Biomedicines

26 pages, 1827 KiB

Open AccessEditor’s ChoiceReview

Anti-Inflammatory Therapeutic Mechanisms of Natural Products: Insight from Rosemary Diterpenes, Carnosic Acid and Carnosol

by Solomon Habtemariam

Biomedicines 2023, 11(2), 545; https://doi.org/10.3390/biomedicines11020545 - 13 Feb 2023

Cited by 31 | Viewed by 5014

Abstract

Carnosic acid (CA) and carnosol (CAR) are two major diterpenes of the rosemary plant (Rosmarinus officinalis). They possess a phenolic structural moiety and are endowed with the power to remove cellular reactive oxygen species (ROS) either through direct scavenging reaction or [...] Read more.

Carnosic acid (CA) and carnosol (CAR) are two major diterpenes of the rosemary plant (Rosmarinus officinalis). They possess a phenolic structural moiety and are endowed with the power to remove cellular reactive oxygen species (ROS) either through direct scavenging reaction or indirectly through upregulation of antioxidant defences. Hand in hand with these activities are their multiple biological effects and therapeutic potential orchestrated through modulating various signalling pathways of inflammation, including the NF-κB, MAPK, Nrf2, SIRT1, STAT3 and NLRP3 inflammasomes, among others. Consequently, they ameliorate the expression of pro-inflammatory cytokines (e.g., TNF-α, IL-1 and IL-6), adhesion molecules, chemokines and prostaglandins. These anti-inflammatory mechanisms of action as a therapeutic link to various effects of these compounds, as in many other natural products, are scrutinised. Full article

(This article belongs to the Collection Feature Papers in Drug Discovery)

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21 pages, 3612 KiB

Open AccessEditor’s ChoiceReview

Towards Quantum-Chemical Level Calculations of SARS-CoV-2 Spike Protein Variants of Concern by First Principles Density Functional Theory

by Wai-Yim Ching, Puja Adhikari, Bahaa Jawad and Rudolf Podgornik

Biomedicines 2023, 11(2), 517; https://doi.org/10.3390/biomedicines11020517 - 10 Feb 2023

Cited by 4 | Viewed by 1989

Abstract

The spike protein (S-protein) is a crucial part of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with its many domains responsible for binding, fusion, and host cell entry. In this review we use the density functional theory (DFT) calculations to analyze the [...] Read more.

The spike protein (S-protein) is a crucial part of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with its many domains responsible for binding, fusion, and host cell entry. In this review we use the density functional theory (DFT) calculations to analyze the atomic-scale interactions and investigate the consequences of mutations in S-protein domains. We specifically describe the key amino acids and functions of each domain, which are essential for structural stability as well as recognition and fusion processes with the host cell; in addition, we speculate on how mutations affect these properties. Such unprecedented large-scale ab initio calculations, with up to 5000 atoms in the system, are based on the novel concept of amino acid–amino acid-bond pair unit (AABPU) that allows for an alternative description of proteins, providing valuable information on partial charge, interatomic bonding and hydrogen bond (HB) formation. In general, our results show that the S-protein mutations for different variants foster an increased positive partial charge, alter the interatomic interactions, and disrupt the HB networks. We conclude by outlining a roadmap for future computational research of biomolecular virus-related systems. Full article

(This article belongs to the Special Issue Conformational Dynamics of Viral Proteins)

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22 pages, 2167 KiB

Open AccessEditor’s ChoiceReview

The Role of Probiotics in Inducing and Maintaining Remission in Crohn’s Disease and Ulcerative Colitis: A Systematic Review of the Literature

by Georgios Vakadaris, Christos Stefanis, Elpida Giorgi, Merkourios Brouvalis, Chrysoula (Chrysa) Voidarou, Yiannis Kourkoutas, Christina Tsigalou and Eugenia Bezirtzoglou

Biomedicines 2023, 11(2), 494; https://doi.org/10.3390/biomedicines11020494 - 8 Feb 2023

Cited by 15 | Viewed by 6296

Abstract

Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the gastrointestinal tract affecting millions of patients worldwide. The gut microbiome partly determines the pathogenesis of both diseases. Even though probiotics have been widely used as a potential treatment, their efficacy [...] Read more.

Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the gastrointestinal tract affecting millions of patients worldwide. The gut microbiome partly determines the pathogenesis of both diseases. Even though probiotics have been widely used as a potential treatment, their efficacy in inducing and maintaining remission is still controversial. Our study aims to review the present-day literature about the possible role of probiotics in treating inflammatory bowel diseases in adults. This research was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. We included studies concerning adult patients who compared probiotics with placebo or non-probiotic intervention. We identified thirty-three studies, including 2713 patients from fourteen countries. The role of probiotics in Crohn’s disease was examined in eleven studies. Only four studies presented statistically significant results in the remission of disease, primarily when used for three to six months. On the other hand, in twenty-one out of twenty-five studies, probiotics proved effective in achieving or maintaining remission in ulcerative colitis. Supplementation with Bifidobacterium sp. or a combination of probiotics is the most effective intervention, especially when compared with a placebo. There is strong evidence supporting the usage of probiotic supplementation in patients with ulcerative colitis, yet more research is needed to justify their efficacy in Crohn’s disease. Full article

(This article belongs to the Special Issue Microbial Ecology in Health and Disease 2.0)

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21 pages, 1221 KiB

Open AccessEditor’s ChoiceReview

The Role of COX-2 and PGE2 in the Regulation of Immunomodulation and Other Functions of Mesenchymal Stromal Cells

by Agnieszka Kulesza, Leszek Paczek and Anna Burdzinska

Biomedicines 2023, 11(2), 445; https://doi.org/10.3390/biomedicines11020445 - 3 Feb 2023

Cited by 39 | Viewed by 7534

Abstract

The ability of MSCs to modulate the inflammatory environment is well recognized, but understanding the molecular mechanisms responsible for these properties is still far from complete. Prostaglandin E2 (PGE2), a product of the cyclooxygenase 2 (COX-2) pathway, is indicated as one of the [...] Read more.

The ability of MSCs to modulate the inflammatory environment is well recognized, but understanding the molecular mechanisms responsible for these properties is still far from complete. Prostaglandin E2 (PGE2), a product of the cyclooxygenase 2 (COX-2) pathway, is indicated as one of the key mediators in the immunomodulatory effect of MSCs. Due to the pleiotropic effect of this molecule, determining its role in particular intercellular interactions and aspects of cell functioning is very difficult. In this article, the authors attempt to summarize the previous observations regarding the role of PGE2 and COX-2 in the immunomodulatory properties and other vital functions of MSCs. So far, the most consistent results relate to the inhibitory effect of MSC-derived PGE2 on the early maturation of dendritic cells, suppressive effect on the proliferation of activated lymphocytes, and stimulatory effect on the differentiation of macrophages into M2 phenotype. Additionally, COX-2/PGE2 plays an important role in maintaining the basic life functions of MSCs, such as the ability to proliferate, migrate and differentiate, and it also positively affects the formation of niches that are conducive to both hematopoiesis and carcinogenesis. Full article

(This article belongs to the Special Issue State-of-the-Art Gene-Target and Cell Therapy in Poland)

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14 pages, 296 KiB

Open AccessEditor’s ChoiceArticle

Effect of Lifestyle Interventions during Pregnancy on Maternal Leptin, Resistin and Offspring Weight at Birth and One Year of Life

by Nina Ferrari, Nikola Schmidt, Lisa Schmidt, Waltraut M. Merz, Konrad Brockmeier, Jörg Dötsch, Inga Bae-Gartz, Esther Mahabir and Christine Joisten

Biomedicines 2023, 11(2), 447; https://doi.org/10.3390/biomedicines11020447 - 3 Feb 2023

Viewed by 1557

Abstract

Lifestyle during pregnancy impacts the health of the mother and child. However, the extent to which physical activity affects maternal biomarkers and factors that might influence birth weight remains unclear. We analysed data from two lifestyle interventions in which the effects of an [...] Read more.

Lifestyle during pregnancy impacts the health of the mother and child. However, the extent to which physical activity affects maternal biomarkers and factors that might influence birth weight remains unclear. We analysed data from two lifestyle interventions in which the effects of an exercise programme (2x/week, 60–90 min) on the course of pregnancy with regard to adipokines and offspring were evaluated. A total of 70 women participated in this study (45, intervention group; 25, control group). Anthropometric data and maternal fasting serum leptin and resistin levels were measured at three time points (approximately 14th (T1), 24th (T2), and 36th (T3) weeks of gestation). Neonatal/child data were retrieved from screening examinations. Independent of the intervention, we found a positive correlation between the fat mass at T1 and both leptin and resistin levels at all time points. Leptin level was significantly higher in the control group at T3; however, no differences between the groups were found for resistin. The birth weight was influenced by the birth length, fat mass at T1/T3, and resistin level at T2. The BMI-SDS at one year of age was influenced by maternal fat-free mass at T3 and resistin at T1/T2. Even if these results can only be interpreted cautiously, lifestyle interventions during pregnancy are important in promoting maternal and child health. Further randomised controlled trials and translational studies are warranted to clarify the underlying mechanisms. Full article

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

27 pages, 5206 KiB

Open AccessEditor’s ChoiceReview

Immune Response and Molecular Mechanisms of Cardiovascular Adverse Effects of Spike Proteins from SARS-CoV-2 and mRNA Vaccines

by Paolo Bellavite, Alessandra Ferraresi and Ciro Isidoro

Biomedicines 2023, 11(2), 451; https://doi.org/10.3390/biomedicines11020451 - 3 Feb 2023

Cited by 17 | Viewed by 22392

Abstract

The SARS-CoV-2 (severe acute respiratory syndrome coronavirus responsible for the COVID-19 disease) uses the Spike proteins of its envelope for infecting target cells expressing on the membrane the angiotensin converting enzyme 2 (ACE2) enzyme that acts as a receptor. To control the pandemic, [...] Read more.

The SARS-CoV-2 (severe acute respiratory syndrome coronavirus responsible for the COVID-19 disease) uses the Spike proteins of its envelope for infecting target cells expressing on the membrane the angiotensin converting enzyme 2 (ACE2) enzyme that acts as a receptor. To control the pandemic, genetically engineered vaccines have been designed for inducing neutralizing antibodies against the Spike proteins. These vaccines do not act like traditional protein-based vaccines, as they deliver the message in the form of mRNA or DNA to host cells that then produce and expose the Spike protein on the membrane (from which it can be shed in soluble form) to alert the immune system. Mass vaccination has brought to light various adverse effects associated with these genetically based vaccines, mainly affecting the circulatory and cardiovascular system. ACE2 is present as membrane-bound on several cell types, including the mucosa of the upper respiratory and of the gastrointestinal tracts, the endothelium, the platelets, and in soluble form in the plasma. The ACE2 enzyme converts the vasoconstrictor angiotensin II into peptides with vasodilator properties. Here we review the pathways for immunization and the molecular mechanisms through which the Spike protein, either from SARS-CoV-2 or encoded by the mRNA-based vaccines, interferes with the Renin-Angiotensin-System governed by ACE2, thus altering the homeostasis of the circulation and of the cardiovascular system. Understanding the molecular interactions of the Spike protein with ACE2 and the consequent impact on cardiovascular system homeostasis will direct the diagnosis and therapy of the vaccine-related adverse effects and provide information for development of a personalized vaccination that considers pathophysiological conditions predisposing to such adverse events. Full article

(This article belongs to the Special Issue Emerging Issues in COVID Vaccine)

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19 pages, 1310 KiB

Open AccessEditor’s ChoiceReview

The Interaction of Gut Microbiota and Heart Failure with Preserved Ejection Fraction: From Mechanism to Potential Therapies

by Wei Yu, Yufeng Jiang, Hui Xu and Yafeng Zhou

Biomedicines 2023, 11(2), 442; https://doi.org/10.3390/biomedicines11020442 - 2 Feb 2023

Cited by 9 | Viewed by 3322

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a disease for which there is no definite and effective treatment, and the number of patients is more than 50% of heart failure (HF) patients. Gut microbiota (GMB) is a general term for a group [...] Read more.

