Biomedicines

19 pages, 3658 KiB

Open AccessEditor’s ChoiceReview

Epidural and Intrathecal Drug Delivery in Rats and Mice for Experimental Research: Fundamental Concepts, Techniques, Precaution, and Application

by Md. Mahbubur Rahman, Ji Yeon Lee, Yong Ho Kim and Chul-Kyu Park

Biomedicines 2023, 11(5), 1413; https://doi.org/10.3390/biomedicines11051413 - 10 May 2023

Cited by 16 | Viewed by 12891

Abstract

Epidural and intrathecal routes are the most effective drug administration methods for pain management in clinical and experimental medicine to achieve quick results, reduce required drug dosages, and overcome the adverse effects associated with the oral and parenteral routes. Beyond pain management with [...] Read more.

Epidural and intrathecal routes are the most effective drug administration methods for pain management in clinical and experimental medicine to achieve quick results, reduce required drug dosages, and overcome the adverse effects associated with the oral and parenteral routes. Beyond pain management with analgesics, the intrathecal route is more widely used for stem cell therapy, gene therapy, insulin delivery, protein therapy, and drug therapy with agonist, antagonist, or antibiotic drugs in experimental medicine. However, clear information regarding intrathecal and epidural drug delivery in rats and mice is lacking, despite differences from human medicine in terms of anatomical space and proximity to the route of entry. In this study, we discussed and compared the anatomical locations of the epidural and intrathecal spaces, cerebrospinal fluid volume, dorsal root ganglion, techniques and challenges of epidural and intrathecal injections, dosage and volume of drugs, needle and catheter sizes, and the purpose and applications of these two routes in different disease models in rats and mice. We also described intrathecal injection in relation to the dorsal root ganglion. The accumulated information about the epidural and intrathecal delivery routes could contribute to better safety, quality, and reliability in experimental research. Full article

(This article belongs to the Special Issue Neuropathic Pain: From Mechanisms to Therapeutic Approaches)

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16 pages, 2864 KiB

Open AccessEditor’s ChoiceArticle

Anionic Phospholipids Shift the Conformational Equilibrium of the Selectivity Filter in the KcsA Channel to the Conductive Conformation: Predicted Consequences on Inactivation

by María Lourdes Renart, Ana Marcela Giudici, Carlos Coll-Díez, José M. González-Ros and José A. Poveda

Biomedicines 2023, 11(5), 1376; https://doi.org/10.3390/biomedicines11051376 - 5 May 2023

Cited by 2 | Viewed by 1738

Abstract

Here, we report an allosteric effect of an anionic phospholipid on a model K⁺ channel, KcsA. The anionic lipid in mixed detergent–lipid micelles specifically induces a change in the conformational equilibrium of the channel selectivity filter (SF) only when the channel inner [...] Read more.

Here, we report an allosteric effect of an anionic phospholipid on a model K⁺ channel, KcsA. The anionic lipid in mixed detergent–lipid micelles specifically induces a change in the conformational equilibrium of the channel selectivity filter (SF) only when the channel inner gate is in the open state. Such change consists of increasing the affinity of the channel for K⁺, stabilizing a conductive-like form by maintaining a high ion occupancy in the SF. The process is highly specific in several aspects: First, lipid modifies the binding of K⁺, but not that of Na⁺, which remains unperturbed, ruling out a merely electrostatic phenomenon of cation attraction. Second, no lipid effects are observed when a zwitterionic lipid, instead of an anionic one, is present in the micelles. Lastly, the effects of the anionic lipid are only observed at pH 4.0, when the inner gate of KcsA is open. Moreover, the effect of the anionic lipid on K⁺ binding to the open channel closely emulates the K⁺ binding behaviour of the non-inactivating E71A and R64A mutant proteins. This suggests that the observed increase in K⁺ affinity caused by the bound anionic lipid should result in protecting the channel against inactivation. Full article

(This article belongs to the Special Issue Fiftieth Anniversary of the Fluid Mosaic Model of Cell Membranes: From Lipid Structure to Biomedicines)

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10 pages, 436 KiB

Open AccessEditor’s ChoiceCommunication

Prognostic Value of the Selected Polymorphisms in the CD36 Gene in the Domain-Encoding Lipid-Binding Region at a 10-Year Follow-Up for Early-Onset CAD Patients

by Michał Bartoszewicz and Monika Rać

Biomedicines 2023, 11(5), 1332; https://doi.org/10.3390/biomedicines11051332 - 30 Apr 2023

Cited by 1 | Viewed by 1730

Abstract

The polymorphism of the CD36 gene may have a decisive impact on the formation and progression of atherosclerotic changes. The aim of the study was to confirm the prognostic values of the previously studied polymorphisms in the CD36 gene within a 10-year follow-up [...] Read more.

The polymorphism of the CD36 gene may have a decisive impact on the formation and progression of atherosclerotic changes. The aim of the study was to confirm the prognostic values of the previously studied polymorphisms in the CD36 gene within a 10-year follow-up period. This is the first published report confirming the long-term observation of patients with CAD. The study group covered 100 early-onset CAD patients. It included 26 women not older than 55 years and 74 men not older than 50 years, tested in a ten-year study as a long-term follow-up after the first cardiovascular episode. There are no notable differences between the CD36 variants and the number of fatalities during observation, fatalities due to cardiological reasons, cases of myocardial infarction within a ten-year observation period, hospitalizations for cardiovascular issues, all cardiovascular occurrences, and the number of months lived. We have shown that the CD36 variants analyzed in this study do not appear to be related to the risk of early CAD occurrence in the Caucasian population in long-term observation. Full article

(This article belongs to the Special Issue Cellular Mechanisms of Cardiovascular Disease 2.0)

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27 pages, 1854 KiB

Open AccessEditor’s ChoiceReview

Targeted DNA Demethylation: Vectors, Effectors and Perspectives

by Naohiro Yano and Alexey V. Fedulov

Biomedicines 2023, 11(5), 1334; https://doi.org/10.3390/biomedicines11051334 - 30 Apr 2023

Cited by 11 | Viewed by 4886

Abstract

Aberrant DNA hypermethylation at regulatory cis-elements of particular genes is seen in a plethora of pathological conditions including cardiovascular, neurological, immunological, gastrointestinal and renal diseases, as well as in cancer, diabetes and others. Thus, approaches for experimental and therapeutic DNA demethylation have a [...] Read more.

Aberrant DNA hypermethylation at regulatory cis-elements of particular genes is seen in a plethora of pathological conditions including cardiovascular, neurological, immunological, gastrointestinal and renal diseases, as well as in cancer, diabetes and others. Thus, approaches for experimental and therapeutic DNA demethylation have a great potential to demonstrate mechanistic importance, and even causality of epigenetic alterations, and may open novel avenues to epigenetic cures. However, existing methods based on DNA methyltransferase inhibitors that elicit genome-wide demethylation are not suitable for treatment of diseases with specific epimutations and provide a limited experimental value. Therefore, gene-specific epigenetic editing is a critical approach for epigenetic re-activation of silenced genes. Site-specific demethylation can be achieved by utilizing sequence-dependent DNA-binding molecules such as zinc finger protein array (ZFA), transcription activator-like effector (TALE) and clustered regularly interspaced short palindromic repeat-associated dead Cas9 (CRISPR/dCas9). Synthetic proteins, where these DNA-binding domains are fused with the DNA demethylases such as ten-eleven translocation (Tet) and thymine DNA glycosylase (TDG) enzymes, successfully induced or enhanced transcriptional responsiveness at targeted loci. However, a number of challenges, including the dependence on transgenesis for delivery of the fusion constructs, remain issues to be solved. In this review, we detail current and potential approaches to gene-specific DNA demethylation as a novel epigenetic editing-based therapeutic strategy. Full article

(This article belongs to the Special Issue Molecular Tools for Epigenetic Engineering)

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41 pages, 1567 KiB

Open AccessEditor’s ChoiceReview

The Role of Adipokines in Health and Disease

by Vicente Javier Clemente-Suárez, Laura Redondo-Flórez, Ana Isabel Beltrán-Velasco, Alexandra Martín-Rodríguez, Ismael Martínez-Guardado, Eduardo Navarro-Jiménez, Carmen Cecilia Laborde-Cárdenas and José Francisco Tornero-Aguilera

Biomedicines 2023, 11(5), 1290; https://doi.org/10.3390/biomedicines11051290 - 27 Apr 2023

Cited by 197 | Viewed by 16678

Abstract

Adipokines are cell-signaling proteins secreted by adipose tissue that has been related to a low-grade state of inflammation and different pathologies. The present review aims to analyze the role of adipokines in health and disease in order to understand the important functions and [...] Read more.

Adipokines are cell-signaling proteins secreted by adipose tissue that has been related to a low-grade state of inflammation and different pathologies. The present review aims to analyze the role of adipokines in health and disease in order to understand the important functions and effects of these cytokines. For this aim, the present review delves into the type of adipocytes and the cytokines produced, as well as their functions; the relations of adipokines in inflammation and different diseases such as cardiovascular, atherosclerosis, mental diseases, metabolic disorders, cancer, and eating behaviors; and finally, the role of microbiota, nutrition, and physical activity in adipokines is discussed. This information would allow for a better understanding of these important cytokines and their effects on body organisms. Full article

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

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14 pages, 26769 KiB

Open AccessEditor’s ChoiceArticle

A Combination of an Angiotensin II Receptor and a Neprilysin Inhibitor Attenuates Liver Fibrosis by Preventing Hepatic Stellate Cell Activation

by Junya Suzuki, Kosuke Kaji, Norihisa Nishimura, Takahiro Kubo, Fumimasa Tomooka, Akihiko Shibamoto, Satoshi Iwai, Yuki Tsuji, Yukihisa Fujinaga, Koh Kitagawa, Tadashi Namisaki, Takemi Akahane and Hitoshi Yoshiji

Biomedicines 2023, 11(5), 1295; https://doi.org/10.3390/biomedicines11051295 - 27 Apr 2023

Cited by 6 | Viewed by 2326

Abstract

The renin–angiotensin–aldosterone system has gained attention due to its role as a mediator of liver fibrosis and hepatic stellate cell (HSC) activation. Meanwhile, the natriuretic peptide (NP) system, including atrial NP (ANP) and C-type NP (CNP), is a counter-regulatory hormone regulated by neprilysin. [...] Read more.

The renin–angiotensin–aldosterone system has gained attention due to its role as a mediator of liver fibrosis and hepatic stellate cell (HSC) activation. Meanwhile, the natriuretic peptide (NP) system, including atrial NP (ANP) and C-type NP (CNP), is a counter-regulatory hormone regulated by neprilysin. Although the combination of an angiotensin receptor and a neprilysin inhibitor (sacubitril/valsartan: SAC/VAL) has shown clinical efficacy in patients with heart failure, its potential effects on hepatic fibrosis have not been clarified. This study assessed the effects of SAC/VAL in carbon tetrachloride (CCl₄)-induced murine liver fibrosis as well as the in vitro phenotypes of HSCs. Treatment with SAC and VAL markedly attenuated CCl₄-induced liver fibrosis while reducing α-SMA⁺-HSC expansion and decreasing hepatic hydroxyproline and mRNA levels of pro-fibrogenic markers. Treatment with SAC increased plasma ANP and CNP levels in CCl₄-treated mice, and ANP effectively suppressed cell proliferation and TGF-β-stimulated MMP2 and TIMP2 expression in LX-2 cells by activating guanylate cyclase-A/cGMP/protein kinase G signaling. Meanwhile, CNP did not affect the pro-fibrogenic activity of LX-2 cells. Moreover, VAL directly inhibited angiotensin II (AT-II)-stimulated cell proliferation and the expression of TIMP1 and CTGF through the blockade of the AT-II type 1 receptor/protein kinase C pathway. Collectively, SAC/VAL may be a novel therapeutic treatment for liver fibrosis. Full article

(This article belongs to the Special Issue Liver Fibrosis: Molecular Mechanisms, Potential Therapeutic Targets and Clinical Biomarkers)

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15 pages, 2262 KiB

Open AccessEditor’s ChoiceReview

Degradation and Failure Phenomena at the Dentin Bonding Interface

by Lamia Sami Mokeem, Isadora Martini Garcia and Mary Anne Melo

Biomedicines 2023, 11(5), 1256; https://doi.org/10.3390/biomedicines11051256 - 23 Apr 2023

Cited by 37 | Viewed by 8202

Abstract

Damage in the bonding interface is a significant factor that leads to premature failure of dental bonded restorations. The imperfectly bonded dentin-adhesive interface is susceptible to hydrolytic degradation and bacterial and enzyme attack, severely jeopardizing restorations’ longevity. Developing caries around previously made restorations, [...] Read more.

