disorders. The review aims to synthesize current knowledge, highlighting recent advancements and the potential of novel therapeutic approaches targeting microbiota-endocrine interactions. Key topics include the impact of microbiota on hormone regulation, its role in endocrine pathologies, and the promising avenues of microbiota modulation through diet, probiotics, prebiotics, and fecal microbiota transplantation. We underscore the importance of this research in advancing personalized medicine, offering insights for more tailored and effective treatments for endocrine-related diseases. Full article

(This article belongs to the Special Issue Microbiota Implication in Endocrine-Related Diseases: From Development to Novel Therapeutic Approaches)

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36 pages, 10309 KiB

Open AccessEditor’s ChoiceReview

Aptamer-Based Smart Targeting and Spatial Trigger–Response Drug-Delivery Systems for Anticancer Therapy

by Dongsik Park, Su Jin Lee and Jee-Woong Park

Biomedicines 2024, 12(1), 187; https://doi.org/10.3390/biomedicines12010187 - 15 Jan 2024

Cited by 16 | Viewed by 3486

Abstract

In recent years, the field of drug delivery has witnessed remarkable progress, driven by the quest for more effective and precise therapeutic interventions. Among the myriad strategies employed, the integration of aptamers as targeting moieties and stimuli-responsive systems has emerged as a promising [...] Read more.

In recent years, the field of drug delivery has witnessed remarkable progress, driven by the quest for more effective and precise therapeutic interventions. Among the myriad strategies employed, the integration of aptamers as targeting moieties and stimuli-responsive systems has emerged as a promising avenue, particularly in the context of anticancer therapy. This review explores cutting-edge advancements in targeted drug-delivery systems, focusing on the integration of aptamers and stimuli-responsive platforms for enhanced spatial anticancer therapy. In the aptamer-based drug-delivery systems, we delve into the versatile applications of aptamers, examining their conjugation with gold, silica, and carbon materials. The synergistic interplay between aptamers and these materials is discussed, emphasizing their potential in achieving precise and targeted drug delivery. Additionally, we explore stimuli-responsive drug-delivery systems with an emphasis on spatial anticancer therapy. Tumor microenvironment-responsive nanoparticles are elucidated, and their capacity to exploit the dynamic conditions within cancerous tissues for controlled drug release is detailed. External stimuli-responsive strategies, including ultrasound-mediated, photo-responsive, and magnetic-guided drug-delivery systems, are examined for their role in achieving synergistic anticancer effects. This review integrates diverse approaches in the quest for precision medicine, showcasing the potential of aptamers and stimuli-responsive systems to revolutionize drug-delivery strategies for enhanced anticancer therapy. Full article

(This article belongs to the Special Issue Feature Reviews in Anticancer Drug Delivery Systems)

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16 pages, 2832 KiB

Open AccessEditor’s ChoiceArticle

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 3 | Viewed by 1535

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 KiB

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 1 | Viewed by 2416

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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16 pages, 1916 KiB

Open AccessEditor’s ChoiceReview

The Role of GLP-1, GIP, MCP-1 and IGFBP-7 Biomarkers in the Development of Metabolic Disorders: A Review and Predictive Analysis in the Context of Diabetes and Obesity

by Malwina Jędrysik, Krzysztof Wyszomirski, Anna Różańska-Walędziak, Emilia Grosicka-Maciąg, Maciej Walędziak and Beata Chełstowska

Biomedicines 2024, 12(1), 159; https://doi.org/10.3390/biomedicines12010159 - 11 Jan 2024

Cited by 7 | Viewed by 5455

Abstract

Metabolic illnesses, including obesity and type 2 diabetes, have become worldwide epidemics that have an effect on public health. Clinical investigations and further exploration of these mechanisms could lead to innovative, effective, and personalized treatment strategies for individuals. It is important to screen [...] Read more.

Metabolic illnesses, including obesity and type 2 diabetes, have become worldwide epidemics that have an effect on public health. Clinical investigations and further exploration of these mechanisms could lead to innovative, effective, and personalized treatment strategies for individuals. It is important to screen biomarkers in previous studies to discover what is missing. Glucagon-like peptide-1′s role in insulin secretion and glucose control highlights its diagnostic and therapeutic potential. Glucose-dependent insulinotropic peptide’s influence on postprandial satiety and weight management signifies its importance in understanding metabolic processes. Monocyte chemoattractant protein-1′s involvement in inflammation and insulin resistance underlines its value as a diagnostic marker. Insulin-like growth factor-binding protein-7’s association with insulin sensitivity and kidney function presents it as a potential target for these diseases’ management. In validating these biomarkers, it will be easier to reflect pathophysiological processes, and clinicians will be able to better assess disease severity, monitor disease progression, and tailor treatment strategies. The purpose of the study was to elucidate the significance of identifying novel biomarkers for type 2 diabetes mellitus and obesity, which can revolutionize early detection, risk assessment, and personalized treatment strategies. Standard literature searches of PubMed (MEDLINE), EMBASE, and Cochrane Library were conducted in the year 2023 to identify both original RCTs and recent systematic reviews that have explored the importance of identifying novel biomarkers for T2D and obesity. This search produced 1964 results, and then was reduced to randomized controlled trial and systematic reviews, producing 145 results and 44 results, respectively. Researchers have discovered potential associations between type 2 diabetes mellitus and obesity and the biomarkers glucagon-like peptide-1, glucose-dependent insulinotropic peptide, monocyte chemoattractant protein-1, and insulin-like growth factor-binding protein-7. Understanding the role of those biomarkers in disease pathogenesis offers hope for improving diagnostics, personalized treatment, and prevention strategies. Full article