Heart failure with preserved ejection fraction (HFpEF) is a disease for which there is no definite and effective treatment, and the number of patients is more than 50% of heart failure (HF) patients. Gut microbiota (GMB) is a general term for a group of microbiota living in humans’ intestinal tracts, which has been proved to be related to cardiovascular diseases, including HFpEF. In HFpEF patients, the composition of GMB is significantly changed, and there has been a tendency toward dysbacteriosis. Metabolites of GMB, such as trimethylamine N-oxide (TMAO), short-chain fatty acids (SCFAs) and bile acids (BAs) mediate various pathophysiological mechanisms of HFpEF. GMB is a crucial influential factor in inflammation, which is considered to be one of the main causes of HFpEF. The role of GMB in its important comorbidity—metabolic syndrome—also mediates HFpEF. Moreover, HF would aggravate intestinal barrier impairment and microbial translocation, further promoting the disease progression. In view of these mechanisms, drugs targeting GMB may be one of the effective ways to treat HFpEF. This review focuses on the interaction of GMB and HFpEF and analyzes potential therapies. Full article

(This article belongs to the Special Issue Recent Advances in Gut Microbiome and Heart Failure)

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13 pages, 2594 KiB

Open AccessEditor’s ChoiceReview

Advancing Medicine with Lipid-Based Nanosystems—The Successful Case of Liposomes

by Hugo Luiz, Jacinta Oliveira Pinho and Maria Manuela Gaspar

Biomedicines 2023, 11(2), 435; https://doi.org/10.3390/biomedicines11020435 - 2 Feb 2023

Cited by 14 | Viewed by 3874

Abstract

Nanomedicine, a promising area of medicine, employs nanosized tools for the diagnosis, prevention, and treatment of disease. Particularly, liposomes, lipid-based nanovesicles, are currently one of the most successful nanosystems, with extensive applications in the clinic and an increasing pipeline of products in preclinical [...] Read more.

Nanomedicine, a promising area of medicine, employs nanosized tools for the diagnosis, prevention, and treatment of disease. Particularly, liposomes, lipid-based nanovesicles, are currently one of the most successful nanosystems, with extensive applications in the clinic and an increasing pipeline of products in preclinical and clinical development. These versatile nanotechnological tools are biocompatible and biodegradable, and can load a variety of molecules and, ultimately, improve the therapeutic performance of drugs while minimizing undesired side effects. In this review, we provide a brief description on liposomes’ composition and classification and mainly focus on their clinical use in various areas, including disease management (e.g., cancer, fungal and bacterial infections, ocular pathologies), analgesia, vaccination, diagnostics, and immunosuppression in organ transplantation. Herein are described examples of current liposomal products already in the clinic, as well as the most recent clinical trials involving liposomes as effective and safe nanomedicine tools. Full article

(This article belongs to the Special Issue Liposomal Drug Delivery: Three Decades from the First Liposomal Drug Delivery Medicine in Clinical Use)

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27 pages, 13753 KiB

Open AccessEditor’s ChoiceReview

DNA Gyrase as a Target for Quinolones

by Angela C. Spencer and Siva S. Panda

Biomedicines 2023, 11(2), 371; https://doi.org/10.3390/biomedicines11020371 - 27 Jan 2023

Cited by 26 | Viewed by 8149

Abstract

Bacterial DNA gyrase is a type II topoisomerase that can introduce negative supercoils to DNA substrates and is a clinically-relevant target for the development of new antibacterials. DNA gyrase is one of the primary targets of quinolones, broad-spectrum antibacterial agents and are used [...] Read more.

Bacterial DNA gyrase is a type II topoisomerase that can introduce negative supercoils to DNA substrates and is a clinically-relevant target for the development of new antibacterials. DNA gyrase is one of the primary targets of quinolones, broad-spectrum antibacterial agents and are used as a first-line drug for various types of infections. However, currently used quinolones are becoming less effective due to drug resistance. Common resistance comes in the form of mutation in enzyme targets, with this type being the most clinically relevant. Additional mechanisms, conducive to quinolone resistance, are arbitrated by chromosomal mutations and/or plasmid-gene uptake that can alter quinolone cellular concentration and interaction with the target, or affect drug metabolism. Significant synthetic strategies have been employed to modify the quinolone scaffold and/or develop novel quinolones to overcome the resistance problem. This review discusses the development of quinolone antibiotics targeting DNA gyrase to overcome bacterial resistance and reduce toxicity. Moreover, structural activity relationship (SAR) data included in this review could be useful for the development of future generations of quinolone antibiotics. Full article

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

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22 pages, 1446 KiB

Open AccessEditor’s ChoiceReview

Design and Prediction of Aptamers Assisted by In Silico Methods

by Su Jin Lee, Junmin Cho, Byung-Hoon Lee, Donghwan Hwang and Jee-Woong Park

Biomedicines 2023, 11(2), 356; https://doi.org/10.3390/biomedicines11020356 - 26 Jan 2023

Cited by 22 | Viewed by 9174

Abstract

An aptamer is a single-stranded DNA or RNA that binds to a specific target with high binding affinity. Aptamers are developed through the process of systematic evolution of ligands by exponential enrichment (SELEX), which is repeated to increase the binding power and specificity. [...] Read more.

An aptamer is a single-stranded DNA or RNA that binds to a specific target with high binding affinity. Aptamers are developed through the process of systematic evolution of ligands by exponential enrichment (SELEX), which is repeated to increase the binding power and specificity. However, the SELEX process is time-consuming, and the characterization of aptamer candidates selected through it requires additional effort. Here, we describe in silico methods in order to suggest the most efficient way to develop aptamers and minimize the laborious effort required to screen and optimise aptamers. We investigated several methods for the estimation of aptamer-target molecule binding through conformational structure prediction, molecular docking, and molecular dynamic simulation. In addition, examples of machine learning and deep learning technologies used to predict the binding of targets and ligands in the development of new drugs are introduced. This review will be helpful in the development and application of in silico aptamer screening and characterization. Full article

(This article belongs to the Special Issue Nucleic Acid Based Sensing for Biomedical Applications)

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26 pages, 1800 KiB

Open AccessEditor’s ChoiceReview

Adipose Tissue and Adipose-Tissue-Derived Cell Therapies for the Treatment of the Face and Hands of Patients Suffering from Systemic Sclerosis

by Anouck Coulange Zavarro, Mélanie Velier, Robin Arcani, Maxime Abellan Lopez, Stéphanie Simoncini, Audrey Benyamine, Quentin Gomes De Pinho, Raphael Coatmeur, Jiucun Wang, Jingjing Xia, Ludovica Barone, Dominique Casanova, Françoise Dignat-George, Florence Sabatier, Brigitte Granel, Jérémy Magalon and Aurélie Daumas

Biomedicines 2023, 11(2), 348; https://doi.org/10.3390/biomedicines11020348 - 26 Jan 2023

Cited by 2 | Viewed by 2755

Abstract

Adipose tissue is recognized as a valuable source of cells with angiogenic, immunomodulatory, reparative and antifibrotic properties and emerged as a therapeutic alternative for the regeneration and repair of damaged tissues. The use of adipose-tissue-based therapy is expanding in autoimmune diseases, particularly in [...] Read more.

Adipose tissue is recognized as a valuable source of cells with angiogenic, immunomodulatory, reparative and antifibrotic properties and emerged as a therapeutic alternative for the regeneration and repair of damaged tissues. The use of adipose-tissue-based therapy is expanding in autoimmune diseases, particularly in Systemic Sclerosis (SSc), a disease in which hands and face are severely affected, leading to disability and a decrease in quality of life. Combining the advantage of an abundant supply of fat tissue and a high abundance of stem/stromal cells, fat grafting and adipose tissue-derived cell-based therapies are attractive therapeutic options in SSc. This review aims to synthesize the evidence to determine the effects of the use of these biological products for face and hands treatment in the context of SSc. This highlights several points: the need to use relevant effectiveness criteria taking into account the clinical heterogeneity of SSc in order to facilitate assessment and comparison of innovative therapies; second, it reveals some impacts of the disease on fat-grafting success; third, an important heterogeneity was noticed regarding the manufacturing of the adipose-derived products and lastly, it shows a lack of robust evidence from controlled trials comparing adipose-derived products with standard care. Full article

(This article belongs to the Section Gene and Cell Therapy)

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19 pages, 2635 KiB

Open AccessEditor’s ChoiceReview

Retinal Pigment Epithelium Cell Development: Extrapolating Basic Biology to Stem Cell Research

by Santosh Gupta, Lyubomyr Lytvynchuk, Taras Ardan, Hana Studenovska, Georgina Faura, Lars Eide, Ljubo Znaor, Slaven Erceg, Knut Stieger, Jan Motlik, Kapil Bharti and Goran Petrovski

Biomedicines 2023, 11(2), 310; https://doi.org/10.3390/biomedicines11020310 - 23 Jan 2023

Cited by 6 | Viewed by 6976

Abstract

The retinal pigment epithelium (RPE) forms an important cellular monolayer, which contributes to the normal physiology of the eye. Damage to the RPE leads to the development of degenerative diseases, such as age-related macular degeneration (AMD). Apart from acting as a physical barrier [...] Read more.

The retinal pigment epithelium (RPE) forms an important cellular monolayer, which contributes to the normal physiology of the eye. Damage to the RPE leads to the development of degenerative diseases, such as age-related macular degeneration (AMD). Apart from acting as a physical barrier between the retina and choroidal blood vessels, the RPE is crucial in maintaining photoreceptor (PR) and visual functions. Current clinical intervention to treat early stages of AMD includes stem cell-derived RPE transplantation, which is still in its early stages of evolution. Therefore, it becomes essential to derive RPEs which are functional and exhibit features as observed in native human RPE cells. The conventional strategy is to use the knowledge obtained from developmental studies using various animal models and stem cell-based exploratory studies to understand RPE biogenies and developmental trajectory. This article emphasises such studies and aims to present a comprehensive understanding of the basic biology, including the genetics and molecular pathways of RPE development. It encompasses basic developmental biology and stem cell-based developmental studies to uncover RPE differentiation. Knowledge of the in utero developmental cues provides an inclusive methodology required for deriving RPEs using stem cells. Full article

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

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24 pages, 1659 KiB

Open AccessEditor’s ChoiceReview

Eph Receptors in Cancer

by Sakshi Arora, Andrew M. Scott and Peter W. Janes

Biomedicines 2023, 11(2), 315; https://doi.org/10.3390/biomedicines11020315 - 23 Jan 2023

Cited by 15 | Viewed by 2858

Abstract

Eph receptor tyrosine kinases play critical functions during development, in the formation of tissue and organ borders, and the vascular and neural systems. Uniquely among tyrosine kinases, their activities are controlled by binding to membrane-bound ligands, called ephrins. Ephs and ephrins generally have [...] Read more.

Eph receptor tyrosine kinases play critical functions during development, in the formation of tissue and organ borders, and the vascular and neural systems. Uniquely among tyrosine kinases, their activities are controlled by binding to membrane-bound ligands, called ephrins. Ephs and ephrins generally have a low expression in adults, functioning mainly in tissue homeostasis and plasticity, but are often overexpressed in cancers, where they are especially associated with undifferentiated or progenitor cells, and with tumour development, vasculature, and invasion. Mutations in Eph receptors also occur in various tumour types and are suspected to promote tumourigenesis. Ephs and ephrins have the capacity to operate as both tumour promoters and tumour suppressors, depending on the circumstances. They have been demonstrated to impact tumour cell proliferation, migration, and invasion in vitro, as well as tumour development, angiogenesis, and metastases in vivo, making them potential therapeutic targets. However, successful development of therapies will require detailed understanding of the opposing roles of Ephs in various cancers. In this review, we discuss the variations in Eph expression and functions in a variety of malignancies. We also describe the multiple strategies that are currently available to target them in tumours, including preclinical and clinical development. Full article

(This article belongs to the Special Issue Kinases and Other Molecular Targets in Cancer: Recent Advances, Therapeutic Opportunities, and Clinical Challenges)

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16 pages, 1802 KiB

Open AccessEditor’s ChoiceSystematic Review

Combination of Conventional Drugs with Biocompounds Derived from Cinnamic Acid: A Promising Option for Breast Cancer Therapy

by Lyvia Eloiza de Freitas Meirelles, Maria Vitória Felipe de Souza, Lucimara Rodrigues Carobeli, Fabrício Morelli, Natália Lourenço Mari, Edilson Damke, Cristiane Suemi Shinobu Mesquita, Jorge Juarez Vieira Teixeira, Marcia Edilaine Lopes Consolaro and Vânia Ramos Sela da Silva

Biomedicines 2023, 11(2), 275; https://doi.org/10.3390/biomedicines11020275 - 19 Jan 2023

Cited by 6 | Viewed by 2617

Abstract

Despite the options available for breast cancer (BC) therapy, several adverse effects and resistance limit the success of the treatment. Furthermore, the use of a single drug is associated with a high failure rate. We investigated through a systematic review the in vitro [...] Read more.