Damage in the bonding interface is a significant factor that leads to premature failure of dental bonded restorations. The imperfectly bonded dentin-adhesive interface is susceptible to hydrolytic degradation and bacterial and enzyme attack, severely jeopardizing restorations’ longevity. Developing caries around previously made restorations, also called “recurrent or secondary caries,” is a significant health problem. The replacement of restorations is the most prevailing treatment in dental clinics, leading to the so-called “tooth death spiral”. In other words, every time a restoration is replaced, more tooth tissue is removed, increasing the size of the restorations until the tooth is eventually lost. This process leads to high financial costs and detriment to patients’ quality of life. Since the complexity of the oral cavity makes prevention a challenging task, novel strategies in Dental Materials and Operative fields are required. This article briefly overviews the physiological dentin substrate, features of dentin bonding, challenges and clinical relevance. We discussed the anatomy of the dental bonding interface, aspects of the degradation at the resin-dentin interface, extrinsic and intrinsic factors affecting dental bonding longevity, perspectives on resin and collagen degradation and how these subjects are connected. In this narrative review, we also outlined the recent progress in overcoming dental bonding challenges through bioinspiration, nanotechnology and advanced techniques to reduce degradation and improve dental bonding longevity. Full article

(This article belongs to the Section Biomedical Engineering and Materials)

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27 pages, 4077 KiB

Open AccessEditor’s ChoiceArticle

MicroRNA Signatures in Cartilage Ageing and Osteoarthritis

by Panagiotis Balaskas, Katarzyna Goljanek-Whysall, Peter D. Clegg, Yongxiang Fang, Andy Cremers, Aibek Smagul, Tim J. M. Welting and Mandy J. Peffers

Biomedicines 2023, 11(4), 1189; https://doi.org/10.3390/biomedicines11041189 - 17 Apr 2023

Cited by 14 | Viewed by 2906

Abstract

Osteoarthritis is the most common degenerative joint disorder. MicroRNAs are gene expression regulators that act post-transcriptionally to control tissue homeostasis. Microarray analysis was undertaken in osteoarthritic intact, lesioned and young intact cartilage. Principal component analysis showed that young intact cartilage samples were clustered [...] Read more.

Osteoarthritis is the most common degenerative joint disorder. MicroRNAs are gene expression regulators that act post-transcriptionally to control tissue homeostasis. Microarray analysis was undertaken in osteoarthritic intact, lesioned and young intact cartilage. Principal component analysis showed that young intact cartilage samples were clustered together; osteoarthritic samples had a wider distribution; and osteoarthritic intact samples were separated into two subgroups, osteoarthritic-Intact-1 and osteoarthritic-Intact-2. We identified 318 differentially expressed microRNAs between young intact and osteoarthritic lesioned cartilage, 477 between young intact and osteoarthritic-Intact-1 cartilage and 332 between young intact and osteoarthritic-Intact-2 cartilage samples. For a selected list of differentially expressed microRNAs, results were verified in additional cartilage samples using qPCR. Of the validated DE microRNAs, four—miR-107, miR-143-3p, miR-361-5p and miR-379-5p—were selected for further experiments in human primary chondrocytes treated with IL-1β. Expression of these microRNAs decreased in human primary chondrocytes treated with IL-1β. For miR-107 and miR-143-3p, gain- and loss-of-function approaches were undertaken and associated target genes and molecular pathways were investigated using qPCR and mass spectrometry proteomics. Analyses showed that WNT4 and IHH, predicted targets of miR-107, had increased expression in osteoarthritic cartilage compared to young intact cartilage and in primary chondrocytes treated with miR-107 inhibitor, and decreased expression in primary chondrocytes treated with miR-107 mimic, suggesting a role of miR-107 in chondrocyte survival and proliferation. In addition, we identified an association between miR-143-3p and EIF2 signalling and cell survival. Our work supports the role of miR-107 and miR-143-3p in important chondrocyte mechanisms regulating proliferation, hypertrophy and protein translation. Full article

(This article belongs to the Special Issue Non-coding RNAs in Health and Disease 2.0)

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10 pages, 1242 KiB

Open AccessEditor’s ChoiceArticle

Dihydrotestosterone, and Not Testosterone, Enhances the LPS-Induced Inflammatory Cytokine Gene Expression in Human Adipocytes

by Angelo Di Vincenzo, Marnie Granzotto, Marika Crescenzi, Vincenzo Vindigni, Roberto Vettor and Marco Rossato

Biomedicines 2023, 11(4), 1194; https://doi.org/10.3390/biomedicines11041194 - 17 Apr 2023

Cited by 7 | Viewed by 3296

Abstract

Background: The development of obesity-related complications lies in the low-grade inflammatory state consequent to adipocyte dysfunction. The direct involvement of sex hormones in adipose tissue inflammation has been previously suggested, but the evidence is scarce. In this study, we evaluated the effects of [...] Read more.

Background: The development of obesity-related complications lies in the low-grade inflammatory state consequent to adipocyte dysfunction. The direct involvement of sex hormones in adipose tissue inflammation has been previously suggested, but the evidence is scarce. In this study, we evaluated the effects of sex steroids on the in-vitroexpression of inflammatory mediators in human-derived adipocytes before and after lipopolysaccharide (LPS) exposure. Methods: Human adipocytes were differentiated from the vascular stromal fraction of adipose tissue samples of subjects undergoing abdominoplasty. We evaluated MCP-1, IL-1β, IL-6, and TNF-α gene expression in the presence of the main sex steroids, testosterone (T), and 17β-estradiol (E). Furthermore, we analyzed the effects of adipocytes exposure to the non-aromatizable androgen dihydrotestosterone (DHT), together with the effects of adipocytes pre-incubation with the aromatase inhibitor anastrozole alone (A), and in combination with T (A/T) before incubation with LPS. Results: DHT, but not T, significantly enhanced the LPSinduction of MCP-1, IL-1β, IL-6, and TNF-α. Intriguingly, the exposure of adipocytes with A/T dramatically increased the LPS-induced expression of all considered inflammatory cytokines, even more than a hundred-fold. Conclusions: DHT and A/T dramatically enhance LPS-induced inflammatory cytokine expression in human-derived adipocytes. These results confirm the involvement of sex hormones in adipose tissue inflammation, suggesting a specific role for non-aromatizable androgens as the amplificatory sex hormones of the inflammatory response. Full article

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

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Graphical abstract

9 pages, 1258 KiB

Open AccessEditor’s ChoiceBrief Report

Long-Term Benefit of Perlingual Polybacterial Vaccines in Patients with Systemic Autoimmune Diseases and Active Immunosuppression

by Inés Pérez-Sancristóbal, Eduardo de la Fuente, María Paula Álvarez-Hernández, Kissy Guevara-Hoyer, Concepción Morado, Cristina Martínez-Prada, Dalifer Freites-Nuñez, Virginia Villaverde, Miguel Fernández-Arquero, Benjamín Fernández-Gutiérrez, Silvia Sánchez-Ramón and Gloria Candelas

Biomedicines 2023, 11(4), 1168; https://doi.org/10.3390/biomedicines11041168 - 13 Apr 2023

Cited by 7 | Viewed by 2529

Abstract

Introduction: We have previously shown that trained-immunity-based vaccines, namely TIbV, significantly reduce the rate of recurrent infections, both of the respiratory tract (RRTI) and urinary tract infections (RUTI) in SAD patients on disease-modifying drugs (DMARDs). Objective: We evaluated the frequency of RRTI and [...] Read more.

Introduction: We have previously shown that trained-immunity-based vaccines, namely TIbV, significantly reduce the rate of recurrent infections, both of the respiratory tract (RRTI) and urinary tract infections (RUTI) in SAD patients on disease-modifying drugs (DMARDs). Objective: We evaluated the frequency of RRTI and RUTI from 2018 to 2021 in those SAD patients that received TIbV until 2018. Secondarily, we evaluated the incidence and clinical course of COVID-19 in this cohort. Methods: A retrospective observational study was conducted in a cohort of SAD patients under active immunosuppression immunized with TIbV (MV130 for RRTI and MV140 for RUTI, respectively). Results: Forty-one SAD patients on active immunosuppression that were given TIbV up to 2018 were studied for RRTI and RUTI during the 2018–2021 period. Approximately half of the patients had no infections during 2018–2021 (51.2% no RUTI and 43.5% no RRTI at all). When we compared the 3-year period with the 1-year pre-TIbV, RRTI (1.61 ± 2.26 vs. 2.76 ± 2.57; p = 0.002) and RUTI (1.56 ± 2.12 vs. 2.69 ± 3.07; p = 0.010) episodes were still significantly lower. Six SAD patients (four RA; one SLE; one MCTD) with RNA-based vaccines were infected with SARS-CoV-2, with mild disease. Conclusions: Even though the beneficial protective effects against infections of TIbV progressively decreased, they remained low for up to 3 years, with significantly reduced infections compared to the year prior to vaccination, further supporting a long-term benefit of TIbV in this setting. Moreover, an absence of infections was observed in almost half of patients. Full article

(This article belongs to the Special Issue Disease Biomarkers in Immunomediated Diseases)

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25 pages, 1336 KiB

Open AccessEditor’s ChoiceReview

Increased Risk of Aging-Related Neurodegenerative Disease after Traumatic Brain Injury

by Sarah Barker, Bindu D. Paul and Andrew A. Pieper

Biomedicines 2023, 11(4), 1154; https://doi.org/10.3390/biomedicines11041154 - 11 Apr 2023

Cited by 30 | Viewed by 5418

Abstract

Traumatic brain injury (TBI) survivors frequently suffer from chronically progressive complications, including significantly increased risk of developing aging-related neurodegenerative disease. As advances in neurocritical care increase the number of TBI survivors, the impact and awareness of this problem are growing. The mechanisms by [...] Read more.

Traumatic brain injury (TBI) survivors frequently suffer from chronically progressive complications, including significantly increased risk of developing aging-related neurodegenerative disease. As advances in neurocritical care increase the number of TBI survivors, the impact and awareness of this problem are growing. The mechanisms by which TBI increases the risk of developing aging-related neurodegenerative disease, however, are not completely understood. As a result, there are no protective treatments for patients. Here, we review the current literature surrounding the epidemiology and potential mechanistic relationships between brain injury and aging-related neurodegenerative disease. In addition to increasing the risk for developing all forms of dementia, the most prominent aging-related neurodegenerative conditions that are accelerated by TBI are amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson’s disease (PD), and Alzheimer’s disease (AD), with ALS and FTD being the least well-established. Mechanistic links between TBI and all forms of dementia that are reviewed include oxidative stress, dysregulated proteostasis, and neuroinflammation. Disease-specific mechanistic links with TBI that are reviewed include TAR DNA binding protein 43 and motor cortex lesions in ALS and FTD; alpha-synuclein, dopaminergic cell death, and synergistic toxin exposure in PD; and brain insulin resistance, amyloid beta pathology, and tau pathology in AD. While compelling mechanistic links have been identified, significantly expanded investigation in the field is needed to develop therapies to protect TBI survivors from the increased risk of aging-related neurodegenerative disease. Full article

(This article belongs to the Special Issue Feature Reviews in Neurodegenerative Diseases and Environmental Factors)

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13 pages, 747 KiB

Open AccessEditor’s ChoiceArticle

The Relationship between Type 1 Diabetes Mellitus, TNF-α, and IL-10 Gene Expression

by Jesselina Francisco dos Santos Haber, Sandra Maria Barbalho, Jose Augusto Sgarbi, Rafael Santos de Argollo Haber, Roger William de Labio, Lucas Fornari Laurindo, Eduardo Federighi Baisi Chagas and Spencer Luiz Marques Payão

Biomedicines 2023, 11(4), 1120; https://doi.org/10.3390/biomedicines11041120 - 7 Apr 2023

Cited by 25 | Viewed by 4180

Abstract

Type 1 diabetes mellitus (T1DM) is one of the major chronic diseases in children worldwide. This study aimed to investigate interleukin-10 (IL-10) gene expression and tumor necrosis factor-alpha (TNF-α) in T1DM. A total of 107 patients were included, 15 were T1DM in ketoacidosis, [...] Read more.

Type 1 diabetes mellitus (T1DM) is one of the major chronic diseases in children worldwide. This study aimed to investigate interleukin-10 (IL-10) gene expression and tumor necrosis factor-alpha (TNF-α) in T1DM. A total of 107 patients were included, 15 were T1DM in ketoacidosis, 30 patients had T1DM and HbA1c ≥ 8%; 32 patients had T1DM and presented HbA1c < 8%; and 30 were controls. The expression of peripheral blood mononuclear cells was performed using the reverse transcriptase–polymerase chain reaction in real time. The cytokines gene expression was higher in patients with T1DM. The IL-10 gene expression increased substantially in patients with ketoacidosis, and there was a positive correlation with HbA1c. A negative correlation was found for IL-10 expression and the age of patients with diabetes, and the time of diagnosis of the disease. There was a positive correlation between TNF-α expression with age. The expression of IL-10 and TNF-α genes showed a significant increase in DM1 patients. Once current T1DM treatment is based on exogenous insulin, there is a need for other therapies, and inflammatory biomarkers could bring new possibilities to the therapeutic approach of the patients. Full article

(This article belongs to the Section Endocrinology and Metabolism Research)

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23 pages, 755 KiB

Open AccessEditor’s ChoiceReview

Non-Alcoholic Fatty Liver Disease or Type 2 Diabetes Mellitus—The Chicken or the Egg Dilemma

by Marcin Kosmalski, Agnieszka Śliwińska and Józef Drzewoski

Biomedicines 2023, 11(4), 1097; https://doi.org/10.3390/biomedicines11041097 - 4 Apr 2023

Cited by 24 | Viewed by 7578

Abstract

In clinical practice, we often deal with patients who suffer from non-alcoholic fatty liver disease (NAFLD) concurrent with type 2 diabetes mellitus (T2DM). The etiopathogenesis of NAFLD is mainly connected with insulin resistance (IR) and obesity. Similarly, the latter patients are in the [...] Read more.