(This article belongs to the Special Issue State-of-the-Art Endocrinology and Metabolism Research in Poland (Volume II))

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20 pages, 4692 KiB

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 1859

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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19 pages, 380 KiB

Open AccessEditor’s ChoiceReview

Pharmacological Approaches Using Diabetic Drugs Repurposed for Alzheimer’s Disease

by Muna A. Adem, Boris Decourt and Marwan N. Sabbagh

Biomedicines 2024, 12(1), 99; https://doi.org/10.3390/biomedicines12010099 - 3 Jan 2024

Cited by 15 | Viewed by 3929

Abstract

Type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) are chronic, progressive disorders affecting the elderly, which fosters global healthcare concern with the growing aging population. Both T2DM and AD have been linked with increasing age, advanced glycosylation end products, obesity, and insulin [...] Read more.

Type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) are chronic, progressive disorders affecting the elderly, which fosters global healthcare concern with the growing aging population. Both T2DM and AD have been linked with increasing age, advanced glycosylation end products, obesity, and insulin resistance. Insulin resistance in the periphery is significant in the development of T2DM and it has been posited that insulin resistance in the brain plays a key role in AD pathogenesis, earning AD the name “type 3 diabetes”. These clinical and epidemiological links between AD and T2DM have become increasingly pronounced throughout the years, and serve as a means to investigate the effects of antidiabetic therapies in AD, such as metformin, intranasal insulin, incretins, DPP4 inhibitors, PPAR-γ agonists, SGLT2 inhibitors. The majority of these drugs have shown benefit in preclinical trials, and have shown some promising results in clinical trials, with the improvement of cognitive faculties in participants with mild cognitive impairment and AD. In this review, we have summarize the benefits, risks, and conflicting data that currently exist for diabetic drugs being repurposed for the treatment of AD. Full article

(This article belongs to the Special Issue Advances in Mechanism Research of Diabetes and Insulin Resistance)

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17 pages, 968 KiB

Open AccessEditor’s ChoiceReview

The Role of Adipokines in Tumor Progression and Its Association with Obesity

by Jae Won Kim, Jun Hyeok Kim and Yoon Jae Lee

Biomedicines 2024, 12(1), 97; https://doi.org/10.3390/biomedicines12010097 - 3 Jan 2024

Cited by 25 | Viewed by 3971

Abstract

Obesity is a well-established risk factor for various malignancies and emerging evidence suggests that adipokines play a pivotal role in linking excess adiposity to tumorigenesis. Adipokines are bioactive molecules secreted by adipose tissue and their altered expression in obesity contributes to a pro-inflammatory, [...] Read more.

Obesity is a well-established risk factor for various malignancies and emerging evidence suggests that adipokines play a pivotal role in linking excess adiposity to tumorigenesis. Adipokines are bioactive molecules secreted by adipose tissue and their altered expression in obesity contributes to a pro-inflammatory, pro-angiogenic, and growth-promoting microenvironment conducive to tumorigenesis. Leptin, a key adipokine, activates survival and proliferative signaling pathways whereas adiponectin exhibits tumor-suppressive effects by inducing apoptosis and cell cycle arrest. Visfatin has also been documented to promote tumor growth, angiogenesis, migration, and invasion. Moreover, emerging studies suggest that adipokines, such as resistin, apelin, and chemerin, which are overexpressed in obesity, may also possess oncogenic functions. Despite advancements in our understanding of the roles of individual adipokines in cancer, the intricate interplay and crosstalk between adipokines, tumor cells, and the tumor microenvironment remain complex and multifaceted. This review highlights the evolving knowledge of how adipokines contribute to obesity-related tumorigenesis, shedding light on the potential of targeting adipokine signaling pathways as a novel therapeutic approach for obesity-associated cancers. Further research on the specific mechanisms and interactions between adipokines and tumor cells is crucial for a comprehensive understanding of obesity-associated cancer pathogenesis. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Recent Advances on Adipokines)

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25 pages, 4204 KiB

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 3128

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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