Despite the options available for breast cancer (BC) therapy, several adverse effects and resistance limit the success of the treatment. Furthermore, the use of a single drug is associated with a high failure rate. We investigated through a systematic review the in vitro effects of the combination between conventional drugs and bioactive compounds derived from cinnamic acid in BC treatment. The information was acquired from the following databases: PubMed, Web of Science, Embase, Scopus, Lilacs and Cochrane library. We focused on “Cinnamates”, “Drug Combinations” and “Breast neoplasms” for publications dating between January 2012 and December 2022, based on the PRISMA statement. The references of the articles were carefully reviewed. Finally, nine eligible studies were included. The majority of these studies were performed using MCF-7, MDA-MB-231, MDA-MB-468 and BT-20 cell lines and the combination between cisplatin, paclitaxel, doxorubicin, tamoxifen, dactolisib and veliparib, with caffeic acid phenethyl ester, eugenol, 3-caffeoylquinic acid, salvianolic acid A, ferulic acid, caffeic acid, rosmarinic acid and ursolic acid. The combination improved overall conventional drug effects, with increased cytotoxicity, antimigratory effect and reversing resistance. Combining conventional drugs with bioactive compounds derived from cinnamic acid could emerge as a privileged scaffold for establishing new treatment options for different BC types. Full article

(This article belongs to the Special Issue Tumor Microenvironment Regulation and Anti-cancer Natural Products)

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27 pages, 2297 KiB

Open AccessEditor’s ChoiceReview

Exploring the Use of Cold Atmospheric Plasma to Overcome Drug Resistance in Cancer

by Dzohara Murillo, Carmen Huergo, Borja Gallego, René Rodríguez and Juan Tornín

Biomedicines 2023, 11(1), 208; https://doi.org/10.3390/biomedicines11010208 - 14 Jan 2023

Cited by 22 | Viewed by 6807

Abstract

Drug resistance is a major problem in cancer treatment, as it limits the effectiveness of pharmacological agents and can lead to disease progression. Cold atmospheric plasma (CAP) is a technology that uses ionized gas (plasma) to generate reactive oxygen and nitrogen species (RONS) [...] Read more.

Drug resistance is a major problem in cancer treatment, as it limits the effectiveness of pharmacological agents and can lead to disease progression. Cold atmospheric plasma (CAP) is a technology that uses ionized gas (plasma) to generate reactive oxygen and nitrogen species (RONS) that can kill cancer cells. CAP is a novel approach for overcoming drug resistance in cancer. In recent years, there has been a growing interest in using CAP to enhance the effectiveness of chemotherapy drugs. In this review, we discuss the mechanisms behind this phenomenon and explore its potential applications in cancer treatment. Going through the existing literature on CAP and drug resistance in cancer, we highlight the challenges and opportunities for further research in this field. Our review suggests that CAP could be a promising option for overcoming drug resistance in cancer and warrants further investigation. Full article

(This article belongs to the Special Issue Cold Atmospheric Plasma Applications in Cancer)

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11 pages, 2796 KiB

Open AccessEditor’s ChoiceArticle

by Suman Chowdhury, Gusheng Wu, Zi-Hua Lu, Ranjeet Kumar and Robert Ledeen

Biomedicines 2023, 11(1), 209; https://doi.org/10.3390/biomedicines11010209 - 14 Jan 2023

Cited by 6 | Viewed by 1885

Abstract

The purpose of this study was to determine whether the age-related decline in a-series gangliosides (especially GM1), shown to be a factor in the brain-related etiology of Parkinson’s disease (PD), also pertains to the peripheral nervous system (PNS) and aspects of PD unrelated [...] Read more.

The purpose of this study was to determine whether the age-related decline in a-series gangliosides (especially GM1), shown to be a factor in the brain-related etiology of Parkinson’s disease (PD), also pertains to the peripheral nervous system (PNS) and aspects of PD unrelated to the central nervous system (CNS). Following Svennerholm’s demonstration of the age-dependent decline in a-series gangliosides (both GM1 and GD1a) in the human brain, we previously demonstrated a similar decline in the normal mouse brain. The present study seeks to determine whether a similar a-series decline occurs in the periphery of normal mice as a possible prelude to the non-CNS symptoms of PD. We used mice of increasing age to measure a-series gangliosides in three peripheral tissues closely associated with PD pathology. Employing high-performance thin-layer chromatography (HPTLC), we found a substantial decrease in both GM1 and GD1a in all three tissues from 191 days of age. Motor and cognitive dysfunction were also shown to worsen, as expected, in synchrony with the decrease in GM1. Based on the previously demonstrated parallel between mice and humans concerning age-related a-series ganglioside decline in the brain, we propose the present findings to suggest a similar a-series decline in human peripheral tissues as the primary contributor to non-CNS pathologies of PD. An onset of sporadic PD would thus be seen as occurring simultaneously throughout the brain and body, albeit at varying rates, in association with the decline in a-series gangliosides. This would obviate the need to postulate the transfer of aggregated α-synuclein between brain and body or to debate brain vs. body as the origin of PD. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Health and Diseases)

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12 pages, 3521 KiB

Open AccessEditor’s ChoiceArticle

The Inflammatory Gene PYCARD of the Entorhinal Cortex as an Early Diagnostic Target for Alzheimer’s Disease

by Wenjia Liu, Sophia Chen, Xin Rao, Yisong Yang, Xiaodong Chen and Liyang Yu

Biomedicines 2023, 11(1), 194; https://doi.org/10.3390/biomedicines11010194 - 12 Jan 2023

Cited by 5 | Viewed by 2203

Abstract

The incidence of Alzheimer’s disease (AD) is increasing year by year, which brings great challenges to human health. However, the pathogenesis of AD is still unclear, and it lacks early diagnostic targets. The entorhinal cortex (EC) is a key brain region for the [...] Read more.

The incidence of Alzheimer’s disease (AD) is increasing year by year, which brings great challenges to human health. However, the pathogenesis of AD is still unclear, and it lacks early diagnostic targets. The entorhinal cortex (EC) is a key brain region for the occurrence of AD neurodegeneration, and neuroinflammation plays a significant role in EC degeneration in AD. This study aimed to reveal the close relationship between inflammation-related genes in the EC and AD by detecting key differentially expressed genes (DEGs) via gene function enrichment pathway analysis. GSE4757 and GSE21779 gene expression profiles of AD were downloaded from the Gene Expression Omnibus (GEO) database. R language was used for the standardization and differential analysis of DEGs. Then, significantly enriched Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were analyzed to predict the potential biological functions of the DEGs. Finally, the significant expressions of identified DEGs were verified, and the therapeutic values were detected by a receiver operating characteristic (ROC) curve. The results showed that eight up-regulated genes (SLC22A2, ITGB2-AS1, NIT1, FGF14-AS2, SEMA3E, PYCARD, PRORY, ADIRF) and two down-regulated genes (AKAIN1, TRMT2B) may have a potential diagnostic value for AD, and participate in inflammatory pathways. The area under curve (AUC) results of the ten genes showed that they had potential diagnostic value for AD. The AUC of PYCARD was 0.95, which had the most significant diagnostic value, and it is involved in inflammatory processes such as the inflammasome complex adaptor protein. The DEGs screened, and subsequent pathway analysis revealed a close relationship between inflammation-related PYCARD and AD, thus providing a new basis for an early diagnostic target for AD. Full article

(This article belongs to the Section Immunology and Immunotherapy)

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15 pages, 3139 KiB

Open AccessEditor’s ChoiceReview

Converging Evidence of Similar Symptomatology of ME/CFS and PASC Indicating Multisystemic Dyshomeostasis

by David F. Marks

Biomedicines 2023, 11(1), 180; https://doi.org/10.3390/biomedicines11010180 - 11 Jan 2023

Cited by 9 | Viewed by 15154

Abstract

The purpose of this article is to review the evidence of similar symptomatology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-acute sequelae of SARS-CoV-2 infection (PASC). Reanalysis of data from a study by Jason comparing symptom reports from two groups of ME/CFS and [...] Read more.

The purpose of this article is to review the evidence of similar symptomatology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-acute sequelae of SARS-CoV-2 infection (PASC). Reanalysis of data from a study by Jason comparing symptom reports from two groups of ME/CFS and PASC patients shows a notably similar symptomatology. Symptom scores of the PASC group and the ME/CFS group correlated 0.902 (p < 0.0001) across items. The hypothesis is presented that ME/CFS and PASC are caused by a chronic state of multisystemic disequilibrium including endocrinological, immunological, and/or metabolic changes. The hypothesis holds that a changed set point persistently pushes the organism towards a pathological dysfunctional state which fails to reset. To use an analogy of a thermostat, if the ‘off switch’ of a thermostat intermittently stops working, for periods the house would become warmer and warmer without limit. The hypothesis draws on recent investigations of the Central Homeostasis Network showing multiple interconnections between the autonomic system, central nervous system, and brain stem. The hypothesis helps to explain the shared symptomatology of ME/CFS and PASC and the unpredictable, intermittent, and fluctuating pattern of symptoms of ME/CFS and PASC. The current theoretical approach remains speculative and requires in-depth investigation before any definite conclusions can be drawn. Full article

(This article belongs to the Special Issue Feature Review Papers on Brain and Nervous Related Diseases)

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19 pages, 4554 KiB

Open AccessEditor’s ChoiceArticle

A Mitochondrion-Targeting Protein (B2) Primes ROS/Nrf2-Mediated Stress Signals, Triggering Apoptosis and Necroptosis in Lung Cancer

by Hsuan-Wen Chiu, Shao-Wen Hung, Ching-Feng Chiu and Jiann-Ruey Hong

Biomedicines 2023, 11(1), 186; https://doi.org/10.3390/biomedicines11010186 - 11 Jan 2023

Cited by 2 | Viewed by 1988

Abstract

The betanodavirus B2 protein targets mitochondria and triggers mitochondrion-mediated cell death signaling in lung cancer cells; however, its molecular mechanism remains unknown. In this study, we observed that B2 triggers hydrogen peroxide/Nrf2-involved stress signals in the dynamic regulation of non-small lung cancer cell [...] Read more.

The betanodavirus B2 protein targets mitochondria and triggers mitochondrion-mediated cell death signaling in lung cancer cells; however, its molecular mechanism remains unknown. In this study, we observed that B2 triggers hydrogen peroxide/Nrf2-involved stress signals in the dynamic regulation of non-small lung cancer cell (NSCLC)-programmed cell death. Here, the B2 protein works as a necrotic inducer that triggers lung cancer death via p53 upregulation and RIP3 expression, suggesting a new perspective on lung cancer therapy. We employed the B2 protein to target A549 lung cancer cells and solid tumors in NOD/SCID mice. Tumors were collected and processed for the hematoxylin and eosin staining of tissue and cell sections, and their sera were used for blood biochemistry analysis. We observed that B2 killed an A549 cell-induced solid tumor in NOD/SCID mice; however, the mutant ΔB2 did not. In NOD/SCID mice, B2 (but not ΔB2) induced both p53/Bax-mediated apoptosis and RIPK3-mediated necroptosis. Finally, immunochemistry analysis showed hydrogen peroxide /p38/Nrf2 stress strongly inhibited the production of tumor markers CD133, Thy1, and napsin, which correlate with migration and invasion in cancer cells. This B2-triggered, ROS/Nrf2-mediated stress signal triggered multiple signals via pathways that killed A549 lung cancer tumor cells in vivo. Our results provide novel insight into lung cancer management and drug therapy. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction in Disease)

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13 pages, 1386 KiB

Open AccessEditor’s ChoiceArticle

Intestinal Barrier Dysfunction and Microbial Translocation in Patients with First-Diagnosed Atrial Fibrillation

by Leon Blöbaum, Marco Witkowski, Max Wegner, Stella Lammel, Philipp-Alexander Schencke, Kai Jakobs, Marianna Puccini, Daniela Reißner, Daniel Steffens, Ulf Landmesser, Ursula Rauch and Julian Friebel

Biomedicines 2023, 11(1), 176; https://doi.org/10.3390/biomedicines11010176 - 10 Jan 2023

Cited by 7 | Viewed by 2783

Abstract

Background: According to the leaky gut concept, microbial products (e.g., lipopolysaccharide, LPS) enter the circulation and mediate pro-inflammatory immunological responses. Higher plasma LPS levels have been reported in patients with various cardiovascular diseases, but not specifically during early atrial fibrillation (AF). Methods: We [...] Read more.