In clinical practice, we often deal with patients who suffer from non-alcoholic fatty liver disease (NAFLD) concurrent with type 2 diabetes mellitus (T2DM). The etiopathogenesis of NAFLD is mainly connected with insulin resistance (IR) and obesity. Similarly, the latter patients are in the process of developing T2DM. However, the mechanisms of NAFLD and T2DM coexistence have not been fully elucidated. Considering that both diseases and their complications are of epidemic proportions and significantly affect the length and quality of life, we aimed to answer which of these diseases appears first and thereby highlight the need for their diagnosis and treatment. To address this question, we present and discuss the epidemiological data, diagnoses, complications and pathomechanisms of these two coexisting metabolic diseases. This question is difficult to answer due to the lack of a uniform procedure for NAFLD diagnosis and the asymptomatic nature of both diseases, especially at their beginning stages. To conclude, most researchers suggest that NAFLD appears as the first disease and starts the sequence of circumstances leading ultimately to the development of T2DM. However, there are also data suggesting that T2DM develops before NAFLD. Despite the fact that we cannot definitively answer this question, it is very important to bring the attention of clinicians and researchers to the coexistence of NAFLD and T2DM in order to prevent their consequences. Full article

(This article belongs to the Special Issue Advanced Research in Metabolic Syndrome)

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13 pages, 467 KiB

Open AccessEditor’s ChoiceReview

Antifungal Drug Resistance: An Emergent Health Threat

by Antonio Vitiello, Francesco Ferrara, Mariarosaria Boccellino, Annarita Ponzo, Carla Cimmino, Emilio Comberiati, Andrea Zovi, Salvatore Clemente and Michela Sabbatucci

Biomedicines 2023, 11(4), 1063; https://doi.org/10.3390/biomedicines11041063 - 31 Mar 2023

Cited by 95 | Viewed by 11202

Abstract

Fungal infections, named mycosis, can cause severe invasive and systemic diseases that can even lead to death. In recent years, epidemiological data have recorded an increase in cases of severe fungal infections, caused mainly by a growing number of immunocompromised patients and the [...] Read more.

Fungal infections, named mycosis, can cause severe invasive and systemic diseases that can even lead to death. In recent years, epidemiological data have recorded an increase in cases of severe fungal infections, caused mainly by a growing number of immunocompromised patients and the emergence of fungal pathogenic forms that are increasingly resistant to antimycotic drug treatments. Consequently, an increase in the incidence of mortality due to fungal infections has also been observed. Among the most drug-resistant fungal forms are those belonging to the Candida and Aspergillus spp. Some pathogens are widespread globally, while others are endemic in some areas only. In addition, some others may represent a health threat for some specific subpopulations and not for the general public. In contrast to the extensive therapeutic armamentarium available for the antimicrobial chemotherapeutic treatment of bacteria, for fungal infections there are only a few classes of antimycotic drugs on the market, such as polyenes, azoles, echinocandins, and a few molecules are under trial. In this review, we focused on the systemic mycosis, highlighted the antifungal drug compounds available in the pipeline, and analyzed the main molecular mechanisms for the development of antifungal resistance to give a comprehensive overview and increase awareness on this growing health threat. Full article

(This article belongs to the Special Issue Antimicrobial Resistance: A Global Challenge)

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20 pages, 5312 KiB

Open AccessEditor’s ChoiceArticle

3D Spheroid Cultivation Alters the Extent and Progression of Osteogenic Differentiation of Mesenchymal Stem/Stromal Cells Compared to 2D Cultivation

by Anne Wolff, Marcus Frank, Susanne Staehlke, Armin Springer, Olga Hahn, Juliane Meyer and Kirsten Peters

Biomedicines 2023, 11(4), 1049; https://doi.org/10.3390/biomedicines11041049 - 29 Mar 2023

Cited by 11 | Viewed by 3301

Abstract

Mesenchymal stem/stromal cells (MSC) are capable of progenitor cell fraction renewal or tissue-specific differentiation. These properties are maintained during in vitro cultivation, making them an interesting model system for testing biological and pharmacological compounds. Cell cultivation in 2D is commonly used to study [...] Read more.

Mesenchymal stem/stromal cells (MSC) are capable of progenitor cell fraction renewal or tissue-specific differentiation. These properties are maintained during in vitro cultivation, making them an interesting model system for testing biological and pharmacological compounds. Cell cultivation in 2D is commonly used to study cellular responses, but the 2D environment does not reflect the structural situation of most cell types. Therefore, 3D culture systems have been developed to provide a more accurate physiological environment in terms of cell–cell interactions. Since knowledge about the effects of 3D culture on specific differentiation processes is limited, we studied the effects on osteogenic differentiation and the release of factors affecting bone metabolism for up to 35 days and compared them with the effects in 2D culture. We demonstrated that the selected 3D model allowed the rapid and reliable formation of spheroids that were stable over several weeks and both accelerated and enhanced osteogenic differentiation compared with the 2D culture. Thus, our experiments provide new insights into the effects of cell arrangement of MSC in 2D and 3D. However, due to the different culture dimensions, various detection methods had to be chosen, which in principle limits the explanatory power of the comparison between 2D and 3D cultures. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—3D In Vitro Models as an Alternative to Animal Experimentation: Advantages and Pitfalls)

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14 pages, 2425 KiB

Open AccessEditor’s ChoiceArticle

In Vitro Effects of PTH (1-84) on Human Skeletal Muscle-Derived Satellite Cells

by Cecilia Romagnoli, Roberto Zonefrati, Elena Lucattelli, Marco Innocenti, Roberto Civinini, Teresa Iantomasi and Maria Luisa Brandi

Biomedicines 2023, 11(4), 1017; https://doi.org/10.3390/biomedicines11041017 - 27 Mar 2023

Cited by 4 | Viewed by 2245

Abstract

Parathyroid hormone (PTH) is a hormone secreted by the parathyroid glands. Despite its well-known characterized anabolic and catabolic actions on the skeleton, the in vitro effects of PTH on skeletal muscle cells are limited and generally performed on animal models. The aim of [...] Read more.

Parathyroid hormone (PTH) is a hormone secreted by the parathyroid glands. Despite its well-known characterized anabolic and catabolic actions on the skeleton, the in vitro effects of PTH on skeletal muscle cells are limited and generally performed on animal models. The aim of this study was to evaluate the effects of a short impulse of PTH (1-84) on the proliferation and the differentiation of skeletal muscle satellite cells isolated from human biopsies. The cells were exposed for 30 min to different concentrations of PTH (1-84), from 10⁻⁶ mol/L to 10⁻¹² mol/L. ELISA was used to assay cAMP and the myosin heavy-chain (MHC) protein. The proliferation was assayed by BrdU and the differentiation by RealTime-qPCR. A statistical analysis was performed by ANOVA followed by Bonferroni’s test. No significant variations in cAMP and the proliferation were detected in the isolated cells treated with PTH. On the other hand, 10⁻⁷ mol/L PTH on differentiated myotubes has shown significant increases in cAMP (p ≤ 0.05), in the expression of myogenic differentiation genes (p ≤ 0.001), and in the MHC protein (p ≤ 0.01) vs. untreated controls. This work demonstrates for the first time the in vitro effects of PTH (1-84) on human skeletal muscle cells and it opens new fields of investigation in muscle pathophysiology. Full article

(This article belongs to the Special Issue Musculoskeletal Diseases: From Molecular Basis to Therapy)

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10 pages, 255 KiB

Open AccessEditor’s ChoiceReview

Mesenchymal Stem Cell-Derived Exosomes Modulate Angiogenesis in Gastric Cancer

by Fawzy Akad, Veronica Mocanu, Sorin Nicolae Peiu, Viorel Scripcariu, Bogdan Filip, Daniel Timofte, Florin Zugun-Eloae, Magdalena Cuciureanu, Monica Hancianu, Teodor Oboroceanu, Laura Condur and Radu Florin Popa

Biomedicines 2023, 11(4), 1031; https://doi.org/10.3390/biomedicines11041031 - 27 Mar 2023

Cited by 20 | Viewed by 3691

Abstract

Individualized gastric cancer (GC) treatment aims at providing targeted therapies that translate the latest research into improved management strategies. Extracellular vesicle microRNAs have been proposed as biomarkers for GC prognosis. Helicobacter pylori infection influences the therapeutic response to and the drivers of malignant [...] Read more.

Individualized gastric cancer (GC) treatment aims at providing targeted therapies that translate the latest research into improved management strategies. Extracellular vesicle microRNAs have been proposed as biomarkers for GC prognosis. Helicobacter pylori infection influences the therapeutic response to and the drivers of malignant changes in chronic gastritis. The successful use of transplanted mesenchymal stem cells (MSCs) for gastric ulcer healing has raised interest in studying their effects on tumor neovascularization and in potential antiangiogenic therapies that could use mesenchymal stem cell secretion into extracellular vesicles—such as exosomes—in GC cells. The use of MSCs isolated from bone marrow in order to achieve angiogenic modulation in the tumor microenvironment could exploit the inherent migration of MSCs into GC tissues. Bone marrow-derived MSCs naturally present in the stomach have been reported to carry a malignancy risk, but their effect in GC is still being researched. The pro- and antiangiogenic effects of MSCs derived from various sources complement their role in immune regulation and tissue regeneration and provide further understanding into the heterogeneous biology of GC, the aberrant morphology of tumor vasculature and the mechanisms of resistance to antiangiogenic drugs. Full article

(This article belongs to the Special Issue Angiogenesis and Lymphangiogenesis in Gastrointestinal Tumor Microenvironment: From Molecular to Clinical Aspects)

62 pages, 2744 KiB

Open AccessEditor’s ChoiceReview

NLRP3 Inflammasome’s Activation in Acute and Chronic Brain Diseases—An Update on Pathogenetic Mechanisms and Therapeutic Perspectives with Respect to Other Inflammasomes

by Anna Chiarini, Li Gui, Chiara Viviani, Ubaldo Armato and Ilaria Dal Prà

Biomedicines 2023, 11(4), 999; https://doi.org/10.3390/biomedicines11040999 - 23 Mar 2023

Cited by 21 | Viewed by 8740

Abstract

Increasingly prevalent acute and chronic human brain diseases are scourges for the elderly. Besides the lack of therapies, these ailments share a neuroinflammation that is triggered/sustained by different innate immunity-related protein oligomers called inflammasomes. Relevant neuroinflammation players such as microglia/monocytes typically exhibit a [...] Read more.

Increasingly prevalent acute and chronic human brain diseases are scourges for the elderly. Besides the lack of therapies, these ailments share a neuroinflammation that is triggered/sustained by different innate immunity-related protein oligomers called inflammasomes. Relevant neuroinflammation players such as microglia/monocytes typically exhibit a strong NLRP3 inflammasome activation. Hence the idea that NLRP3 suppression might solve neurodegenerative ailments. Here we review the recent Literature about this topic. First, we update conditions and mechanisms, including RNAs, extracellular vesicles/exosomes, endogenous compounds, and ethnic/pharmacological agents/extracts regulating NLRP3 function. Second, we pinpoint NLRP3-activating mechanisms and known NLRP3 inhibition effects in acute (ischemia, stroke, hemorrhage), chronic (Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, MS, ALS), and virus-induced (Zika, SARS-CoV-2, and others) human brain diseases. The available data show that (i) disease-specific divergent mechanisms activate the (mainly animal) brains NLRP3; (ii) no evidence proves that NLRP3 inhibition modifies human brain diseases (yet ad hoc trials are ongoing); and (iii) no findings exclude that concurrently activated other-than-NLRP3 inflammasomes might functionally replace the inhibited NLRP3. Finally, we highlight that among the causes of the persistent lack of therapies are the species difference problem in disease models and a preference for symptomatic over etiologic therapeutic approaches. Therefore, we posit that human neural cell-based disease models could drive etiological, pathogenetic, and therapeutic advances, including NLRP3’s and other inflammasomes’ regulation, while minimizing failure risks in candidate drug trials. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Translational Laboratory and Experimental Medicine for the Sake of Neurological Diseases and Mental Illnesses)

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18 pages, 5639 KiB

Open AccessEditor’s ChoiceArticle

In Silico Identification of Lead Compounds for Pseudomonas Aeruginosa PqsA Enzyme: Computational Study to Block Biofilm Formation

by Muhammad Shahab, Muhammad Danial, Taimur Khan, Chaoqun Liang, Xiuyuan Duan, Daixi Wang, Hanzi Gao and Guojun Zheng

Biomedicines 2023, 11(3), 961; https://doi.org/10.3390/biomedicines11030961 - 21 Mar 2023

Cited by 11 | Viewed by 3140

Abstract

Pseudomonas aeruginosa is an opportunistic Gram-negative bacterium implicated in acute and chronic nosocomial infections and a leading cause of patient mortality. Pseudomonas aeruginosa infections are frequently associated with the development of biofilms, which give the bacteria additional drug resistance and increase their virulence. [...] Read more.