Background: According to the leaky gut concept, microbial products (e.g., lipopolysaccharide, LPS) enter the circulation and mediate pro-inflammatory immunological responses. Higher plasma LPS levels have been reported in patients with various cardiovascular diseases, but not specifically during early atrial fibrillation (AF). Methods: We studied data and blood samples from patients presenting with first-diagnosed AF (FDAF) (n = 80) and 20 controls. Results: Circulating biomarkers that are suggestive of mucosal inflammation (zonulin, mucosal adhesion molecule MAdCAM-1) and intestinal epithelium damage (intestinal fatty acid binding protein, IFABP) were increased in the plasma of patients with FDAF when compared to patients with chronic cardiovascular diseases but without AF. Surrogate plasma markers of increased intestinal permeability (LPS, CD14, LPS-binding protein, gut-derived LPS-neutralising IgA antibodies, EndoCAbs) were detected during early AF. A reduced ratio of IgG/IgM EndoCAbs titres indicated chronic endotoxaemia. Collagen turnover biomarkers, which corresponded to the LPS values, suggested an association of gut-derived low-grade endotoxaemia with adverse structural remodelling. The LPS concentrations were higher in FDAF patients who experienced a major adverse cardiovascular event. Conclusions: Intestinal barrier dysfunction and microbial translocation accompany FDAF. Improving gut permeability and low-grade endotoxaemia might be a potential therapeutic approach to reducing the disease progression and cardiovascular complications in FDAF. Full article

(This article belongs to the Special Issue Recent Advances in Gut Microbiome and Heart Failure)

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15 pages, 1712 KiB

Open AccessEditor’s ChoiceReview

SERPINA3: Stimulator or Inhibitor of Pathological Changes

by Mateusz de Mezer, Jan Rogaliński, Stanisław Przewoźny, Michał Chojnicki, Leszek Niepolski, Magdalena Sobieska and Agnieszka Przystańska

Biomedicines 2023, 11(1), 156; https://doi.org/10.3390/biomedicines11010156 - 7 Jan 2023

Cited by 23 | Viewed by 6067

Abstract

SERPINA3, also called α-1-antichymotrypsin (AACT, ACT), is one of the inhibitors of serine proteases, one of which is cathepsin G. As an acute-phase protein secreted into the plasma by liver cells, it plays an important role in the anti-inflammatory response and antiviral response. [...] Read more.

SERPINA3, also called α-1-antichymotrypsin (AACT, ACT), is one of the inhibitors of serine proteases, one of which is cathepsin G. As an acute-phase protein secreted into the plasma by liver cells, it plays an important role in the anti-inflammatory response and antiviral response. Elevated levels of SERPINA3 have been observed in heart failure and neurological diseases such as Alzheimer’s disease or Creutzfeldt–Jakob disease. Many studies have shown increased expression levels of the SERPINA3 gene in various types of cancer, such as glioblastoma, colorectal cancer, endometrial cancer, breast cancer, or melanoma. In this case, the SERPINA3 protein is associated with an antiapoptotic function implemented by adjusting the PI3K/AKT or MAPK/ERK 1/2 signal pathways. However, the functions of the SERPINA3 protein are still only partially understood, mainly in the context of cancerogenesis, so it seems necessary to summarize the available information and describe its mechanism of action. In particular, we sought to amass the existing body of research focusing on the description of the underlying mechanisms of various diseases not related to cancer. Our goal was to present an overview of the correct function of SERPINA3 as part of the defense system, which unfortunately easily becomes the “Fifth Column” and begins to support processes of destruction. Full article

(This article belongs to the Special Issue State-of-the-Art Gene-Target and Cell Therapy in Poland)

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30 pages, 11986 KiB

Open AccessEditor’s ChoiceArticle

Automated Detection of Broncho-Arterial Pairs Using CT Scans Employing Different Approaches to Classify Lung Diseases

by Sami Azam, A.K.M. Rakibul Haque Rafid, Sidratul Montaha, Asif Karim, Mirjam Jonkman and Friso De Boer

Biomedicines 2023, 11(1), 133; https://doi.org/10.3390/biomedicines11010133 - 5 Jan 2023

Cited by 10 | Viewed by 3878

Abstract

Current research indicates that for the identification of lung disorders, comprising pneumonia and COVID-19, structural distortions of bronchi and arteries (BA) should be taken into account. CT scans are an effective modality to detect lung anomalies. However, anomalies in bronchi and arteries can [...] Read more.

Current research indicates that for the identification of lung disorders, comprising pneumonia and COVID-19, structural distortions of bronchi and arteries (BA) should be taken into account. CT scans are an effective modality to detect lung anomalies. However, anomalies in bronchi and arteries can be difficult to detect. Therefore, in this study, alterations of bronchi and arteries are considered in the classification of lung diseases. Four approaches to highlight these are introduced: (a) a Hessian-based approach, (b) a region-growing algorithm, (c) a clustering-based approach, and (d) a color-coding-based approach. Prior to this, the lungs are segmented, employing several image preprocessing algorithms. The utilized COVID-19 Lung CT scan dataset contains three classes named Non-COVID, COVID, and community-acquired pneumonia, having 6983, 7593, and 2618 samples, respectively. To classify the CT scans into three classes, two deep learning architectures, (a) a convolutional neural network (CNN) and (b) a CNN with long short-term memory (LSTM) and an attention mechanism, are considered. Both these models are trained with the four datasets achieved from the four approaches. Results show that the CNN model achieved test accuracies of 88.52%, 87.14%, 92.36%, and 95.84% for the Hessian, the region-growing, the color-coding, and the clustering-based approaches, respectively. The CNN with LSTM and an attention mechanism model results in an increase in overall accuracy for all approaches with an 89.61%, 88.28%, 94.61%, and 97.12% test accuracy for the Hessian, region-growing, color-coding, and clustering-based approaches, respectively. To assess overfitting, the accuracy and loss curves and k-fold cross-validation technique are employed. The Hessian-based and region-growing algorithm-based approaches produced nearly equivalent outcomes. Our proposed method outperforms state-of-the-art studies, indicating that it may be worthwhile to pay more attention to BA features in lung disease classification based on CT images. Full article

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

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18 pages, 1645 KiB

Open AccessEditor’s ChoiceReview

Seventy Years of Antipsychotic Development: A Critical Review

by Mujeeb U. Shad

Biomedicines 2023, 11(1), 130; https://doi.org/10.3390/biomedicines11010130 - 4 Jan 2023

Cited by 7 | Viewed by 5479

Abstract

Since the mid-1950s discovery of the first effective antipsychotic medications (APM), we have only been able to improve the tolerability but not the overall efficacy of currently available APMs, as reflected by effectiveness trials in Europe and the United States. This inability to [...] Read more.

Since the mid-1950s discovery of the first effective antipsychotic medications (APM), we have only been able to improve the tolerability but not the overall efficacy of currently available APMs, as reflected by effectiveness trials in Europe and the United States. This inability to develop more effective APMs is attributable to multiple factors, including failure to create and use assessment tools to assess core symptom domains in schizophrenia, move beyond the dopaminergic hypothesis and to develop “me too” drugs, imposing ill-defined research domain criteria, and lacking federal funding for clinical trials. The classification of APMs is also confusing, including second-generation, partial agonists, and multimodal APMs in the same class of APMs, despite significant differences in their mechanisms of action. Other factors stagnating drug development include inadequate sample sizes to address heterogeneity, lack of statistical measures correlating with clinical significance, using the atheoretical basis of psychiatric diagnoses, failure to control placebo response, and high cost of newer and perhaps more tolerable APMs. Furthermore, there has been a failure to develop early predictors of antipsychotic response and various tools to optimize an APM response. Finally, some mental health providers are also responsible for the suboptimal use of APMs, by using excessive maintenance doses, often with irrational polypharmacy, further compromising effectiveness and medication adherence. However, some bright spots in antipsychotic development include improved tolerability of APMs and long-acting injectables to address the high prevalence of medication nonadherence. This review critically reviews 70 years of antipsychotic development, the reasons behind the failure to develop more effective APMs, and suggestions for future direction. Full article

(This article belongs to the Special Issue Antipsychotics: 70 Years)

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20 pages, 2029 KiB

Open AccessEditor’s ChoiceReview

Stem Cell Therapy for Alzheimer’s Disease: A Scoping Review for 2017–2022

by Yunxiao Duan, Linshuoshuo Lyu and Siyan Zhan

Biomedicines 2023, 11(1), 120; https://doi.org/10.3390/biomedicines11010120 - 3 Jan 2023

Cited by 6 | Viewed by 6773

Abstract

Alzheimer’s disease (AD) has been a major causal factor for mortality among elders around the world. The treatments for AD, however, are still in the stage of development. Stem cell therapy, compared to drug therapies and many other therapeutic options, has many advantages [...] Read more.

Alzheimer’s disease (AD) has been a major causal factor for mortality among elders around the world. The treatments for AD, however, are still in the stage of development. Stem cell therapy, compared to drug therapies and many other therapeutic options, has many advantages and is very promising in the future. There are four major types of stem cells used in AD therapy: neural stem cells, mesenchymal stem cells, embryonic stem cells, and induced pluripotent stem cells. All of them have applications in the treatments, either at the (1) cellular level, in an (2) animal model, or at the (3) clinical level. In general, many more types of stem cells were studied on the cellular level and animal model, than the clinical level. We suggest for future studies to increase research on various types of stem cells and include cross-disciplinary research with other diseases. In the future, there could also be improvements in the timeliness of research and individualization for stem cell therapies for AD. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines: Neuroinflammation and Neuroprotection)

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17 pages, 1264 KiB

Open AccessEditor’s ChoiceReview

Targeting PI3K/AKT/mTOR Pathway in Breast Cancer: From Biology to Clinical Challenges

by Krisida Cerma, Federico Piacentini, Luca Moscetti, Monica Barbolini, Fabio Canino, Antonio Tornincasa, Federica Caggia, Sara Cerri, Alessia Molinaro, Massimo Dominici and Claudia Omarini

Biomedicines 2023, 11(1), 109; https://doi.org/10.3390/biomedicines11010109 - 1 Jan 2023

Cited by 32 | Viewed by 4969

Abstract

Breast cancer (BC) is the most common women cancer and cause of cancer death. Despite decades of scientific progress in BC treatments, the clinical benefit of new drugs is modest in several cases. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin [...] Read more.

Breast cancer (BC) is the most common women cancer and cause of cancer death. Despite decades of scientific progress in BC treatments, the clinical benefit of new drugs is modest in several cases. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway mutations are frequent in BC (20–40%) and are significant causes of aggressive tumor behavior, as well as treatment resistance. Improving knowledge of the PI3K/AKT/mTOR pathway is an urgent need. This review aims to highlight the central role of PI3K-mTORC1/C2 mutations in the different BC subtypes, in terms of clinical outcomes and treatment efficacy. The broad base of knowledge in tumor biology is a key point for personalized BC therapy in the precision medicine era. Full article

(This article belongs to the Section Cancer Biology and Oncology)

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20 pages, 813 KiB

Open AccessEditor’s ChoiceReview

How the Tumor Micromilieu Modulates the Recruitment and Activation of Colorectal Cancer-Infiltrating Lymphocytes

by Imke Atreya and Markus F. Neurath

Biomedicines 2022, 10(11), 2940; https://doi.org/10.3390/biomedicines10112940 - 15 Nov 2022

Cited by 5 | Viewed by 3013

Abstract

The successful treatment of advanced colorectal cancer disease still represents an insufficiently solved clinical challenge, which is further complicated by the fact that the majority of malignant colon tumors show only relatively low immunogenicity and therefore have only limited responsiveness to immunotherapeutic approaches, [...] Read more.

The successful treatment of advanced colorectal cancer disease still represents an insufficiently solved clinical challenge, which is further complicated by the fact that the majority of malignant colon tumors show only relatively low immunogenicity and therefore have only limited responsiveness to immunotherapeutic approaches, such as, for instance, the use of checkpoint inhibitors. As it has been well established over the past two decades that the local tumor microenvironment and, in particular, the quantity, quality, and activation status of intratumoral immune cells critically influence the clinical prognosis of patients diagnosed with colorectal cancer and their individual benefits from immunotherapy, the enhancement of the intratumoral accumulation of cytolytic effector T lymphocytes and other cellular mediators of the antitumor immune response has emerged as a targeted objective. For the future identification and clinical validation of novel therapeutic target structures, it will thus be essential to further decipher the molecular mechanisms and cellular interactions in the intestinal tumor microenvironment, which are crucially involved in immune cell recruitment and activation. In this context, our review article aims at providing an overview of the key chemokines and cytokines whose presence in the tumor micromilieu relevantly modulates the numeric composition and antitumor capacity of tumor-infiltrating lymphocytes. Full article

(This article belongs to the Special Issue The Role of Inflammatory Cytokines in Cancer Progression)

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11 pages, 1558 KiB

Open AccessEditor’s ChoiceArticle

Sorafenib versus Lenvatinib Causes Stronger Oxidative Damage to Membrane Lipids in Noncancerous Tissues of the Thyroid, Liver, and Kidney: Effective Protection by Melatonin and Indole-3-Propionic Acid

by Jan Stępniak, Joanna Krawczyk-Lipiec, Andrzej Lewiński and Małgorzata Karbownik-Lewińska

Biomedicines 2022, 10(11), 2890; https://doi.org/10.3390/biomedicines10112890 - 11 Nov 2022

Cited by 10 | Viewed by 2364

Abstract

Sorafenib and lenvatinib are multi-targeted tyrosine kinase inhibitors which are currently approved to treat advanced hepatocellular carcinoma, renal cell carcinoma and radioiodine-refractory differentiated thyroid carcinoma. However this treatment is often limited due to common adverse events which may occur via oxidative stress. The [...] Read more.

Sorafenib and lenvatinib are multi-targeted tyrosine kinase inhibitors which are currently approved to treat advanced hepatocellular carcinoma, renal cell carcinoma and radioiodine-refractory differentiated thyroid carcinoma. However this treatment is often limited due to common adverse events which may occur via oxidative stress. The study aims to compare sorafenib- and lenvatinib-induced oxidative damage to membrane lipids (lipid peroxidation, LPO) in homogenates of porcine noncancerous tissues of the thyroid, the liver, and the kidney and to check if it can be prevented by antioxidants melatonin and indole-3-propionic acid (IPA). Homogenates of individual tissues were incubated in the presence of sorafenib or lenvatinib (1 mM, 100 µM, 10 µM, 1 µM, 100 nM, 10 nM, 1 nM, 100 pM) together with/without melatonin (5.0 mM) or IPA (5.0 mM). The concentration of malondialdehyde + 4-hydroxyalkenals, as the LPO index, was measured spectrophotometrically. The incubation of tissue homogenates with sorafenib resulted in a concentration-dependent increase in LPO (statistically significant for concentrations of 1mM and 100 µM in the thyroid and the liver, and of 1 mM, 100 µM, and 10 µM in the kidney). The incubation of thyroid homogenates with lenvatinib did not change LPO level. In case of the liver and the kidney, lenvatinib increased LPO but only in its highest concentration of 1 mM. Melatonin and IPA reduced completely (to the level of control) sorafenib- and lenvatinib-induced LPO in all examined tissues regardless of the drug concentration. In conclusion, sorafenib comparing to lenvatinib is a stronger damaging agent of membrane lipids in noncancerous tissues of the thyroid, the liver, and the kidney. The antioxidants melatonin and IPA can be considered to be used in co-treatment with sorafenib and lenvatinib to prevent their undesirable toxicity occurring via oxidative stress. Full article

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

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21 pages, 3483 KiB

Open AccessEditor’s ChoiceArticle

osr1 Maintains Renal Progenitors and Regulates Podocyte Development by Promoting wnt2ba via the Antagonism of hand2

by Bridgette E. Drummond, Brooke E. Chambers, Hannah M. Wesselman, Shannon Gibson, Liana Arceri, Marisa N. Ulrich, Gary F. Gerlach, Paul T. Kroeger, Ignaty Leshchiner, Wolfram Goessling and Rebecca A. Wingert

Biomedicines 2022, 10(11), 2868; https://doi.org/10.3390/biomedicines10112868 - 9 Nov 2022

Cited by 10 | Viewed by 2748

Abstract

Knowledge about the genetic pathways that control nephron development is essential for better understanding the basis of congenital malformations of the kidney. The transcription factors Osr1 and Hand2 are known to exert antagonistic influences to balance kidney specification. Here, we performed a forward [...] Read more.

Knowledge about the genetic pathways that control nephron development is essential for better understanding the basis of congenital malformations of the kidney. The transcription factors Osr1 and Hand2 are known to exert antagonistic influences to balance kidney specification. Here, we performed a forward genetic screen to identify nephrogenesis regulators, where whole genome sequencing identified an osr1 lesion in the novel oceanside (ocn) mutant. The characterization of the mutant revealed that osr1 is needed to specify not renal progenitors but rather their maintenance. Additionally, osr1 promotes the expression of wnt2ba in the intermediate mesoderm (IM) and later the podocyte lineage. wnt2ba deficiency reduced podocytes, where overexpression of wnt2ba was sufficient to rescue podocytes and osr1 deficiency. Antagonism between osr1 and hand2 mediates podocyte development specifically by controlling wnt2ba expression. These studies reveal new insights about the roles of Osr1 in promoting renal progenitor survival and lineage choice. Full article

(This article belongs to the Special Issue Zebrafish Models for Development and Disease 3.0)

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16 pages, 3475 KiB

Open AccessEditor’s ChoiceArticle

Clinical Outcomes of 3D-Printed Bioresorbable Scaffolds for Bone Tissue Engineering—A Pilot Study on 126 Patients for Burrhole Covers in Subdural Hematoma

by Emma M. S. Toh, Ashiley A. Thenpandiyan, Aaron S. C. Foo, John J. Y. Zhang, Mervyn J. R. Lim, Chun Peng Goh, Nivedh Dinesh, Srujana V. Vedicherla, Ming Yang, Kejia Teo, Tseng Tsai Yeo and Vincent D. W. Nga

Biomedicines 2022, 10(11), 2702; https://doi.org/10.3390/biomedicines10112702 - 26 Oct 2022

Cited by 9 | Viewed by 2816

Abstract

Burrhole craniostomy is commonly performed for subdural hematoma (SDH) evacuation, but residual scalp depressions are often cosmetically suboptimal for patients. Osteoplug^TM, a bioresorbable polycaprolactone burrhole cover, was introduced by the National University Hospital, Singapore, in 2006 to cover these defects, allowing [...] Read more.

Burrhole craniostomy is commonly performed for subdural hematoma (SDH) evacuation, but residual scalp depressions are often cosmetically suboptimal for patients. Osteoplug^TM, a bioresorbable polycaprolactone burrhole cover, was introduced by the National University Hospital, Singapore, in 2006 to cover these defects, allowing osseous integration and vascular ingrowth. However, the cosmetic and safety outcomes of Osteoplug^TM-C—the latest (2017) iteration, with a chamfered hole for subdural drains—remain unexplored. Data were collected from a single institution from April 2017 to March 2021. Patient-reported aesthetic outcomes (Aesthetic Numeric Analog (ANA)) and quality of life (EQ-5D-3L including Visual Analog Scale (VAS)) were assessed via telephone interviews. Clinical outcomes included SDH recurrence, postoperative infections, and drain complications. Osteoplug^TM-C patients had significantly higher satisfaction and quality of life compared to those without a burrhole cover (ANA: 9 [7, 9] vs. 7 [5, 8], p = 0.019; VAS: 85 [75, 90] vs. 70 [50, 80], p = 0.021), and the absence of a burrhole cover was associated with poorer aesthetic outcomes after multivariable adjustment (adjusted OR: 4.55, 95% CI: 1.09–22.68, p = 0.047). No significant differences in other clinical outcomes were observed between Osteoplug^TM-C, Osteoplug^TM, or no burrhole cover. Our pilot study supports Osteoplug^TM-C and its material polycaprolactone as suitable adjuncts to burrhole craniostomy, improving cosmetic outcomes while achieving comparable safety outcomes. Full article

(This article belongs to the Special Issue Scaffolds for Bone Tissue Engineering)

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8 pages, 220 KiB

Open AccessEditor’s ChoiceArticle

Predictive Risk Factors Associated with Severe Radiation-Induced Mucositis in Nasopharyngeal or Oropharyngeal Cancer Patients: A Retrospective Study

by Yumiko Kawashita, Sakiko Soutome, Masahiro Umeda and Toshiyuki Saito

Biomedicines 2022, 10(10), 2661; https://doi.org/10.3390/biomedicines10102661 - 21 Oct 2022

Cited by 6 | Viewed by 2077

Abstract

Radiation-induced mucositis in head and neck cancer patients generates difficulties in eating and swallowing, and may influence treatment tolerance, compliance, and quality of life. However, predictive factors have not been studied in detail. Thus, the aim of this study was to describe the [...] Read more.

Radiation-induced mucositis in head and neck cancer patients generates difficulties in eating and swallowing, and may influence treatment tolerance, compliance, and quality of life. However, predictive factors have not been studied in detail. Thus, the aim of this study was to describe the association between pre-radiotherapy clinical factors and the incidence of severe radiation-induced mucositis in nasopharyngeal or oropharyngeal cancer patients. This retrospective study included all patients with definitive radiotherapy or chemoradiotherapy for nasopharyngeal or oropharyngeal cancer between July 2011 and June 2021 in a single center. The eligibility criteria included patients who received oral management during radiotherapy. Exclusion criteria was patients who received postoperative radiotherapy. The data were acquired from the medical records of patients. One hundred patients were included in this retrospective study. Grade 3 radiation-induced mucositis occurred in 47 patients (47%). Lymphocyte count was significantly associated with grade 3 mucositis (OR = 0.40; 95% CI = 0.19–0.86; p = 0.018). It is suggested that pre-radiation lower lymphocyte counts are a predictive risk factor for severe mucositis in patients who undergo definitive radiotherapy or chemoradiotherapy for nasopharyngeal or oropharyngeal cancer Full article

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

17 pages, 1031 KiB

Open AccessEditor’s ChoiceArticle

Bronchial Asthma as a Cardiovascular Risk Factor: A Prospective Observational Study

by Marcela Kreslová, Olga Kirchnerová, Daniel Rajdl, Vendula Sudová, Jiří Blažek, Aneta Sýkorová, Petr Jehlička, Ladislav Trefil, Jan Schwarz, Renata Pomahačová and Josef Sýkora

Biomedicines 2022, 10(10), 2614; https://doi.org/10.3390/biomedicines10102614 - 18 Oct 2022

Cited by 7 | Viewed by 7625

Abstract

Introduction: Asthma as a chronic inflammatory disorder has been suggested as a risk factor for endothelial dysfunction (ED), but studies on the association between asthma and cardiovascular disease (CVD) risk are limited. Background: We assessed associations of ED with the severity of asthma, [...] Read more.

Introduction: Asthma as a chronic inflammatory disorder has been suggested as a risk factor for endothelial dysfunction (ED), but studies on the association between asthma and cardiovascular disease (CVD) risk are limited. Background: We assessed associations of ED with the severity of asthma, eosinophilic inflammation, lung function, and asthma control. Methods: 52 young asthmatics (median age of 25.22 years) and 45 healthy individuals were included. Demographic, clinical, and laboratory findings were recorded. We evaluated microvascular responsiveness by recording the reactive hyperemia index (RHI) indicating post-occlusive peripheral endothelium-dependent changes in vascular tone using the Itamar Medical EndoPAT2000. VCAM-1, ADMA, high-sensitive CRP (hsCRP), and E-selectin were measured. Results: Asthmatics had considerably lower RHI values (p < 0.001) with a dynamic decreasing trend by asthma severity and higher hsCRP levels (p < 0.001). A substantial increase in hsCRP and E-selectin with asthma severity (p < 0.05) was also observed. We confirmed a higher body mass index (BMI) in asthmatics (p < 0.001), especially in women and in severe asthma. Conclusions: We demonstrated the progression of CVD in asthmatics and the association of the ongoing deterioration of ED with the inflammatory severity, suggesting that the increased risk of CVD in young asthmatics is dependent on disease severity. The underlying mechanisms of risk factors for CVD and disease control require further study. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Advances in Endothelial Dysfunction)

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20 pages, 1052 KiB

Open AccessEditor’s ChoiceReview

Role of Extracellular Vesicles in Thyroid Physiology and Diseases: Implications for Diagnosis and Treatment

by Ophélie Delcorte, Jonathan Degosserie and Christophe E. Pierreux

Biomedicines 2022, 10(10), 2585; https://doi.org/10.3390/biomedicines10102585 - 15 Oct 2022

Cited by 5 | Viewed by 5364

Abstract

Extracellular vesicles are spherical subcellular structures delimited by a lipid bilayer and released by most cells in the human body. They are loaded with a myriad of molecules (i.e., nucleic acids and proteins) depending on their cell of origin and provide the ability [...] Read more.