Pseudomonas aeruginosa is an opportunistic Gram-negative bacterium implicated in acute and chronic nosocomial infections and a leading cause of patient mortality. Pseudomonas aeruginosa infections are frequently associated with the development of biofilms, which give the bacteria additional drug resistance and increase their virulence. The goal of this study was to find strong compounds that block the Anthranilate-CoA ligase enzyme made by the pqsA gene. This would stop the P. aeruginosa quorum signaling system. This enzyme plays a crucial role in the pathogenicity of P. aeruginosa by producing autoinducers for cell-to-cell communication that lead to the production of biofilms. Pharmacophore-based virtual screening was carried out utilizing a library of commercially accessible enzyme inhibitors. The most promising hits obtained during virtual screening were put through molecular docking with the help of MOE. The virtual screening yielded 7/160 and 10/249 hits (ZINC and Chembridge). Finally, 2/7 ZINC hits and 2/10 ChemBridge hits were selected as potent lead compounds employing diverse scaffolds due to their high pqsA enzyme binding affinity. The results of the pharmacophore-based virtual screening were subsequently verified using a molecular dynamic simulation-based study (MDS). Using MDS and post-MDS, the stability of the complexes was evaluated. The most promising lead compounds exhibited a high binding affinity towards protein-binding pocket and interacted with the catalytic dyad. At least one of the scaffolds selected will possibly prove useful for future research. However, further scientific confirmation in the form of preclinical and clinical research is required before implementation. Full article

(This article belongs to the Special Issue Drug Discovery for Infectious Diseases)

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13 pages, 3068 KiB

Open AccessEditor’s ChoiceReview

Updates on Lymphovascular Invasion in Breast Cancer

by Elisabetta Kuhn, Donatella Gambini, Luca Despini, Dario Asnaghi, Letterio Runza and Stefano Ferrero

Biomedicines 2023, 11(3), 968; https://doi.org/10.3390/biomedicines11030968 - 21 Mar 2023

Cited by 28 | Viewed by 13513

Abstract

Traditionally, lymphovascular invasion (LVI) has represented one of the foremost pathological features of malignancy and has been associated with a worse prognosis in different cancers, including breast carcinoma. According to the most updated reporting protocols, the assessment of LVI is required in the [...] Read more.

Traditionally, lymphovascular invasion (LVI) has represented one of the foremost pathological features of malignancy and has been associated with a worse prognosis in different cancers, including breast carcinoma. According to the most updated reporting protocols, the assessment of LVI is required in the pathology report of breast cancer surgical specimens. Importantly, strict histological criteria should be followed for LVI assessment, which nevertheless is encumbered by inconsistency in interpretation among pathologists, leading to significant interobserver variability and scarce reproducibility. Current guidelines for breast cancer indicate biological factors as the main determinants of oncological and radiation therapy, together with TNM staging and age. In clinical practice, the widespread use of genomic assays as a decision-making tool for hormone receptor-positive, HER2-negative breast cancer and the subsequent availability of a reliable prognostic predictor have likely scaled back interest in LVI’s predictive value. However, in selected cases, the presence of LVI impacts adjuvant therapy. This review summarizes current knowledge on LVI in breast cancer with regard to definition, histopathological assessment, its biological understanding, clinicopathological association, and therapeutic implications. Full article

(This article belongs to the Special Issue Cancer Immunology: From Molecular Mechanisms to Therapeutic Target through Emerging In Vitro Approaches)

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29 pages, 4972 KiB

Open AccessEditor’s ChoiceReview

G-Quadruplexes in c-MYC Promoter as Targets for Cancer Therapy

by Bárbara Bahls, Israa M. Aljnadi, Rita Emídio, Eduarda Mendes and Alexandra Paulo

Biomedicines 2023, 11(3), 969; https://doi.org/10.3390/biomedicines11030969 - 21 Mar 2023

Cited by 29 | Viewed by 4988

Abstract

Cancer is a societal burden demanding innovative approaches. A major problem with the conventional chemotherapeutic agents is their strong toxicity and other side effects due to their poor selectivity. Uncontrolled proliferation of cancer cells is due to mutations, deletions, or amplifications in genes [...] Read more.

Cancer is a societal burden demanding innovative approaches. A major problem with the conventional chemotherapeutic agents is their strong toxicity and other side effects due to their poor selectivity. Uncontrolled proliferation of cancer cells is due to mutations, deletions, or amplifications in genes (oncogenes) encoding for proteins that regulate cell growth and division, such as transcription factors, for example, c-MYC. The direct targeting of the c-MYC protein has been attempted but so far unsuccessfully, as it lacks a definite binding site for the modulators. Meanwhile, another approach has been explored since the discovery that G-quadruplex secondary DNA structures formed in the guanine-rich sequences of the c-MYC promoter region can downregulate the transcription of this oncogene. Here, we will overview the major achievements made in the last decades towards the discovery of a new class of anticancer drugs targeting G-quadruplexes in the c-MYC promoter of cancer cells. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series in Drug Discovery)

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12 pages, 1602 KiB

Open AccessEditor’s ChoiceArticle

An Observational Study on Chronic Pain Biomarkers in Fibromyalgia and Osteoarthritis Patients: Which Role for Mu Opioid Receptor’s Expression on NK Cells?

by Valentina Malafoglia, Sara Ilari, Chiara Gioia, Laura Vitiello, Michael Tenti, Cristina Iannuccelli, Costanza Maria Cristiani, Cinzia Garofalo, Lucia Carmela Passacatini, Giuseppe Viglietto, Antonio Sili Scavalli, Carlo Tomino, Vincenzo Mollace, William Raffaeli, Manuela Di Franco and Carolina Muscoli

Biomedicines 2023, 11(3), 931; https://doi.org/10.3390/biomedicines11030931 - 17 Mar 2023

Cited by 12 | Viewed by 2879

Abstract

The evaluation of chronic pain is challenging because of the lack of specific biomarkers. We identified the Mu opioid receptor-positive (Mu+) B cell percentage of expression, named Mu-Lympho-Marker (MLM), as a candidate marker for chronic pain in fibromyalgia (FM) and osteoarthritis (OA) patients. [...] Read more.

The evaluation of chronic pain is challenging because of the lack of specific biomarkers. We identified the Mu opioid receptor-positive (Mu+) B cell percentage of expression, named Mu-Lympho-Marker (MLM), as a candidate marker for chronic pain in fibromyalgia (FM) and osteoarthritis (OA) patients. Here, we investigate the role of MLM on natural killer (NK) cells in the same patients. Twenty-nine FM and twelve OA patients were analyzed, and twenty-three pain-free subjects were considered as the control group. Blood samples were collected to perform immunophenotyping and Western blot analysis. Biological and clinical data were statistically analyzed. The final results showed that the percentage of NK cells expressing Mu was statistically lower in FM and OA patients than in pain-free subjects, as already demonstrated for B cells. A Western blot analysis was performed in order to detect NK cells’ functional status. Moreover, the correlation analysis of MLM expression with pharmacological therapy did not show any significant results. In conclusion, here, we confirm the role of MLM as a suitable marker for chronic pain and underline NK cells as a new possible immune cell type involved in the “Mu opioid receptor reserve theory”. Full article

(This article belongs to the Special Issue Advanced Research on Fibromyalgia)

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11 pages, 1713 KiB

Open AccessEditor’s ChoiceArticle

The Effects of the Levosimendan Metabolites OR-1855 and OR-1896 on Endothelial Pro-Inflammatory Responses

by Hannah Kipka, Rebecca Schaflinger, Roland Tomasi, Kristin Pogoda and Hanna Mannell

Biomedicines 2023, 11(3), 918; https://doi.org/10.3390/biomedicines11030918 - 16 Mar 2023

Cited by 4 | Viewed by 2394

Abstract

The calcium sensitizer levosimendan is used for the treatment of acute decompensated heart failure. A small portion (4–7%) of levosimendan is metabolized to the pharmacologically active metabolite OR-1896 via the inactive intermediate OR-1855. In addition, levosimendan has been shown to exert positive effects [...] Read more.

The calcium sensitizer levosimendan is used for the treatment of acute decompensated heart failure. A small portion (4–7%) of levosimendan is metabolized to the pharmacologically active metabolite OR-1896 via the inactive intermediate OR-1855. In addition, levosimendan has been shown to exert positive effects on the endothelium in vitro antagonizing vascular dysfunction and inflammation. However, the function of the levosimendan metabolites within this context is still unknown. In this study, we thus investigated the impact of the metabolites OR-1896 and OR-1855 on endothelial inflammatory processes in vitro. We observed a reduction of IL-1β-dependent endothelial adhesion molecule ICAM-1 and VCAM-1 as well as interleukin (IL) -6 expression upon levosimendan treatment but not after treatment with OR-1855 or OR-1896, as assessed by western blotting, flow cytometry, and qRT-PCR. Instead, the metabolites impaired IL-1β-induced ROS formation via inactivation of the MAPK p38, ERK1/2, and JNK. Our results suggest that the levosimendan metabolites OR-1896 and OR-1855 have certain anti-inflammatory properties, partly other than levosimendan. Importantly, they additionally show that the intermediate metabolite OR-1855 does, in fact, have pharmacological effects in the endothelium. This is interesting, as the metabolites are responsible for the long-term therapeutic effects of levosimendan, and heart failure is associated with vascular dysfunction and inflammation. Full article

(This article belongs to the Special Issue Vascular Diseases and Therapeutics)

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20 pages, 37650 KiB

Open AccessEditor’s ChoiceArticle

Nicotine Exerts a Stronger Immunosuppressive Effect Than Its Structural Analogs and Regulates Experimental Colitis in Rats

by Kohki Okada and Kano Matsuo

Biomedicines 2023, 11(3), 922; https://doi.org/10.3390/biomedicines11030922 - 16 Mar 2023

Cited by 8 | Viewed by 9206

Abstract

Ulcerative colitis (UC) is an intractable disease that causes persistent colonic inflammation. Numerous studies have reported that smoking can afford clinical benefits in UC. This study aimed to elucidate whether nicotine, the main component in cigarettes, can exert pharmacological effects against experimental UC. [...] Read more.

Ulcerative colitis (UC) is an intractable disease that causes persistent colonic inflammation. Numerous studies have reported that smoking can afford clinical benefits in UC. This study aimed to elucidate whether nicotine, the main component in cigarettes, can exert pharmacological effects against experimental UC. To achieve this objective, we compared the effects of nicotine with those of structural nicotine analogs in a UC rodent model (Slc: Wistar rats, male, 9-week-old, and 220–250 g/rat). Nicotine, or a respective structural analog (nornicotine, cotinine, anabasine, myosmine, and anatabine), was administered intraperitoneally daily to rats (n = 6/group) exhibiting dextran sulfate sodium-induced experimental colitis. Examining the colon tissues of model rats, we compared disease severity, cytokine secretion, and α7 nicotine acetylcholine receptor (nAChR7) expression. We observed that nicotine administration induced weight loss at 2.35% in 10 days. Notably, the reduction in histological severity (score) of UC was more pronounced in rats treated with nicotine (score = 4.83, p = 0.042) than in untreated rats (score = 8.17). Nicotine administration increased nAChR7 expression 6.88-fold (p = 0.022) in inflammatory sites of the colon, mainly by suppressing the production of interleukin (IL)-1β and IL-6. Moreover, the secretion of these cytokines was suppressed in lipopolysaccharide-stimulated rat macrophages (MΦ) treated with nicotine. In conclusion, nicotine better alleviates experimental UC than the examined structural analogs by activating nAChR7 expression and suppressing proinflammatory cytokines in MΦ. Full article

(This article belongs to the Special Issue Molecular Research on Colitis)

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15 pages, 2986 KiB

Open AccessEditor’s ChoiceArticle

Knockdown SENP1 Suppressed the Angiogenic Potential of Mesenchymal Stem Cells by Impacting CXCR4-Regulated MRTF-A SUMOylation and CCN1 Expression

by Rui Zhang, Qingxi Liu, Cuicui Lyu, Xing Gao and Wenjian Ma

Biomedicines 2023, 11(3), 914; https://doi.org/10.3390/biomedicines11030914 - 15 Mar 2023

Cited by 1 | Viewed by 2244

Abstract

The angiogenic potential of mesenchymal stem cells (MSCs) is critical for adult vascular regeneration and repair, which is regulated by various growth factors and cytokines. In the current study, we report that knockdown SUMO-specific peptidase 1 (SENP1) stimulated the SUMOylation of MRTF-A and [...] Read more.