Extracellular vesicles are spherical subcellular structures delimited by a lipid bilayer and released by most cells in the human body. They are loaded with a myriad of molecules (i.e., nucleic acids and proteins) depending on their cell of origin and provide the ability to transmit a message to surrounding or distant target cells. In several organs, including the thyroid, abundant recent literature reports that extracellular vesicles are responsible for intercellular communication in physiological and pathological processes, and that their utilization as a potential biomarker of pathological states (i.e., cancer, autoimmune diseases) or as therapeutic delivery vehicles promise clinical options. In this review, we present the current knowledge and understanding regarding the role of extracellular vesicles in developing thyroid diseases and diagnosis. Full article

(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Thyroid Diseases)

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12 pages, 3112 KiB

Open AccessEditor’s ChoiceArticle

Prognostic Significance of STING Immunoexpression in Relation to HPV16 Infection in Patients with Squamous Cell Carcinomas of Oral Cavity and Oropharynx

by Beata Biesaga, Ryszard Smolarczyk, Anna Mucha-Małecka, Justyna Czapla, Janusz Ryś and Krzysztof Małecki

Biomedicines 2022, 10(10), 2538; https://doi.org/10.3390/biomedicines10102538 - 12 Oct 2022

Cited by 5 | Viewed by 2220

Abstract

Infection with HPV16 in cancers of the oral cavity (OCSCC) and oropharynx (OPSCC) is, today, an important etiological and prognostic factor. Patients with HPV-positive OPSCC have a better prognosis than uninfected patients. However, in over 40% of these patients, cancer progression is noticed. [...] Read more.

Infection with HPV16 in cancers of the oral cavity (OCSCC) and oropharynx (OPSCC) is, today, an important etiological and prognostic factor. Patients with HPV-positive OPSCC have a better prognosis than uninfected patients. However, in over 40% of these patients, cancer progression is noticed. Their identification is particularly important due to the ongoing clinical trials regarding the possibility of de-escalation of anticancer treatment in patients with HPV-positive OPSCC. Some studies suggest that there is possibility to differentiate prognosis of HPV16-positive patients by STING (Stimulator of Interferon Genes) immunoexpression. The aim of the present study was to analyze the influence of STING immunoexpression on overall (OS) and disease-free survival (DFS) of patients with HPV16-positive and -negative OCSCC and OPSCC. The study was performed in a group of 87 patients with OCSCC and OPSCC for which in our earlier study active HPV16 infection was assessed by P16 expression followed by HPV DNA detection. To analyze STING immunoexpression in tumor area (THS) and in adjacent stromal tissues (SHS) H score (HS) was applied. In the subgroup with HPV16, active infection patients with tumors with THS had significantly better DFS (p = 0.047) than those without THS. In this subgroup, TSH did not significantly influence OS, and SHS did not significantly correlate with OS and DFS. In the subgroup of patients without active HPV16 infection, THS and SHS also did not significantly influence patients’ survival. Presented results indicated prognostic potential of tumor STING immunoexpression in patients with active HPV16 infection in cancers of oral cavity and oropharynx. Full article

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

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9 pages, 1194 KiB

Open AccessEditor’s ChoiceArticle

Adalimumab Originator vs. Biosimilar in Hidradenitis Suppurativa: A Multicentric Retrospective Study

by Martina Burlando, Gabriella Fabbrocini, Claudio Marasca, Paolo Dapavo, Andrea Chiricozzi, Dalma Malvaso, Valentina Dini, Anna Campanati, Annamaria Offidani, Annunziata Dattola, Raffaele Dante Caposiena Caro, Luca Bianchi, Marina Venturini, Paolo Gisondi, Claudio Guarneri, Giovanna Malara, Caterina Trifirò, Piergiorigio Malagoli, Maria Concetta Fargnoli, Stefano Piaserico, Luca Carmisciano, Riccardo Castelli and Aurora Parodi Show full author list Hide full author list

Biomedicines 2022, 10(10), 2522; https://doi.org/10.3390/biomedicines10102522 - 9 Oct 2022

Cited by 10 | Viewed by 2949

Abstract

This study aimed to compare adalimumab originator vs. biosimilar in HS patients, and to evaluate the effect of a switch to a biosimilar, or a switch back to the originator, in terms of treatment ineffectiveness. Patients with a diagnosis of HS were enrolled [...] Read more.

This study aimed to compare adalimumab originator vs. biosimilar in HS patients, and to evaluate the effect of a switch to a biosimilar, or a switch back to the originator, in terms of treatment ineffectiveness. Patients with a diagnosis of HS were enrolled from 14 Italian sites. Treatment ineffectiveness was measured using Hurley score. The major analyses were 1) comparison between the two treatment groups (non-switcher analysis), and 2) the cross-over trend of Hurley score between treatment switchers (switcher analysis). Cox and Poisson regression models were used to compare the treatment ineffectiveness between groups. A total of 326 patients were divided into four groups: 171 (52.5%) taking originator; 61 (18.7%) patients taking biosimilar; 66 (20.2%) switchers; 28 (8.6%) switchers from originator to biosimilar and switched. A greater loss of efficacy was observed in the group allocated to the biosimilar than the originator group. The switcher analysis showed an effectiveness loss in the biosimilar compared to the originator. These results seem to indicate that a switch from one drug to the other may lead to a greater risk of inefficacy. A return to the previous treatment also does not ensure efficaciousness. Full article

(This article belongs to the Special Issue Immune-Mediated Skin Diseases: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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31 pages, 1015 KiB

Open AccessEditor’s ChoiceReview

Immune Checkpoint Inhibitors and Other Immune Therapies in Breast Cancer: A New Paradigm for Prolonged Adjuvant Immunotherapy

by Andrea Nicolini, Paola Ferrari and Angelo Carpi

Biomedicines 2022, 10(10), 2511; https://doi.org/10.3390/biomedicines10102511 - 8 Oct 2022

Cited by 12 | Viewed by 5015

Abstract

Background: Breast cancer is the most common form of cancer in women worldwide. Advances in the early diagnosis and treatment of cancer in the last decade have progressively decreased the cancer mortality rate, and in recent years, immunotherapy has emerged as a relevant [...] Read more.

Background: Breast cancer is the most common form of cancer in women worldwide. Advances in the early diagnosis and treatment of cancer in the last decade have progressively decreased the cancer mortality rate, and in recent years, immunotherapy has emerged as a relevant tool against cancer. HER2+ and triple-negative breast cancers (TNBCs) are considered more immunogenic and suitable for this kind of treatment due to the higher rate of tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression. In TNBC, genetic aberrations further favor immunogenicity due to more neo-antigens in cancer cells. Methods: This review summarizes the principal ongoing conventional and investigational immunotherapies in breast cancer. Particularly, immune checkpoint inhibitors (ICIs) and their use alone or combined with DNA damage repair inhibitors (DDRis) are described. Then, the issue on immunotherapy with monoclonal antibodies against HER-2 family receptors is updated. Other investigational immunotherapies include a new schedule based on the interferon beta-interleukin-2 sequence that was given in ER+ metastatic breast cancer patients concomitant with anti-estrogen therapy, which surprisingly showed promising results. Results: Based on the scientific literature and our own findings, the current evaluation of tumor immunogenicity and the conventional model of adjuvant chemotherapy (CT) are questioned. Conclusions: A novel strategy based on additional prolonged adjuvant immunotherapy combined with hormone therapy or alternated with CT is proposed. Full article

(This article belongs to the Special Issue Immune Checkpoints and Autoimmunity)

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32 pages, 1786 KiB

Open AccessEditor’s ChoiceReview

The Complex Roles of Adipokines in Polycystic Ovary Syndrome and Endometriosis

by Susanne Schüler-Toprak, Olaf Ortmann, Christa Buechler and Oliver Treeck

Biomedicines 2022, 10(10), 2503; https://doi.org/10.3390/biomedicines10102503 - 7 Oct 2022

Cited by 22 | Viewed by 5105

Abstract

Polycystic ovary syndrome (PCOS) and endometriosis are frequent diseases of the female reproductive tract causing high morbidity as they can significantly affect fertility and quality of life. Adipokines are pleiotropic signaling molecules secreted by white or brown adipose tissues with a central role [...] Read more.

Polycystic ovary syndrome (PCOS) and endometriosis are frequent diseases of the female reproductive tract causing high morbidity as they can significantly affect fertility and quality of life. Adipokines are pleiotropic signaling molecules secreted by white or brown adipose tissues with a central role in energy metabolism. More recently, their involvement in PCOS and endometriosis has been demonstrated. In this review article, we provide an update on the role of adipokines in both diseases and summarize previous findings. We also address the results of multi-omics approaches in adipokine research to examine the role of single nucleotide polymorphisms (SNPs) in genes coding for adipokines and their receptors, the secretome of adipocytes and to identify epigenetic alterations of adipokine genes that might be conferred from mother to child. Finally, we address novel data on the role of brown adipose tissue (BAT), which seems to have notable effects on PCOS. For this review, original research articles on adipokine actions in PCOS and endometriosis are considered, which are listed in the PubMed database. Full article

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

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13 pages, 977 KiB

Open AccessEditor’s ChoiceReview

Vericiguat in Heart Failure: Characteristics, Scientific Evidence and Potential Clinical Applications

by Francesca Vannuccini, Alessandro Campora, Maria Barilli and Alberto Palazzuoli

Biomedicines 2022, 10(10), 2471; https://doi.org/10.3390/biomedicines10102471 - 3 Oct 2022

Cited by 18 | Viewed by 8519

Abstract

Despite recent advances in heart failure (HF) management, the risk of death and hospitalizations remains high in the long term. HF is characterized by endothelial dysfunction, inflammation and increased oxidative stress, due to a reduction in the activity of the nitric oxide (NO)-soluble [...] Read more.

Despite recent advances in heart failure (HF) management, the risk of death and hospitalizations remains high in the long term. HF is characterized by endothelial dysfunction, inflammation and increased oxidative stress, due to a reduction in the activity of the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling pathway. All these factors contribute to direct damage at the myocardial, vascular and renal level. Vericiguat restores the deficiency in this signaling pathway, through stimulation and activation of sGC, aiming to increase cGMP levels, with a reduction in HF-related oxidative stress and endothelial dysfunction. Two main clinical trials were developed in this setting: the SOCRATES-REDUCED phase II study and the VICTORIA phase III study. They found that vericiguat is safe, well tolerated and effective with an absolute event-rate reduction in patients affected by HF with reduced ejection fraction (HFrEF) and recent cardiac decompensation. In patients with HF with preserved ejection fraction (HfpEF), the SOCRATES-PRESERVED trial demonstrated an improvement in quality of life and health status, but the proven beneficial effects with vericiguat are still limited. Further studies are needed to correctly define the role of this drug in heart failure syndromes. Our paper reviews the potential applications and pharmacological characteristics of vericiguat in HFrEF and HFpEF. Full article

(This article belongs to the Special Issue Advances in Therapy for Heart Failure)

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13 pages, 2362 KiB

Open AccessEditor’s ChoiceArticle

Study on Tissue Homogenization Buffer Composition for Brain Mass Spectrometry-Based Proteomics

by Adam Aleksander Karpiński, Julio Cesar Torres Elguera, Anne Sanner, Witold Konopka, Leszek Kaczmarek, Dominic Winter, Anna Konopka and Ewa Bulska

Biomedicines 2022, 10(10), 2466; https://doi.org/10.3390/biomedicines10102466 - 2 Oct 2022

Cited by 2 | Viewed by 3564

Abstract

Mass spectrometry-based proteomics aims to study the proteome both qualitatively and quantitatively. A key step in proteomic analysis is sample preparation, which is crucial for reliable results. We investigated the effect of the composition of the homogenization buffer used to extract proteins from [...] Read more.

Mass spectrometry-based proteomics aims to study the proteome both qualitatively and quantitatively. A key step in proteomic analysis is sample preparation, which is crucial for reliable results. We investigated the effect of the composition of the homogenization buffer used to extract proteins from brain tissue on the yield of protein extraction and the number and type of extracted proteins. Three different types of buffers were compared—detergent-based buffer (DB), chaotropic agent-based buffer (CAB) and buffer without detergent and chaotropic agent (DFB). Based on label-free quantitative protein analysis, detergent buffer was identified as the most suitable for global proteomic profiling of brain tissue. It allows the most efficient extraction of membrane proteins, synaptic and synaptic membrane proteins along with ribosomal, mitochondrial and myelin sheath proteins, which are of particular interest in the field of neurodegenerative disorders research. Full article

(This article belongs to the Special Issue Mass Spectrometry Based Proteomics in Medical Research)

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10 pages, 303 KiB

Open AccessEditor’s ChoiceArticle

Plasma and Peritoneal Fluid ZEB Levels in Patients with Endometriosis and Infertility

by Paweł Bartnik, Joanna Kacperczyk-Bartnik, Ksawery Goławski, Janusz Sierdziński, Grzegorz Mańka, Mariusz Kiecka, Michał Lipa, Damian Warzecha, Robert Spaczyński, Piotr Piekarski, Beata Banaszewska, Artur J. Jakimiuk, Tadeusz Issat, Wojciech Rokita, Jakub Młodawski, Maria Szubert, Piotr Sieroszewski, Grzegorz Raba, Kamil Szczupak, Tomasz Kluz, Marek Kluza, Krzysztof Czajkowski, Mirosław Wielgoś, Ewa Koc-Żórawska, Marcin Żórawski and Piotr Laudański Show full author list Hide full author list

Biomedicines 2022, 10(10), 2460; https://doi.org/10.3390/biomedicines10102460 - 1 Oct 2022

Cited by 7 | Viewed by 2416

Abstract

Zinc finger E-box-binding homeobox 1 (ZEB1) and zinc finger E-box-binding homeobox 2 (ZEB2) are transcription factors that regulate epithelial–mesenchymal transformation (EMT). The aim of this study was to compare levels of ZEB1 and ZEB2 in the peritoneal fluid and plasma between patients with [...] Read more.