The angiogenic potential of mesenchymal stem cells (MSCs) is critical for adult vascular regeneration and repair, which is regulated by various growth factors and cytokines. In the current study, we report that knockdown SUMO-specific peptidase 1 (SENP1) stimulated the SUMOylation of MRTF-A and prevented its translocation into the nucleus, leading to downregulation of the cytokine and angiogenic factor CCN1, which significantly impacted MSC-mediated angiogenesis and cell migration. Further studies showed that SENP1 knockdown also suppressed the expression of a chemokine receptor CXCR4, and overexpression of CXCR4 could partially abrogate MRTF-A SUMOylation and reestablish the CCN1 level. Mutation analysis confirmed that SUMOylation occurred on three lysine residues (Lys-499, Lys-576, and Lys-624) of MRTF-A. In addition, SENP1 knockdown abolished the synergistic co-activation of CCN1 between MRTF-A and histone acetyltransferase p300 by suppressing acetylation on histone3K9, histone3K14, and histone4. These results revealed an important signaling pathway to regulate MSC differentiation and angiogenesis by MRTF-A SUMOylation involving cytokine/chemokine activities mediated by CCN1 and CXCR4, which may potentially impact a variety of cellular processes such as revascularization, wound healing, and progression of cancer. Full article

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

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36 pages, 1395 KiB

Open AccessEditor’s ChoiceReview

Novel Oxidative Stress Biomarkers with Risk Prognosis Values in Heart Failure

by Mei Li Ng, Xu Ang, Kwan Yi Yap, Jun Jie Ng, Eugene Chen Howe Goh, Benjamin Bing Jie Khoo, Arthur Mark Richards and Chester Lee Drum

Biomedicines 2023, 11(3), 917; https://doi.org/10.3390/biomedicines11030917 - 15 Mar 2023

Cited by 27 | Viewed by 5030

Abstract

Oxidative stress (OS) is mediated by reactive oxygen species (ROS), which in cardiovascular and other disease states, damage DNA, lipids, proteins, other cellular and extra-cellular components. OS is both initiated by, and triggers inflammation, cardiomyocyte apoptosis, matrix remodeling, myocardial fibrosis, and neurohumoral activation. [...] Read more.

Oxidative stress (OS) is mediated by reactive oxygen species (ROS), which in cardiovascular and other disease states, damage DNA, lipids, proteins, other cellular and extra-cellular components. OS is both initiated by, and triggers inflammation, cardiomyocyte apoptosis, matrix remodeling, myocardial fibrosis, and neurohumoral activation. These have been linked to the development of heart failure (HF). Circulating biomarkers generated by OS offer potential utility in patient management and therapeutic targeting. Novel OS-related biomarkers such as NADPH oxidases (sNox2-dp, Nrf2), advanced glycation end-products (AGE), and myeloperoxidase (MPO), are signaling molecules reflecting pathobiological changes in HF. This review aims to evaluate current OS-related biomarkers and their associations with clinical outcomes and to highlight those with greatest promise in diagnosis, risk stratification and therapeutic targeting in HF. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of CVD: Focus on Atherosclerosis)

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19 pages, 571 KiB

Open AccessEditor’s ChoiceReview

Pancreatic Cancer Organoids: An Emerging Platform for Precision Medicine?

by Evangelia Sereti, Irida Papapostolou and Konstantinos Dimas

Biomedicines 2023, 11(3), 890; https://doi.org/10.3390/biomedicines11030890 - 14 Mar 2023

Cited by 16 | Viewed by 4736

Abstract

Despite recent therapeutic advances, pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies, with remarkable resistance to treatment, poor prognosis, and poor clinical outcome. More efficient therapeutic approaches are urgently needed to improve patients’ survival. Recently, the development of organoid culture [...] Read more.

Despite recent therapeutic advances, pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies, with remarkable resistance to treatment, poor prognosis, and poor clinical outcome. More efficient therapeutic approaches are urgently needed to improve patients’ survival. Recently, the development of organoid culture systems has gained substantial attention as an emerging preclinical research model. PDAC organoids have been developed to study pancreatic cancer biology, progression, and treatment response, filling the translational gap between in vitro and in vivo models. Here, we review the rapidly evolving field of PDAC organoids and their potential as powerful preclinical tools that could pave the way towards precision medicine for pancreatic cancer. Full article

(This article belongs to the Special Issue Pancreatic Ductal Adenocarcinoma: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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13 pages, 1319 KiB

Open AccessEditor’s ChoiceArticle

The Influence of Ultra-Low Tidal Volume Ventilation during Cardiopulmonary Resuscitation on Renal and Hepatic End-Organ Damage in a Porcine Model

by Katja Mohnke, Victoria Buschmann, Thomas Baller, Julian Riedel, Miriam Renz, René Rissel, Alexander Ziebart, Erik K. Hartmann and Robert Ruemmler

Biomedicines 2023, 11(3), 899; https://doi.org/10.3390/biomedicines11030899 - 14 Mar 2023

Cited by 2 | Viewed by 1613

Abstract

The optimal ventilation strategy during cardiopulmonary resuscitation (CPR) has eluded scientists for years. This porcine study aims to validate the hypothesis that ultra-low tidal volume ventilation (tidal volume 2–3 mL kg⁻¹; ULTVV) minimizes renal and hepatic end-organ damage when compared to [...] Read more.

The optimal ventilation strategy during cardiopulmonary resuscitation (CPR) has eluded scientists for years. This porcine study aims to validate the hypothesis that ultra-low tidal volume ventilation (tidal volume 2–3 mL kg⁻¹; ULTVV) minimizes renal and hepatic end-organ damage when compared to standard intermittent positive pressure ventilation (tidal volume 8–10 mL kg⁻¹; IPPV) during CPR. After induced ventricular fibrillation, the animals were ventilated using an established CPR protocol. Upon return of spontaneous circulation (ROSC), the follow-up was 20 h. After sacrifice, kidney and liver samples were harvested and analyzed histopathologically using an Endothelial, Glomerular, Tubular, and Interstitial (EGTI) scoring system for the kidney and a newly developed scoring system for the liver. Of 69 animals, 5 in the IPPV group and 6 in the ULTVV group achieved sustained ROSC and were enlisted, while 4 served as the sham group. Creatinine clearance was significantly lower in the IPPV-group than in the sham group (p < 0.001). The total EGTI score was significantly higher for ULTVV than for the sham group (p = 0.038). Aminotransferase levels and liver score showed no significant difference between the intervention groups. ULTVV may be advantageous when compared to standard ventilation during CPR in the short-term ROSC follow-up period. Full article

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

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23 pages, 1085 KiB

Open AccessEditor’s ChoiceReview

The Impact of Artificial Intelligence in the Odyssey of Rare Diseases

by Anna Visibelli, Bianca Roncaglia, Ottavia Spiga and Annalisa Santucci

Biomedicines 2023, 11(3), 887; https://doi.org/10.3390/biomedicines11030887 - 13 Mar 2023

Cited by 48 | Viewed by 16601

Abstract

Emerging machine learning (ML) technologies have the potential to significantly improve the research and treatment of rare diseases, which constitute a vast set of diseases that affect a small proportion of the total population. Artificial Intelligence (AI) algorithms can help to quickly identify [...] Read more.

Emerging machine learning (ML) technologies have the potential to significantly improve the research and treatment of rare diseases, which constitute a vast set of diseases that affect a small proportion of the total population. Artificial Intelligence (AI) algorithms can help to quickly identify patterns and associations that would be difficult or impossible for human analysts to detect. Predictive modeling techniques, such as deep learning, have been used to forecast the progression of rare diseases, enabling the development of more targeted treatments. Moreover, AI has also shown promise in the field of drug development for rare diseases with the identification of subpopulations of patients who may be most likely to respond to a particular drug. This review aims to highlight the achievements of AI algorithms in the study of rare diseases in the past decade and advise researchers on which methods have proven to be most effective. The review will focus on specific rare diseases, as defined by a prevalence rate that does not exceed 1–9/100,000 on Orphanet, and will examine which AI methods have been most successful in their study. We believe this review can guide clinicians and researchers in the successful application of ML in rare diseases. Full article

(This article belongs to the Special Issue Artificial Intelligence in the Detection of Diseases)

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15 pages, 7044 KiB

Open AccessEditor’s ChoiceArticle

Bag-1 Protects Nucleus Pulposus Cells from Oxidative Stress by Interacting with HSP70

by Kaori Suyama, Daisuke Sakai, Shogo Hayashi, Ning Qu, Hayato Terayama, Daisuke Kiyoshima, Kenta Nagahori and Masahiko Watanabe

Biomedicines 2023, 11(3), 863; https://doi.org/10.3390/biomedicines11030863 - 12 Mar 2023

Cited by 4 | Viewed by 1941

Abstract

Bcl-2-associated athanogene 1 (Bag-1) is a multifunctional prosurvival protein that binds to several intracellular targets and promotes cell survival. HSP70 and Raf-1 are important targets of Bag-1; however, the protective function of Bag-1 in nucleus pulposus (NP) cells remains unclear. In this study, [...] Read more.

Bcl-2-associated athanogene 1 (Bag-1) is a multifunctional prosurvival protein that binds to several intracellular targets and promotes cell survival. HSP70 and Raf-1 are important targets of Bag-1; however, the protective function of Bag-1 in nucleus pulposus (NP) cells remains unclear. In this study, we determined the effects of Bag-1 on NP cells under oxidative stress induced by treatment with hydrogen peroxide (H₂O₂). We found that Bag-1 was bound to HSP70, but Bag-1–Raf1 binding did not occur in NP cells. Bag-1 overexpression in NP cells enhanced cell viability and mitochondrial function and significantly suppressed p38/MAPKs phosphorylation during oxidative stress, although NP cells treated with a Bag-1 C-terminal inhibitor, which is the binding site of HSP70 and Raf-1, decreased cell viability and mitochondrial function during oxidative stress. Furthermore, the phosphorylation of the ERK/MAPKs was significantly increased in Bag-1 C-terminal inhibitor-treated NP cells without H₂O₂ treatment but did not change with H₂O₂ exposure. The phosphorylation of Raf-1 was not influenced by Bag-1 overexpression or Bag-1 C-terminal binding site inhibition. Overall, the results suggest that Bag-1 preferentially interacts with HSP70, rather than Raf-1, to protect NP cells against oxidative stress. Full article

(This article belongs to the Section Cell Biology and Pathology)

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17 pages, 1635 KiB

Open AccessEditor’s ChoiceReview

Modelling the Complexity of Human Skin In Vitro

by Elisabeth Hofmann, Anna Schwarz, Julia Fink, Lars-Peter Kamolz and Petra Kotzbeck

Biomedicines 2023, 11(3), 794; https://doi.org/10.3390/biomedicines11030794 - 6 Mar 2023

Cited by 54 | Viewed by 17129

Abstract

The skin serves as an important barrier protecting the body from physical, chemical and pathogenic hazards as well as regulating the bi-directional transport of water, ions and nutrients. In order to improve the knowledge on skin structure and function as well as on [...] Read more.

The skin serves as an important barrier protecting the body from physical, chemical and pathogenic hazards as well as regulating the bi-directional transport of water, ions and nutrients. In order to improve the knowledge on skin structure and function as well as on skin diseases, animal experiments are often employed, but anatomical as well as physiological interspecies differences may result in poor translatability of animal-based data to the clinical situation. In vitro models, such as human reconstructed epidermis or full skin equivalents, are valuable alternatives to animal experiments. Enormous advances have been achieved in establishing skin models of increasing complexity in the past. In this review, human skin structures are described as well as the fast evolving technologies developed to reconstruct the complexity of human skin structures in vitro. Full article

(This article belongs to the Special Issue Researches on Biomaterials for Tissue Engineering and Tissue Regeneration 2.0)

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16 pages, 1935 KiB

Open AccessEditor’s ChoiceArticle

Sensitivity Analysis for Survival Prognostic Prediction with Gene Selection: A Copula Method for Dependent Censoring

by Chih-Tung Yeh, Gen-Yih Liao and Takeshi Emura

Biomedicines 2023, 11(3), 797; https://doi.org/10.3390/biomedicines11030797 - 6 Mar 2023

Cited by 19 | Viewed by 3092

Abstract

Prognostic analysis for patient survival often employs gene expressions obtained from high-throughput screening for tumor tissues from patients. When dealing with survival data, a dependent censoring phenomenon arises, and thus the traditional Cox model may not correctly identify the effect of each gene. [...] Read more.