Zinc finger E-box-binding homeobox 1 (ZEB1) and zinc finger E-box-binding homeobox 2 (ZEB2) are transcription factors that regulate epithelial–mesenchymal transformation (EMT). The aim of this study was to compare levels of ZEB1 and ZEB2 in the peritoneal fluid and plasma between patients with and without endometriosis in order to assess their utility in the diagnostic process. Plasma and peritoneal fluid samples were collected from 50 patients with and 48 without endometriosis during planned surgical procedures in eight clinical centers. Quantitative ZEB1 and ZEB2 levels analyses were performed using a double-antibody sandwich enzyme-linked immunosorbent assay (ELISA). No significant differences were observed in ZEB1 levels in any of the subanalyses nor any differences regarding ZEB2 levels between patients with and without endometriosis. Plasma ZEB2 levels were significantly higher among patients with infertility compared to fertile women (16.07 ± 12.70 ng/L vs. 12.07 ± 11.92 ng/L; p < 0.04). Both ZEB1 and ZEB2 do not seem to have a significant value in the initial diagnosis of endometriosis as a single marker. The differences in ZEB2 plasma levels between patients with and without infertility indicate the possibility of EMT dysregulation in the pathogenesis of adverse fertility outcomes. Full article

(This article belongs to the Special Issue Advanced Research in Endometriosis 3.0)

12 pages, 1958 KiB

Open AccessEditor’s ChoiceArticle

The Role of [¹⁸F]F-Choline PET/CT in the Initial Management and Outcome Prediction of Prostate Cancer: A Real-World Experience from a Multidisciplinary Approach

by Luca Urso, Giovanni Christian Rocca, Francesca Borgia, Federica Lancia, Antonio Malorgio, Mauro Gagliano, Mauro Zanetto, Licia Uccelli, Corrado Cittanti, Carmelo Ippolito, Laura Evangelista and Mirco Bartolomei

Biomedicines 2022, 10(10), 2463; https://doi.org/10.3390/biomedicines10102463 - 1 Oct 2022

Cited by 8 | Viewed by 2314

Abstract

Initial staging of prostate cancer (PCa) is usually performed with conventional imaging (CI), involving computed tomography (CT) and bone scanning (BS). The aim of this study was to analyze the role of [¹⁸F]F-choline positron emission tomography (PET)/CT in the initial management [...] Read more.

Initial staging of prostate cancer (PCa) is usually performed with conventional imaging (CI), involving computed tomography (CT) and bone scanning (BS). The aim of this study was to analyze the role of [¹⁸F]F-choline positron emission tomography (PET)/CT in the initial management and outcome prediction of PCa patients by analyzing data from a multidisciplinary approach. We retrospectively analyzed 82 patients who were discussed by the uro-oncology board of the University Hospital of Ferrara for primary staging newly diagnosed PCa (median age 72 (56–86) years; median baseline prostate specific antigen (PSA) equal to 8.73 ng/mL). Patients were divided into three groups based on the imaging performed: group A = only CI; group B = CI + [¹⁸F]F-choline PET/CT; group C = only [¹⁸F]F-choline PET/CT. All data on imaging findings, therapy decisions and patient outcomes were retrieved from hospital information systems. Moreover, we performed a sub-analysis of semiquantitative parameters extracted from [¹⁸F]F-choline PET/CT to search any correlation with patient outcomes. The number of patients included in each group was 35, 35 and 12, respectively. Patients with higher values of initial PSA were subjected to CI + PET/CT (p = 0.005). Moreover, the use of [¹⁸F]F-choline PET/CT was more frequent in patients with higher Gleason score (GS) or ISUP grade (p = 0.013). The type of treatment performed (surgery n = 33; radiation therapy n = 22; surveillance n = 6; multimodality therapy n = 6; systemic therapy n = 13; not available n = 2) did not show any relationship with the modality adopted to stage the disease. [¹⁸F]F-choline PET/CT induced a change of planned therapy in 5/35 patients in group B (14.3%). Moreover, patients investigated with [¹⁸F]F-choline PET/CT alone demonstrated longer biochemical recurrence (BCR)-free survival (30.8 months) in comparison to patients of groups A and B (15.5 and 23.5 months, respectively, p = 0.006), probably due to a more accurate selection of primary treatment. Finally, total lesion choline kinase activity (TLCKA) of the primary lesion, calculated by multiplying metabolic tumor volume and mean standardized uptake value (SUVmean), was able to more effectively discriminate patients who had recurrence after therapy compared to those without (p = 0.03). In our real-world experience [¹⁸F]F-choline PET/CT as a tool for the initial management of PCa had a relevant impact in terms of therapy selection and was associated with longer BCR-free survival. Moreover, TLCKA of the primary lesion looks a promising parameter for predicting recurrence after curative therapy. Full article

(This article belongs to the Special Issue Prostate Cancer: from Molecular Imaging to Immunological and Target Therapies II)

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10 pages, 1288 KiB

Open AccessEditor’s ChoiceArticle

High Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios Are Associated with a Higher Risk of Hemodialysis Vascular Access Failure

by Edoardo Pasqui, Gianmarco de Donato, Elisa Lazzeri, Cecilia Molino, Giuseppe Galzerano, Michele Giubbolini and Giancarlo Palasciano

Biomedicines 2022, 10(9), 2218; https://doi.org/10.3390/biomedicines10092218 - 7 Sep 2022

Cited by 14 | Viewed by 2542

Abstract

Our aim was to determine the predictive role of the preoperative neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in vascular access malfunctioning in patients who had undergone their first native arterio-venous fistula (AVF) for hemodialysis. Methods: This was a single-center retrospective observational study. [...] Read more.

Our aim was to determine the predictive role of the preoperative neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in vascular access malfunctioning in patients who had undergone their first native arterio-venous fistula (AVF) for hemodialysis. Methods: This was a single-center retrospective observational study. All patients who underwent the procedure of the creation of a first native AVF for hemodialysis from January 2019 to December 2020 were considered eligible to be part of this study. Reinterventions for AVF malfunctioning were registered and the population was subdivided into two groups with respect to AVF malfunctioning. ROC curves were obtained to find the appropriate cut-off values for the NLR and PLR. A multivariate analysis was used to identify the independent predictors for an AVF malfunction. Kaplan–Meier curves were used to evaluate the AVF patency rates. A total of 178 patients were enrolled in the study, of them 70% (n = 121) were male. The mean age was 67.5 ± 12 years. Reinterventions for AVF malfunctioning were performed on 102 patients (57.3%). An NLR > 4.21 and a PLR > 208.8 was selected as the cut-off for AVF malfunctioning. The study population was divided into two groups depending on the NLR and PLR values of the individual. For the NLR < 4.21 group, the AVF patency rates were 90.7%, 85.3%, and 84% at the 3-, 6-, and 12-month follow-up, respectively, and 77.5%, 65.8%, and 39.3% at 3, 6, and 12 months for the NLR > 4.21 group, respectively (p < 0.0001). For the PLR < 208.8 group, the patency rates were 85.6%, 76.7%, and 67.7% at the 3-, 6-, and 12-month follow-up. For the PLR > 208.28 group, the patency rates were 80.8%, 71.2%, and 50.7% for the 3-, 6-, and 12-month follow-up, respectively (p = 0.014). The multivariate analysis highlighted that diabetes mellitus, the neutrophil count, the lymphocyte count, and the NLR were independent risk factors for an AVF failure. In our experience, the NLR and PLR are useful markers for the stratification of vascular access failure in hemodialysis patients. The inexpensive nature and ready availability of the values of these biomarkers are two points of strength for everyday clinical practice. Full article

(This article belongs to the Special Issue Neutrophils, Fast and Strong 2.0)

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25 pages, 1731 KiB

Open AccessEditor’s ChoiceReview

Lipid Nanoparticles as Delivery Vehicles for Inhaled Therapeutics

by Ellenmae W. X. Leong and Ruowen Ge

Biomedicines 2022, 10(9), 2179; https://doi.org/10.3390/biomedicines10092179 - 2 Sep 2022

Cited by 51 | Viewed by 8371

Abstract

Lipid nanoparticles (LNPs) have emerged as a powerful non-viral carrier for drug delivery. With the prevalence of respiratory diseases, particularly highlighted by the current COVID-19 pandemic, investigations into applying LNPs to deliver inhaled therapeutics directly to the lungs are underway. The progress in [...] Read more.

Lipid nanoparticles (LNPs) have emerged as a powerful non-viral carrier for drug delivery. With the prevalence of respiratory diseases, particularly highlighted by the current COVID-19 pandemic, investigations into applying LNPs to deliver inhaled therapeutics directly to the lungs are underway. The progress in LNP development as well as the recent pre-clinical studies in three main classes of inhaled encapsulated drugs: small molecules, nucleic acids and proteins/peptides will be discussed. The advantages of the pulmonary drug delivery system such as reducing systemic toxicity and enabling higher local drug concentration in the lungs are evaluated together with the challenges and design considerations for improved formulations. This review provides a perspective on the future prospects of LNP-mediated delivery of inhaled therapeutics for respiratory diseases. Full article

(This article belongs to the Special Issue Advances in Nanomedicine for Disease Treatment and Diagnosis)

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16 pages, 1390 KiB

Open AccessEditor’s ChoiceReview

Lipid-Based Drug Delivery Systems for Diseases Managements

by Douweh Leyla Gbian and Abdelwahab Omri

Biomedicines 2022, 10(9), 2137; https://doi.org/10.3390/biomedicines10092137 - 31 Aug 2022

Cited by 21 | Viewed by 4459

Abstract

Liposomes are tiny lipid-based vesicles composed of one or more lipid bilayers, which facilitate the encapsulation of hydrophilic, lipophilic, and amphiphilic biological active agents. The description of the physicochemical properties, formulation methods, characteristics, mechanisms of action, and large-scale manufacturing of liposomes as delivery [...] Read more.

Liposomes are tiny lipid-based vesicles composed of one or more lipid bilayers, which facilitate the encapsulation of hydrophilic, lipophilic, and amphiphilic biological active agents. The description of the physicochemical properties, formulation methods, characteristics, mechanisms of action, and large-scale manufacturing of liposomes as delivery systems are deeply discussed. The benefits, toxicity, and limitations of the use of liposomes in pharmacotherapeutics including in diagnostics, brain targeting, eye and cancer diseases, and in infections are provided. The experimental approaches that may reduce, or even bypass, the use of liposomal drug drawbacks is described. The application of liposomes in the treatment of numerous diseases is discussed. Full article

(This article belongs to the Special Issue Advances in Nanomedicine for Disease Treatment and Diagnosis)

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15 pages, 631 KiB

Open AccessEditor’s ChoiceReview

Inflammatory Cytokine: An Attractive Target for Cancer Treatment

by Hyang-Mi Lee, Hye-Jin Lee and Ji-Eun Chang

Biomedicines 2022, 10(9), 2116; https://doi.org/10.3390/biomedicines10092116 - 29 Aug 2022

Cited by 27 | Viewed by 4046

Abstract

The relationship between inflammation and cancer has attracted attention for a long time. The inflammatory tumor microenvironment consists of inflammatory cells, chemokines, cytokines, and signaling pathways. Among them, inflammatory cytokines play an especially pivotal role in cancer development, prognosis, and treatment. Interleukins, tumor [...] Read more.