Prognostic analysis for patient survival often employs gene expressions obtained from high-throughput screening for tumor tissues from patients. When dealing with survival data, a dependent censoring phenomenon arises, and thus the traditional Cox model may not correctly identify the effect of each gene. A copula-based gene selection model can effectively adjust for dependent censoring, yielding a multi-gene predictor for survival prognosis. However, methods to assess the impact of various types of dependent censoring on the multi-gene predictor have not been developed. In this article, we propose a sensitivity analysis method using the copula-graphic estimator under dependent censoring, and implement relevant methods in the R package “compound.Cox”. The purpose of the proposed method is to investigate the sensitivity of the multi-gene predictor to a variety of dependent censoring mechanisms. In order to make the proposed sensitivity analysis practical, we develop a web application. We apply the proposed method and the web application to a lung cancer dataset. We provide a template file so that developers can modify the template to establish their own web applications. Full article

(This article belongs to the Special Issue Advanced Research in Cancer Genomics and Genetics: Evolution from Single-Gene Analysis to AI-Driven Data Analysis of High-Throughput Data Generation)

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13 pages, 3672 KiB

Open AccessEditor’s ChoiceArticle

Application of Biodegradable Magnesium Membrane Shield Technique for Immediate Dentoalveolar Bone Regeneration

by Akiva Elad, Patrick Rider, Svenja Rogge, Frank Witte, Dražen Tadić, Željka Perić Kačarević and Larissa Steigmann

Biomedicines 2023, 11(3), 744; https://doi.org/10.3390/biomedicines11030744 - 1 Mar 2023

Cited by 17 | Viewed by 4654

Abstract

For the first time, the clinical application of the first CE registered magnesium membrane is reported. Due to the material characteristics of magnesium metal, new treatment methodologies become possible. This has led to the development of a new technique: the magnesium membrane shield [...] Read more.

For the first time, the clinical application of the first CE registered magnesium membrane is reported. Due to the material characteristics of magnesium metal, new treatment methodologies become possible. This has led to the development of a new technique: the magnesium membrane shield technique, used to rebuild the buccal or palatal walls of compromised extraction sockets. Four clinical cases are reported, demonstrating the handling options of this new technique for providing a successful regenerative outcome. Using the technique, immediate implant placement is possible with a provisional implant in the aesthetic zone. It can also be used for rebuilding both the buccal and palatal walls simultaneously. For instances where additional mechanical support is required, the membrane can be bent into a double layer, which additionally provides a rounder edge for interfacing with the soft tissue. In all reported clinical cases, there was a good bone tissue regeneration and soft tissue healing. In some instances, the new bone had formed a thick cortical bone visible in cone beam computed tomography (CBCT) radiographs of the regenerated sites, which is known to be remodeled in the post treatment period. Overall, the magnesium membrane shield technique is presented as an alternative treatment option for compromised extraction sockets. Full article

(This article belongs to the Special Issue Progress in Biomaterials and Technologies in Dentistry)

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23 pages, 1955 KiB

Open AccessEditor’s ChoiceReview

Extracellular Vesicles, Cell-Penetrating Peptides and miRNAs as Future Novel Therapeutic Interventions for Parkinson’s and Alzheimer’s Disease

by Cameron Noah Keighron, Sahar Avazzadeh, Katarzyna Goljanek-Whysall, Brian McDonagh, Linda Howard, Thomas Ritter and Leo R. Quinlan

Biomedicines 2023, 11(3), 728; https://doi.org/10.3390/biomedicines11030728 - 28 Feb 2023

Cited by 14 | Viewed by 5970

Abstract

Neurodegeneration is hallmarked by the progressive loss of dopaminergic neurons and/or a significant increase in protein aggregates in the brain. Neurodegenerative diseases are a leading cause of death worldwide with over 15 million people currently suffering from either Parkinson’s disease (PD) or Alzheimer’s [...] Read more.

Neurodegeneration is hallmarked by the progressive loss of dopaminergic neurons and/or a significant increase in protein aggregates in the brain. Neurodegenerative diseases are a leading cause of death worldwide with over 15 million people currently suffering from either Parkinson’s disease (PD) or Alzheimer’s disease (AD). PD is often characterized by both motor and non-motor symptoms, including muscle rigidity, tremors and bradykinesia, with AD displaying symptoms of confusion and dementia. The current mainstay of therapeutics includes pharmacological approaches such as levodopa to replace dopamine in PD patients, deep brain stimulation in affected regions of the brain and physical therapy. However, these treatments are typically not disease-modifying, though they do help at least for some time with symptom management. These treatments often also fail due to their inability to cross the blood–brain barrier. There is a need to develop new strategies to target neurodegeneration in an ever-ageing population. First, we review the current PD and AD treatments and their limitations. Second, we review the current use of extracellular vesicles (EVs), cell-penetrating peptides (CPPs) and miRNAs as neuroprotective agents. Finally, we discuss the possibility of exploiting these as a combinatory therapeutic, alongside some potential drawbacks. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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10 pages, 1005 KiB

Open AccessEditor’s ChoiceArticle

Telomere Shortening in Three Diabetes Mellitus Types in a Mexican Sample

by Pavel Cuevas Diaz, Humberto Nicolini, German Alberto Nolasco-Rosales, Isela Juarez Rojop, Carlos Alfonso Tovilla-Zarate, Ester Rodriguez Sanchez and Alma Delia Genis-Mendoza

Biomedicines 2023, 11(3), 730; https://doi.org/10.3390/biomedicines11030730 - 28 Feb 2023

Cited by 9 | Viewed by 2354

Abstract

This study aimed to explore the role of telomere length in three different diabetes types: latent autoimmune diabetes of adulthood (LADA), latent autoimmune diabetes in the young (LADY), and type 2 diabetes mellitus (T2DM). A total of 115 patients were included, 72 (62.61%) [...] Read more.

This study aimed to explore the role of telomere length in three different diabetes types: latent autoimmune diabetes of adulthood (LADA), latent autoimmune diabetes in the young (LADY), and type 2 diabetes mellitus (T2DM). A total of 115 patients were included, 72 (62.61%) had LADA, 30 (26.09%) had T2DM, and 13 (11.30%) had LADY. Telomere length was measured using real-time Polymerase Chain Reaction. For statistical analysis, we used the ANOVA test, X2 test, and the Mann–Whitney U test. Patients with T2DM had higher BMI compared to LADA and LADY groups, with a BMI average of 31.32 kg/m² (p = 0.0235). While the LADA group had more patients with comorbidities, there was not a statistically significant difference (p = 0.3164, p = 0.3315, p = 0.3742 for each of the previously mentioned conditions). There was a difference between those patients with T2DM who took metformin plus any other oral antidiabetic agent and those who took metformin plus insulin, the ones who had longer telomeres. LADA patients had shorter telomeres compared to T2DM patients but not LADY patients. Furthermore, T2DM may have longer telomeres thanks to the protective effects of both metformin and insulin, despite the higher BMI in this group. Full article

(This article belongs to the Special Issue Novel Aspects in the Pathophysiology and Treatment of Diabetes Mellitus)

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15 pages, 2446 KiB

Open AccessEditor’s ChoiceArticle

Rapid Biomarker-Based Diagnosis of Fibromyalgia Syndrome and Related Rheumatologic Disorders by Portable FT-IR Spectroscopic Techniques

by Siyu Yao, Haona Bao, Shreya Madhav Nuguri, Lianbo Yu, Zhanna Mikulik, Michelle M. Osuna-Diaz, Katherine R. Sebastian, Kevin V. Hackshaw and Luis Rodriguez-Saona

Biomedicines 2023, 11(3), 712; https://doi.org/10.3390/biomedicines11030712 - 27 Feb 2023

Cited by 13 | Viewed by 4262

Abstract

Fibromyalgia syndrome (FM), one of the most common illnesses that cause chronic widespread pain, continues to present significant diagnostic challenges. The objective of this study was to develop a rapid vibrational biomarker-based method for diagnosing fibromyalgia syndrome and related rheumatologic disorders (systemic lupus [...] Read more.

Fibromyalgia syndrome (FM), one of the most common illnesses that cause chronic widespread pain, continues to present significant diagnostic challenges. The objective of this study was to develop a rapid vibrational biomarker-based method for diagnosing fibromyalgia syndrome and related rheumatologic disorders (systemic lupus erythematosus (SLE), osteoarthritis (OA) and rheumatoid arthritis (RA)) through portable FT-IR techniques. Bloodspot samples were collected from patients diagnosed with FM (n = 122) and related rheumatologic disorders (n = 70), including SLE (n = 17), RA (n = 43), and OA (n = 10), and stored in conventional protein saver bloodspot cards. The blood samples were prepared by four different methods (blood aliquots, protein-precipitated extraction, and non-washed and water-washed semi-permeable membrane filtration extractions), and spectral data were collected with a portable FT-IR spectrometer. Pattern recognition analysis, OPLS-DA, was able to identify the signature profile and classify the spectra into corresponding classes (Rcv > 0.93) with excellent sensitivity and specificity. Peptide backbones and aromatic amino acids were predominant for the differentiation and might serve as candidate biomarkers for syndromes such as FM. This research evaluated the feasibility of portable FT-IR combined with chemometrics as an accurate and high-throughput tool for distinct spectral signatures of biomarkers related to the human syndrome (FM), which could allow for real-time and in-clinic diagnostics of FM. Full article

(This article belongs to the Special Issue Advanced Research on Fibromyalgia)

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19 pages, 597 KiB

Open AccessEditor’s ChoiceArticle

Natural IgG Anti-F (ab’)₂ Autoantibody Activity in Children with Autism

by Sylvie Tordjman, Annaëlle Charrier, Michel Kazatchkine, Pierre Roubertoux, Michel Botbol, Guillaume Bronsard and Stratis Avrameas

Biomedicines 2023, 11(3), 715; https://doi.org/10.3390/biomedicines11030715 - 27 Feb 2023

Cited by 3 | Viewed by 2394

Abstract

Background: Many and diverse autoimmune abnormalities have been reported in children with autism. Natural autoantibodies (NAAbs) play important immunoregulatory roles in recognition of the immune self. The objective of this study was to examine the presence of NAAbs in the sera of children [...] Read more.

Background: Many and diverse autoimmune abnormalities have been reported in children with autism. Natural autoantibodies (NAAbs) play important immunoregulatory roles in recognition of the immune self. The objective of this study was to examine the presence of NAAbs in the sera of children with autism and across severity subgroups of autistic behavioral impairments. Methods: NAAbs were titrated in sera through an ELISA procedure in 60 low-functioning children with autism and 112 typically developing controls matched for age, sex and puberty. Results: Serum titers of IgG anti-F(ab’)₂ autoantibodies were significantly lower in children with autism compared to typically developing controls (p < 0.0001), and were significantly negatively associated with autism severity (p = 0.0001). This data appears to be related more specifically to autism than to intellectual disability, given that IgG anti-F(ab’)₂ levels were significantly negatively correlated with IQ scores in the autism group (p = 0.01). Conclusions: This is the first report in autism of abnormally low natural anti-F(ab’)₂ autoantibody activity. The findings suggest a dysfunction of self-recognition mechanisms which may play a role in the pathogenesis of autism, especially for the severely affected children. These findings strengthen the hypothesis of an autoimmune process in autism and open the prospect of alternative medical treatment. Further neuroimmunological research is warranted to understand the exact mechanisms underlying this reduced natural IgG anti-F (ab’)₂ autoantibody activity, and to assess its impact on the pathophysiology and behavioral expression of autism. Full article

(This article belongs to the Special Issue Immune Dysfunction in Brain Disorders)

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23 pages, 4472 KiB

Open AccessEditor’s ChoiceReview

Endostatin and Cancer Therapy: A Novel Potential Alternative to Anti-VEGF Monoclonal Antibodies

by Gabriel Méndez-Valdés, Francisca Gómez-Hevia, José Lillo-Moya, Tommy González-Fernández, Joaquin Abelli, Antonia Cereceda-Cornejo, Maria Chiara Bragato, Luciano Saso and Ramón Rodrigo

Biomedicines 2023, 11(3), 718; https://doi.org/10.3390/biomedicines11030718 - 27 Feb 2023

Cited by 22 | Viewed by 4192

Abstract

Angiogenesis is a physiological process that consists of the formation of new blood vessels from preexisting ones. Angiogenesis helps in growth, development, and wound healing through the formation of granulation tissue. However, this physiological process has also been linked to tumor growth and [...] Read more.

Angiogenesis is a physiological process that consists of the formation of new blood vessels from preexisting ones. Angiogenesis helps in growth, development, and wound healing through the formation of granulation tissue. However, this physiological process has also been linked to tumor growth and metastasis formation. Indeed, angiogenesis has to be considered as a fundamental step to the evolution of benign tumors into malignant neoplasms. The main mediator of angiogenesis is vascular endothelial growth factor (VEGF), which is overexpressed in certain cancers. Thus, there are anti-VEGF monoclonal antibodies, such as bevacizumab, used as anti-cancer therapies. However, bevacizumab has shown adverse events, such as hypertension and proteinuria, which in the most severe cases can lead to cessation of therapy, thus contributing to worsening patients’ prognosis. On the other hand, endostatin is an endogenous protein that strongly inhibits VEGF expression and angiogenesis and shows a better safety profile. Moreover, endostatin has already given promising results on small scale clinical studies. Hence, in this review, we present data supporting the use of endostatin as a replacement for anti-VEGF monoclonal antibodies. Full article

(This article belongs to the Special Issue Anti-cancer Peptides and Peptide-Like Molecules)

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23 pages, 674 KiB

Open AccessEditor’s ChoiceReview

Estrogens in Adipose Tissue Physiology and Obesity-Related Dysfunction

by Alina Kuryłowicz

Biomedicines 2023, 11(3), 690; https://doi.org/10.3390/biomedicines11030690 - 24 Feb 2023

Cited by 55 | Viewed by 20984

Abstract

Menopause-related decline in estrogen levels is accompanied by a change in adipose tissue distribution from a gynoid to an android and an increased prevalence of obesity in women. These unfavorable phenomena can be partially restored by hormone replacement therapy, suggesting a significant role [...] Read more.

Menopause-related decline in estrogen levels is accompanied by a change in adipose tissue distribution from a gynoid to an android and an increased prevalence of obesity in women. These unfavorable phenomena can be partially restored by hormone replacement therapy, suggesting a significant role for estrogen in the regulation of adipocytes’ function. Indeed, preclinical studies proved the involvement of these hormones in adipose tissue development, metabolism, and inflammatory activity. However, the relationship between estrogen and obesity is bidirectional. On the one hand-their deficiency leads to excessive fat accumulation and impairs adipocyte function, on the other-adipose tissue of obese individuals is characterized by altered expression of estrogen receptors and key enzymes involved in their synthesis. This narrative review aims to summarize the role of estrogen in adipose tissue development, physiology, and in obesity-related dysfunction. Firstly, the estrogen classification, synthesis, and modes of action are presented. Next, their role in regulating adipogenesis and adipose tissue activity in health and the course of obesity is described. Finally, the potential therapeutic applications of estrogen and its derivates in obesity treatment are discussed. Full article

(This article belongs to the Special Issue Molecular Regulators and Therapeutic Strategies for Obesity and Diabetes)

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15 pages, 1302 KiB

Open AccessEditor’s ChoiceArticle

The Third Dose of BNT162b2 COVID-19 Vaccine Does Not “Boost” Disease Flares and Adverse Events in Patients with Rheumatoid Arthritis

by Andrea Picchianti Diamanti, Assunta Navarra, Gilda Cuzzi, Alessandra Aiello, Simonetta Salemi, Roberta Di Rosa, Chiara De Lorenzo, Daniele Vio, Giandomenico Sebastiani, Mario Ferraioli, Maurizio Benucci, Francesca Li Gobbi, Fabrizio Cantini, Vittoria Polidori, Maurizio Simmaco, Esmeralda Cialdi, Palma Scolieri, Vincenzo Bruzzese, Emanuele Nicastri, Raffaele D’Amelio, Bruno Laganà and Delia Goletti Show full author list Hide full author list

Biomedicines 2023, 11(3), 687; https://doi.org/10.3390/biomedicines11030687 - 23 Feb 2023

Cited by 8 | Viewed by 2579

Abstract

Data on the risk of adverse events (AEs) and disease flares in autoimmune rheumatic diseases (ARDs) after the third dose of COVID-19 vaccine are scarce. The aim of this multicenter, prospective study is to analyze the clinical and immunological safety of BNT162b2 vaccine [...] Read more.

Data on the risk of adverse events (AEs) and disease flares in autoimmune rheumatic diseases (ARDs) after the third dose of COVID-19 vaccine are scarce. The aim of this multicenter, prospective study is to analyze the clinical and immunological safety of BNT162b2 vaccine in a cohort of rheumatoid arthritis (RA) patients followed-up from the first vaccine cycle to the third dose. The vaccine showed an overall good safety profile with no patient reporting serious AEs, and a low percentage of total AEs at both doses (40/78 (51.3%) and 13/47 (27.7%) patients after the second and third dose, respectively (p < 0.002). Flares were observed in 10.3% of patients after the end of the vaccination cycle and 12.8% after the third dose. Being vaccinated for influenza was inversely associated with the onset of AEs after the second dose, at both univariable (p = 0.013) and multivariable analysis (p = 0.027). This result could allow identification of a predictive factor of vaccine tolerance, if confirmed in larger patient populations. A higher disease activity at baseline was not associated with a higher incidence of AEs or disease flares. Effectiveness was excellent after the second dose, with only 1/78 (1.3%) mild breakthrough infection (BI) and worsened after the third dose, with 9/47 (19.2%) BI (p < 0.002), as a probable expression of the higher capacity of the Omicron variants to escape vaccine recognition. Full article

(This article belongs to the Special Issue Clinical Immunology in Italy, with Special Emphasis to Primary and Acquired Immunodeficiencies: A Commemorative Issue in Honor of Prof. Fernando Aiuti)

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25 pages, 1280 KiB

Open AccessEditor’s ChoiceReview

Role of Mesenchymal Stem/Stromal Cells in Modulating Ischemia/Reperfusion Injury: Current State of the Art and Future Perspectives

by Vitale Miceli, Matteo Bulati, Alessia Gallo, Gioacchin Iannolo, Rosalia Busà, Pier Giulio Conaldi and Giovanni Zito

Biomedicines 2023, 11(3), 689; https://doi.org/10.3390/biomedicines11030689 - 23 Feb 2023

Cited by 16 | Viewed by 3401

Abstract

Ischemia/reperfusion injury (IRI) is a multistep damage that occurs in several tissues when a blood flow interruption is inevitable, such as during organ surgery or transplantation. It is responsible for cell death and tissue dysfunction, thus leading, in the case of transplantation, to [...] Read more.

Ischemia/reperfusion injury (IRI) is a multistep damage that occurs in several tissues when a blood flow interruption is inevitable, such as during organ surgery or transplantation. It is responsible for cell death and tissue dysfunction, thus leading, in the case of transplantation, to organ rejection. IRI takes place during reperfusion, i.e., when blood flow is restored, by activating inflammation and reactive oxygen species (ROS) production, causing mitochondrial damage and apoptosis of parenchymal cells. Unfortunately, none of the therapies currently in use are definitive, prompting the need for new therapeutic approaches. Scientific evidence has proven that mesenchymal stem/stromal cells (MSCs) can reduce inflammation and ROS, prompting this cellular therapy to also be investigated for treatment of IRI. Moreover, it has been shown that MSC therapeutic effects were mediated in part by their secretome, which appears to be involved in immune regulation and tissue repair. For these reasons, mediated MSC paracrine function might be key for injury amelioration upon IRI damage. In this review, we highlight the scientific literature on the potential beneficial use of MSCs and their products for improving IRI outcomes in different tissues/organs, focusing in particular on the paracrine effects mediated by MSCs, and on the molecular mechanisms behind these effects. Full article

(This article belongs to the Special Issue Mesenchymal Stem Cell Application in Regenerative Medicine: From Mechanisms to Therapeutic Approaches)

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14 pages, 2744 KiB

Open AccessEditor’s ChoiceArticle

Newborns from Mothers Who Intensely Consumed Sucralose during Pregnancy Are Heavier and Exhibit Markers of Metabolic Alteration and Low-Grade Systemic Inflammation: A Cross-Sectional, Prospective Study

by José Alfredo Aguayo-Guerrero, Lucía Angélica Méndez-García, Aarón Noe Manjarrez-Reyna, Marcela Esquivel-Velázquez, Sonia León-Cabrera, Guillermo Meléndez, Elena Zambrano, Espiridión Ramos-Martínez, José Manuel Fragoso, Juan Carlos Briones-Garduño and Galileo Escobedo

Biomedicines 2023, 11(3), 650; https://doi.org/10.3390/biomedicines11030650 - 21 Feb 2023

Cited by 13 | Viewed by 8984

Abstract

Robust data in animals show that sucralose intake during gestation can predispose the offspring to weight gain, metabolic disturbances, and low-grade systemic inflammation; however, concluding information remains elusive in humans. In this cross-sectional, prospective study, we examined the birth weight, glucose and insulin [...] Read more.

Robust data in animals show that sucralose intake during gestation can predispose the offspring to weight gain, metabolic disturbances, and low-grade systemic inflammation; however, concluding information remains elusive in humans. In this cross-sectional, prospective study, we examined the birth weight, glucose and insulin cord blood levels, monocyte subsets, and inflammatory cytokine profile in 292 neonates at term from mothers with light sucralose ingestion (LSI) of less than 60 mg sucralose/week or heavy sucralose intake (HSI) of more than 36 mg sucralose/day during pregnancy. Mothers in the LSI (n = 205) or HSI (n = 87) groups showed no differences in age, pregestational body mass index, blood pressure, and glucose tolerance. Although there were no differences in glucose, infants from HSI mothers displayed significant increases in birth weight and insulin compared to newborns from LSI mothers. Newborns from HSI mothers showed a substantial increase in the percentage of inflammatory nonclassical monocytes compared to neonates from LSI mothers. Umbilical cord tissue of infants from HSI mothers exhibited higher IL-1 beta and TNF-alpha with lower IL-10 expression than that found in newborns from LSI mothers. Present results demonstrate that heavy sucralose ingestion during pregnancy affects neonates’ anthropometric, metabolic, and inflammatory features. Full article

(This article belongs to the Special Issue Bioactive Compounds in Chronic Diseases)

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13 pages, 2421 KiB

Open AccessEditor’s ChoiceArticle

Unexpected Absence of Skeletal Responses to Dietary Magnesium Depletion: Basis for Future Perspectives?

by Marzia Ferretti, Francesco Cavani, Vincenza Rita Lo Vasco, Marta Checchi, Serena Truocchio, Pierpaola Davalli, Chiara Frassineti, Federica Rizzi and Carla Palumbo

Biomedicines 2023, 11(3), 655; https://doi.org/10.3390/biomedicines11030655 - 21 Feb 2023

Viewed by 1473

Abstract

It’s known that a magnesium (Mg)-deficient diet is associated with an increased risk of osteoporosis. The aim of this work is to investigate, by a histological approach, the effects of a Mg-deprived diet on the bone of 8-weeks-old C57BL/6J male mice. Treated and [...] Read more.

It’s known that a magnesium (Mg)-deficient diet is associated with an increased risk of osteoporosis. The aim of this work is to investigate, by a histological approach, the effects of a Mg-deprived diet on the bone of 8-weeks-old C57BL/6J male mice. Treated and control mice were supplied with a Mg-deprived or normal diet for 8 weeks, respectively. Body weight, serum Mg concentration, expression of kidney magnesiotropic genes, and histomorphometry on L5 vertebrae, femurs, and tibiae were evaluated. Body weight gain and serum Mg concentration were significantly reduced, while a trend toward increase was found in gene expression in mice receiving the Mg-deficient diet, suggesting the onset of an adaptive response to Mg depletion. Histomorphometric parameters on the amount of trabecular and cortical bone, number of osteoclasts, and thickness of the growth plate in femoral distal and tibial proximal metaphyses did not differ between groups; these findings partially differ from most data present in the literature showing that animals fed a Mg-deprived diet develop bone loss and may be only in part explained by differences among the experimental protocols. However, the unexpected findings we recorded on bones could be attributed to genetic differences that may have developed after multiple generations of inbreeding. Full article

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

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16 pages, 1925 KiB

Open AccessEditor’s ChoiceReview

Targeted Therapy Development in Acute Myeloid Leukemia

by Tulasigeri M. Totiger, Anirban Ghoshal, Jenna Zabroski, Anya Sondhi, Saanvi Bucha, Jacob Jahn, Yangbo Feng and Justin Taylor

Biomedicines 2023, 11(2), 641; https://doi.org/10.3390/biomedicines11020641 - 20 Feb 2023

Cited by 27 | Viewed by 6899

Abstract

Therapeutic developments targeting acute myeloid leukemia (AML) have been in the pipeline for five decades and have recently resulted in the approval of multiple targeted therapies. However, there remains an unmet need for molecular treatments that can deliver long-term remissions and cure for [...] Read more.