The relationship between inflammation and cancer has attracted attention for a long time. The inflammatory tumor microenvironment consists of inflammatory cells, chemokines, cytokines, and signaling pathways. Among them, inflammatory cytokines play an especially pivotal role in cancer development, prognosis, and treatment. Interleukins, tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-β), interferons, and vascular endothelial growth factor (VEGF) are the representative inflammatory cytokines in various cancers, which may promote or inhibit cancer progression. The pro-inflammatory cytokines are associated with advanced cancer stages, resistance to immunotherapy, and poor prognoses, such as in objective response and disease control rates, and progression-free and overall survival. In this review, we selected colorectal, pancreatic, breast, gastric, lung, and prostate cancers, which are well-reported for an association between cancer and inflammatory cytokines. The related cytokines and their effects on each cancer’s development and prognosis were summarized. In addition, the treatment strategies targeting inflammatory cytokines in each carcinoma were also described here. By understanding the biological roles of cancer-related inflammatory cytokines, we may modulate the inflammatory tumor microenvironment for potential cancer treatment. Full article

(This article belongs to the Special Issue The Role of Inflammatory Cytokines in Cancer Progression)

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33 pages, 2235 KiB

Open AccessEditor’s ChoiceReview

Bioavailability Enhancement Techniques for Poorly Aqueous Soluble Drugs and Therapeutics

by Dixit V. Bhalani, Bhingaradiya Nutan, Avinash Kumar and Arvind K. Singh Chandel

Biomedicines 2022, 10(9), 2055; https://doi.org/10.3390/biomedicines10092055 - 23 Aug 2022

Cited by 152 | Viewed by 18644

Abstract

The low water solubility of pharmacoactive molecules limits their pharmacological potential, but the solubility parameter cannot compromise, and so different approaches are employed to enhance their bioavailability. Pharmaceutically active molecules with low solubility convey a higher risk of failure for drug innovation and [...] Read more.

The low water solubility of pharmacoactive molecules limits their pharmacological potential, but the solubility parameter cannot compromise, and so different approaches are employed to enhance their bioavailability. Pharmaceutically active molecules with low solubility convey a higher risk of failure for drug innovation and development. Pharmacokinetics, pharmacodynamics, and several other parameters, such as drug distribution, protein binding and absorption, are majorly affected by their solubility. Among all pharmaceutical dosage forms, oral dosage forms cover more than 50%, and the drug molecule should be water-soluble. For good therapeutic activity by the drug molecule on the target site, solubility and bioavailability are crucial factors. The pharmaceutical industry’s screening programs identified that around 40% of new chemical entities (NCEs) face various difficulties at the formulation and development stages. These pharmaceuticals demonstrate less solubility and bioavailability. Enhancement of the bioavailability and solubility of drugs is a significant challenge in the area of pharmaceutical formulations. According to the Classification of Biopharmaceutics, Class II and IV drugs (APIs) exhibit poor solubility, lower bioavailability, and less dissolution. Various technologies are discussed in this article to improve the solubility of poorly water-soluble drugs, for example, the complexation of active molecules, the utilization of emulsion formation, micelles, microemulsions, cosolvents, polymeric micelle preparation, particle size reduction technologies, pharmaceutical salts, prodrugs, the solid-state alternation technique, soft gel technology, drug nanocrystals, solid dispersion methods, crystal engineering techniques and nanomorph technology. This review mainly describes several other advanced methodologies for solubility and bioavailability enhancement, such as crystal engineering, micronization, solid dispersions, nano sizing, the use of cyclodextrins, solid lipid nanoparticles, colloidal drug delivery systems and drug conjugates, referring to a number of appropriate research reports. Full article

(This article belongs to the Special Issue Topical Drug Delivery: Challenges, Opportunities, Novel Approaches and Recent Advances)

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51 pages, 13524 KiB

Open AccessEditor’s ChoiceArticle

Arc Regulates Transcription of Genes for Plasticity, Excitability and Alzheimer’s Disease

by How-Wing Leung, Gabriel Foo and Antonius VanDongen

Biomedicines 2022, 10(8), 1946; https://doi.org/10.3390/biomedicines10081946 - 11 Aug 2022

Cited by 15 | Viewed by 6063

Abstract

The immediate early gene Arc is a master regulator of synaptic function and a critical determinant of memory consolidation. Here, we show that Arc interacts with dynamic chromatin and closely associates with histone markers for active enhancers and transcription in cultured rat hippocampal [...] Read more.

The immediate early gene Arc is a master regulator of synaptic function and a critical determinant of memory consolidation. Here, we show that Arc interacts with dynamic chromatin and closely associates with histone markers for active enhancers and transcription in cultured rat hippocampal neurons. Both these histone modifications, H3K27Ac and H3K9Ac, have recently been shown to be upregulated in late-onset Alzheimer’s disease (AD). When Arc induction by pharmacological network activation was prevented using a short hairpin RNA, the expression profile was altered for over 1900 genes, which included genes associated with synaptic function, neuronal plasticity, intrinsic excitability, and signalling pathways. Interestingly, about 100 Arc-dependent genes are associated with the pathophysiology of AD. When endogenous Arc expression was induced in HEK293T cells, the transcription of many neuronal genes was increased, suggesting that Arc can control expression in the absence of activated signalling pathways. Taken together, these data establish Arc as a master regulator of neuronal activity-dependent gene expression and suggest that it plays a significant role in the pathophysiology of AD. Full article

(This article belongs to the Special Issue Alzheimer's Disease—115 Years after Its Discovery)

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31 pages, 2309 KiB

Open AccessEditor’s ChoiceReview

Therapeutic Strategies in Huntington’s Disease: From Genetic Defect to Gene Therapy

by Anamaria Jurcau and Maria Carolina Jurcau

Biomedicines 2022, 10(8), 1895; https://doi.org/10.3390/biomedicines10081895 - 5 Aug 2022

Cited by 17 | Viewed by 5521

Abstract

Despite the identification of an expanded CAG repeat on exon 1 of the huntingtin gene located on chromosome 1 as the genetic defect causing Huntington’s disease almost 30 years ago, currently approved therapies provide only limited symptomatic relief and do not influence the [...] Read more.

Despite the identification of an expanded CAG repeat on exon 1 of the huntingtin gene located on chromosome 1 as the genetic defect causing Huntington’s disease almost 30 years ago, currently approved therapies provide only limited symptomatic relief and do not influence the age of onset or disease progression rate. Research has identified various intricate pathogenic cascades which lead to neuronal degeneration, but therapies interfering with these mechanisms have been marked by many failures and remain to be validated. Exciting new opportunities are opened by the emerging techniques which target the mutant protein DNA and RNA, allowing for “gene editing”. Although some issues relating to “off-target” effects or immune-mediated side effects need to be solved, these strategies, combined with stem cell therapies and more traditional approaches targeting specific pathogenic cascades, such as excitotoxicity and bioavailability of neurotrophic factors, could lead to significant improvement of the outcomes of treated Huntington’s disease patients. Full article

(This article belongs to the Special Issue State of the Art: Prerequisites, Prevention and Treatment of Neurodegenerative Diseases)

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16 pages, 1723 KiB

Open AccessEditor’s ChoiceArticle

GLUT3 Promotes Epithelial–Mesenchymal Transition via TGF-β/JNK/ATF2 Signaling Pathway in Colorectal Cancer Cells

by Moon-Young Song, Da-Young Lee, Sun-Mi Yun and Eun-Hee Kim

Biomedicines 2022, 10(8), 1837; https://doi.org/10.3390/biomedicines10081837 - 29 Jul 2022

Cited by 14 | Viewed by 3127

Abstract

Glucose transporter (GLUT) 3, a member of the GLUTs family, is involved in cellular glucose utilization and the first step in glycolysis. GLUT3 is highly expressed in colorectal cancer (CRC) and it leads to poor prognosis to CRC patient outcome. However, the molecular [...] Read more.

Glucose transporter (GLUT) 3, a member of the GLUTs family, is involved in cellular glucose utilization and the first step in glycolysis. GLUT3 is highly expressed in colorectal cancer (CRC) and it leads to poor prognosis to CRC patient outcome. However, the molecular mechanisms of GLUT3 on the epithelial–mesenchymal transition (EMT) process in metastatic CRC is not yet clear. Here, we identified that activation of the c-Jun N-terminal kinase (JNK)/activating transcription factor-2 (ATF2) signaling pathway by transforming growth factor-β (TGF-β) promotes GLUT3-induced EMT in CRC cells. The regulation of GLUT3 expression was significantly associated with EMT-related markers such as E-cadherin, α- smooth muscle actin (α-SMA), plasminogen activator inhibitor-1 (PAI-1), vimentin and zinc finger E-box binding homeobox 1 (ZEB1). We also found that GLUT3 accelerated the invasive ability of CRC cells. Mechanistically, TGF-β induced the expression of GLUT3 through the phosphorylation of JNK/ATF2, one of the SMAD-independent pathways. TGF-β induced the expression of GLUT3 by increasing the phosphorylation of JNK, the nuclear translocation of the ATF2 transcription factor, and the binding of ATF2 to the promoter region of GLUT3, which increased EMT in CRC cells. Collectively, our results provide a new comprehensive mechanism that GLUT3 promotes EMT process through the TGF-β/JNK/ATF2 signaling pathway, which could be a potential target for the treatment of metastatic CRC. Full article

(This article belongs to the Special Issue The Role of Epithelial-Mesenchymal Transition (EMT) in Cancer Development and Metastasis)

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12 pages, 1772 KiB

Open AccessEditor’s ChoiceArticle

Bioactive Cell-Derived ECM Scaffold Forms a Unique Cellular Microenvironment for Lung Tissue Engineering

by Ali Doryab and Otmar Schmid

Biomedicines 2022, 10(8), 1791; https://doi.org/10.3390/biomedicines10081791 - 26 Jul 2022

Cited by 10 | Viewed by 2819

Abstract

Chronic lung diseases are one of the leading causes of death worldwide. Lung transplantation is currently the only causal therapeutic for lung diseases, which is restricted to end-stage disease and limited by low access to donor lungs. Lung tissue engineering (LTE) is a [...] Read more.

Chronic lung diseases are one of the leading causes of death worldwide. Lung transplantation is currently the only causal therapeutic for lung diseases, which is restricted to end-stage disease and limited by low access to donor lungs. Lung tissue engineering (LTE) is a promising approach to regenerating a replacement for at least a part of the damaged lung tissue. Currently, lung regeneration is limited to a simplified local level (e.g., alveolar–capillary barrier) due to the sophisticated and complex structure and physiology of the lung. Here, we introduce an extracellular matrix (ECM)-integrated scaffold using a cellularization–decellularization–recellularization technique. This ECM-integrated scaffold was developed on our artificial co-polymeric BETA (biphasic elastic thin for air–liquid interface cell culture conditions) scaffold, which were initially populated with human lung fibroblasts (IMR90 cell line), as the main generator of ECM proteins. Due to the interconnected porous structure of the thin (<5 µm) BETA scaffold, the cells can grow on and infiltrate into the scaffold and deposit their own ECM. After a mild decellularization procedure, the ECM proteins remained on the scaffold, which now closely mimicked the cellular microenvironment of pulmonary cells more realistically than the plain artificial scaffolds. We assessed several decellularization methods and found that 20 mM NH₄OH and 0.1% Triton X100 with subsequent DNase treatment completely removed the fibroblasts (from the first cellularization) and maintains collagen I and IV as the key ECM proteins on the scaffold. We also showed the repopulation of the primary fibroblast from human (without chronic lung disease (non-CLD) donors) and human bronchial epithelial (16HBE14o⁻) cells on the ECM-integrated BETA scaffold. With this technique, we developed a biomimetic scaffold that can mimic both the physico-mechanical properties and the native microenvironment of the lung ECM. The results indicate the potential of the presented bioactive scaffold for LTE application. Full article

(This article belongs to the Special Issue Human Extracellular Matrix in Homeostasis and Pathology)

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19 pages, 1888 KiB

Open AccessEditor’s ChoiceReview

Obesity and Endothelial Function

by Masato Kajikawa and Yukihito Higashi

Biomedicines 2022, 10(7), 1745; https://doi.org/10.3390/biomedicines10071745 - 19 Jul 2022

Cited by 27 | Viewed by 4570

Abstract

Obesity is a major public health problem and is related to increasing rates of cardiovascular morbidity and mortality. Over 1.9 billion adults are overweight or obese worldwide and the prevalence of obesity is increasing. Obesity influences endothelial function through obesity-related complications such as [...] Read more.

Obesity is a major public health problem and is related to increasing rates of cardiovascular morbidity and mortality. Over 1.9 billion adults are overweight or obese worldwide and the prevalence of obesity is increasing. Obesity influences endothelial function through obesity-related complications such as hypertension, dyslipidemia, diabetes, metabolic syndrome, and obstructive sleep apnea syndrome. The excess fat accumulation in obesity causes adipocyte dysfunction and induces oxidative stress, insulin resistance, and inflammation leading to endothelial dysfunction. Several anthropometric indices and imaging modalities that are used to evaluate obesity have demonstrated an association between obesity and endothelial function. In the past few decades, there has been great focus on the mechanisms underlying endothelial dysfunction caused by obesity for the prevention and treatment of cardiovascular events. This review focuses on pathophysiological mechanisms of obesity-induced endothelial dysfunction and therapeutic targets of obesity. Full article

(This article belongs to the Special Issue Endothelial Dysfunction: From a Pathophysiological Mechanism to a Potential Therapeutic Target (Volume II))

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