Therapeutic developments targeting acute myeloid leukemia (AML) have been in the pipeline for five decades and have recently resulted in the approval of multiple targeted therapies. However, there remains an unmet need for molecular treatments that can deliver long-term remissions and cure for this heterogeneous disease. Previously, a wide range of small molecule drugs were developed to target sub-types of AML, mainly in the relapsed and refractory setting; however, drug resistance has derailed the long-term efficacy of these as monotherapies. Recently, the small molecule venetoclax was introduced in combination with azacitidine, which has improved the response rates and the overall survival in older adults with AML compared to those of chemotherapy. However, this regimen is still limited by cytotoxicity and is not curative. Therefore, there is high demand for therapies that target specific abnormalities in AML while sparing normal cells and eliminating leukemia-initiating cells. Despite this, the urgent need to develop these therapies has been hampered by the complexities of this heterogeneous disease, spurring the development of innovative therapies that target different mechanisms of leukemogenesis. This review comprehensively addresses the development of novel targeted therapies and the translational perspective for acute myeloid leukemia, including the development of selective and non-selective drugs. Full article

(This article belongs to the Special Issue Development of Small Molecules for Acute Myeloid Leukemia Therapy)

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11 pages, 456 KiB

Open AccessEditor’s ChoiceArticle

Outcomes of Pregnancy in Sickle Cell Disease Patients: Results from the Prospective ESCORT-HU Cohort Study

by Anoosha Habibi, Giovanna Cannas, Pablo Bartolucci, Ersi Voskaridou, Laure Joseph, Emmanuelle Bernit, Justine Gellen-Dautremer, Corine Charneau, Stephanie Ngo and Frédéric Galactéros

Biomedicines 2023, 11(2), 597; https://doi.org/10.3390/biomedicines11020597 - 17 Feb 2023

Cited by 11 | Viewed by 3443

Abstract

Sickle cell disease (SCD) refers to a group of inherited hemoglobin disorders in which sickle red blood cells display altered deformability, leading to a significant burden of acute and chronic complications, such as vaso-occlusive pain crises (VOCs). Hydroxyurea is a major therapeutic agent [...] Read more.

Sickle cell disease (SCD) refers to a group of inherited hemoglobin disorders in which sickle red blood cells display altered deformability, leading to a significant burden of acute and chronic complications, such as vaso-occlusive pain crises (VOCs). Hydroxyurea is a major therapeutic agent in adult and pediatric sickle cell patients. This treatment is an alternative to transfusion in some complications. Indeed, it increases hemoglobin F and has an action on the endothelial adhesion of red blood cells, leukocytes, and platelets. Although the safety profile of hydroxyurea (HU) in patients with sickle cell disease has been well established, the existing literature on HU exposure during pregnancy is limited and incomplete. Pregnancy in women with SCD has been identified as a high risk for the mother and fetus due to the increased incidence of maternal and non-fetal complications in various studies and reports. For women on hydroxyurea at the time of pregnancy, transfusion therapy should probably be initiated after pregnancy. In addition, there is still a significant lack of knowledge about the incidence of pregnancy, fetal and maternal outcomes, and management of pregnant women with SCD, making it difficult to advise women or clinicians on outcomes and best practices. Therefore, the objective of this study was to describe pregnancy outcomes (n = 128) reported in the noninterventional European Sickle Cell Disease COhoRT-HydroxyUrea (ES-CORT-HU) study. We believe that our results are important and relevant enough to be shared with the scientific community. Full article

(This article belongs to the Special Issue Sickle Cell Disease: Recent Advances in Pathophysiology and Therapy)

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12 pages, 744 KiB

Open AccessEditor’s ChoiceReview

Novel Therapeutic Targets for Migraine

by Areeba Nisar, Zubair Ahmed and Hsiangkuo Yuan

Biomedicines 2023, 11(2), 569; https://doi.org/10.3390/biomedicines11020569 - 15 Feb 2023

Cited by 12 | Viewed by 7512

Abstract

Migraine, a primary headache disorder involving a dysfunctional trigeminal vascular system, remains a major debilitating neurological condition impacting many patients’ quality of life. Despite the success of multiple new migraine therapies, not all patients achieve significant clinical benefits. The success of CGRP pathway-targeted [...] Read more.

Migraine, a primary headache disorder involving a dysfunctional trigeminal vascular system, remains a major debilitating neurological condition impacting many patients’ quality of life. Despite the success of multiple new migraine therapies, not all patients achieve significant clinical benefits. The success of CGRP pathway-targeted therapy highlights the importance of translating the mechanistic understanding toward effective therapy. Ongoing research has identified multiple potential mechanisms in migraine signaling and nociception. In this narrative review, we discuss several potential emerging therapeutic targets, including pituitary adenylate cyclase-activating polypeptide (PACAP), adenosine, δ-opioid receptor (DOR), potassium channels, transient receptor potential ion channels (TRP), and acid-sensing ion channels (ASIC). A better understanding of these mechanisms facilitates the discovery of novel therapeutic targets and provides more treatment options for improved clinical care. Full article

(This article belongs to the Special Issue Recent Advances in Craniofacial Pain and Headaches)

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13 pages, 1220 KiB

Open AccessEditor’s ChoiceReview

Mint3 as a Potential Target for Cooling Down HIF-1α-Mediated Inflammation and Cancer Aggressiveness

by Noritaka Tanaka and Takeharu Sakamoto

Biomedicines 2023, 11(2), 549; https://doi.org/10.3390/biomedicines11020549 - 14 Feb 2023

Cited by 8 | Viewed by 3036

Abstract

Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that plays a crucial role in cells adapting to a low-oxygen environment by facilitating a switch from oxygen-dependent ATP production to glycolysis. Mediated by membrane type-1 matrix metalloproteinase (MT1-MMP) expression, Munc-18-1 interacting protein 3 (Mint3) binds [...] Read more.

Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that plays a crucial role in cells adapting to a low-oxygen environment by facilitating a switch from oxygen-dependent ATP production to glycolysis. Mediated by membrane type-1 matrix metalloproteinase (MT1-MMP) expression, Munc-18-1 interacting protein 3 (Mint3) binds to the factor inhibiting HIF-1 (FIH-1) and inhibits its suppressive effect, leading to HIF-1α activation. Defects in Mint3 generally lead to improved acute inflammation, which is regulated by HIF-1α and subsequent glycolysis, as well as the suppression of the proliferation and metastasis of cancer cells directly through its expression in cancer cells and indirectly through its expression in macrophages or fibroblasts associated with cancer. Mint3 in inflammatory monocytes enhances the chemotaxis into metastatic sites and the production of vascular endothelial growth factors, which leads to the expression of E-selectin at the metastatic sites and the extravasation of cancer cells. Fibroblasts express L1 cell adhesion molecules in a Mint3-dependent manner and enhance integrin-mediated cancer progression. In pancreatic cancer cells, Mint3 directly promotes cancer progression. Naphthofluorescein, a Mint3 inhibitor, can disrupt the interaction between FIH-1 and Mint3 and potently suppress Mint3-mediated inflammation, cancer progression, and metastasis without causing marked adverse effects. In this review, we will introduce the potential of Mint3 as a therapeutic target for inflammatory diseases and cancers. Full article

(This article belongs to the Special Issue State-of-the-Art Cancer Biology, Biodiagnostics and Therapeutics in Japan)

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30 pages, 9472 KiB

Open AccessEditor’s ChoiceArticle

Structural Basis of the Interaction of the G Proteins, Gαi₁, Gβ₁γ₂ and Gαi₁β₁γ₂, with Membrane Microdomains and Their Relationship to Cell Localization and Activity

by Rafael Álvarez and Pablo V. Escribá

Biomedicines 2023, 11(2), 557; https://doi.org/10.3390/biomedicines11020557 - 14 Feb 2023

Cited by 1 | Viewed by 2452

Abstract

GPCRs receive signals from diverse messengers and activate G proteins that regulate downstream signaling effectors. Efficient signaling is achieved through the organization of these proteins in membranes. Thus, protein–lipid interactions play a critical role in bringing G proteins together in specific membrane microdomains [...] Read more.

GPCRs receive signals from diverse messengers and activate G proteins that regulate downstream signaling effectors. Efficient signaling is achieved through the organization of these proteins in membranes. Thus, protein–lipid interactions play a critical role in bringing G proteins together in specific membrane microdomains with signaling partners. Significantly, the molecular basis underlying the membrane distribution of each G protein isoform, fundamental to fully understanding subsequent cell signaling, remains largely unclear. We used model membranes with lipid composition resembling different membrane microdomains, and monomeric, dimeric and trimeric Gi proteins with or without single and multiple mutations to investigate the structural bases of G protein–membrane interactions. We demonstrated that cationic amino acids in the N-terminal region of the Gαi₁ and C-terminal region of the Gγ₂ subunit, as well as their myristoyl, palmitoyl and geranylgeranyl moieties, define the differential G protein form interactions with membranes containing different lipid classes (PC, PS, PE, SM, Cho) and the various microdomains they may form (Lo, Ld, PC bilayer, charged, etc.). These new findings in part explain the molecular basis underlying amphitropic protein translocation to membranes and localization to different membrane microdomains and the role of these interactions in cell signal propagation, pathophysiology and therapies targeted to lipid membranes. Full article

(This article belongs to the Special Issue Fiftieth Anniversary of the Fluid Mosaic Model of Cell Membranes: From Lipid Structure to Biomedicines)

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13 pages, 1316 KiB

Open AccessEditor’s ChoiceArticle

Efficient Liposome Loading onto Surface of Mesenchymal Stem Cells via Electrostatic Interactions for Tumor-Targeted Drug Delivery

by Yusuke Kono, Renpei Kamino, Soma Hirabayashi, Takuya Kishimoto, Himi Kanbara, Saki Danjo, Mika Hosokawa and Ken-ichi Ogawara

Biomedicines 2023, 11(2), 558; https://doi.org/10.3390/biomedicines11020558 - 14 Feb 2023

Cited by 6 | Viewed by 2885

Abstract

Mesenchymal stem cells (MSCs) have a tumor-homing capacity; therefore, MSCs are a promising drug delivery carrier for cancer therapy. To maintain the viability and activity of MSCs, anti-cancer drugs are preferably loaded on the surface of MSCs, rather than directly introduced into MSCs. [...] Read more.

Mesenchymal stem cells (MSCs) have a tumor-homing capacity; therefore, MSCs are a promising drug delivery carrier for cancer therapy. To maintain the viability and activity of MSCs, anti-cancer drugs are preferably loaded on the surface of MSCs, rather than directly introduced into MSCs. In this study, we attempted to load liposomes on the surface of MSCs by using the magnetic anionic liposome/atelocollagen complexes that we previously developed and assessed the characters of liposome-loaded MSCs as drug carriers. We observed that large-sized magnetic anionic liposome/atelocollagen complexes were abundantly associated with MSCs via electrostatic interactions under a magnetic field, and its cellular internalization was lower than that of the small-sized complexes. Moreover, the complexes with higher atelocollagen concentrations showed lower cellular internalization than the complexes with lower atelocollagen concentrations. Based on these results, we succeeded in the efficient loading of liposomes on the surface of MSCs by using large-sized magnetic anionic liposomes complexed with a high concentration of atelocollagen. The constructed liposome-loaded MSCs showed a comparable proliferation rate and differentiation potential to non-loaded MSCs. Furthermore, the liposome-loaded MSCs efficiently adhered to vascular endothelial cells and migrated toward the conditioned medium from cancer cells in vitro and solid tumor tissue in vivo. These findings suggest that liposome-loaded MSCs could serve as an efficient cell-based drug carrier for tumor-targeted delivery. Full article

(This article belongs to the Special Issue Mesenchymal Stromal (Stem) Cells)

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19 pages, 2215 KiB

Open AccessEditor’s ChoiceReview

Complement 1q/Tumor Necrosis Factor-Related Proteins (CTRPs): Structure, Receptors and Signaling

by Constanze Schanbacher, Heike M. Hermanns, Kristina Lorenz, Harald Wajant and Isabell Lang

Biomedicines 2023, 11(2), 559; https://doi.org/10.3390/biomedicines11020559 - 14 Feb 2023

Cited by 8 | Viewed by 3636

Abstract

Adiponectin and the other 15 members of the complement 1q (C1q)/tumor necrosis factor (TNF)-related protein (CTRP) family are secreted proteins composed of an N-terminal variable domain followed by a stalk region and a characteristic C-terminal trimerizing globular C1q (gC1q) domain originally identified in [...] Read more.

Adiponectin and the other 15 members of the complement 1q (C1q)/tumor necrosis factor (TNF)-related protein (CTRP) family are secreted proteins composed of an N-terminal variable domain followed by a stalk region and a characteristic C-terminal trimerizing globular C1q (gC1q) domain originally identified in the subunits of the complement protein C1q. We performed a basic PubMed literature search for articles mentioning the various CTRPs or their receptors in the abstract or title. In this narrative review, we briefly summarize the biology of CTRPs and focus then on the structure, receptors and major signaling pathways of CTRPs. Analyses of CTRP knockout mice and CTRP transgenic mice gave overwhelming evidence for the relevance of the anti-inflammatory and insulin-sensitizing effects of CTRPs in autoimmune diseases, obesity, atherosclerosis and cardiac dysfunction. CTRPs form homo- and heterotypic trimers and oligomers which can have different activities. The receptors of some CTRPs are unknown and some receptors are redundantly targeted by several CTRPs. The way in which CTRPs activate their receptors to trigger downstream signaling pathways is largely unknown. CTRPs and their receptors are considered as promising therapeutic targets but their translational usage is still hampered by the limited knowledge of CTRP redundancy and CTRP signal transduction. Full article

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

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