Biomedicines

8 pages, 255 KiB

Open AccessBrief Report

by Mikhail Kostik, Elvira Kalashnikova, Raupov Rinat, Eugenia Isupova, Ekaterina Gaidar, Anton A. Soloviev, Vera Masalova, Ludmila Snegireva, Tatyana Kornishina, Natalia Abramova, Evgeny Suspitsin, Lubov Sorokina, Maria Kaneva, Margarita F. Dubko, Natalia Lubimova, Ekaterina Kuchuinskaya, Olga Kalashnikova and Vyacheslav Chasnyk

Biomedicines 2023, 11(5), 1503; https://doi.org/10.3390/biomedicines11051503 - 22 May 2023

Cited by 3 | Viewed by 1577

Abstract

Background: Pediatric lupus nephritis (LN) is one of the most serious manifestations of systemic lupus erythematosus (SLE) in children, determining the outcomes of the disease. There are no standardized treatment protocols for pediatric LN, and the role of biologics has not yet been [...] Read more.

Background: Pediatric lupus nephritis (LN) is one of the most serious manifestations of systemic lupus erythematosus (SLE) in children, determining the outcomes of the disease. There are no standardized treatment protocols for pediatric LN, and the role of biologics has not yet been conclusively defined. Objectives: analyze the safety and efficacy of rituximab biosimilar BCD020 in pediatric patients with lupus nephritis. Methods: in a retrospective cohort study, the data from the case histories of 25 patients with LN (10 boys and 15 girls) with an onset age of 13 (9–16) years, who failed conventional non-biologic treatment or developed corticosteroid dependence/toxicity, were included. The diagnosis was made using Systemic Lupus International Collaborating Clinics (SLICC) classification criteria. Rituximab biosimilar BCD020 was prescribed in a dosage of 375 mg/m² every week (2–4 infusions) with repeated courses every 6–12 months (2–4 infusions) according to disease activity, B-cell depletion, and IgG levels. The dynamics of clinical and laboratory data, the activity of the disease by SLEDAI, and corticosteroid doses were assessed at the onset and during the rituximab trial. Results: The main patient’s characteristics were: Pre-rituximab non-biologic conventional treatment included: cyclophosphamide 15 (60%), MMF 8 (32%), azathioprine 3 (12%), hydroxychloroquine 12 (48%), and pulse therapy of methylprednisolone followed by oral methylprednisolone 25 (100%). The time before rituximab was 7.0 (3.0–24.0) months, and the whole observation period was 7.0 (0; 24) months. The initial pre-rituximab treatment slightly reduced SLEDAI levels and the proportion of patients with LN. A significant reduction of SLEDAI, the anti-dsDNA level, proteinuria, hematuria, C4 complement, ESR, and the median corticosteroid dose by 80% from the initial value, as well as the proportion of patients without corticosteroids, was observed after rituximab administration. Two deaths were observed due to catastrophic SLE with macrophage activation syndrome, accompanied by a severe infection (invasive aspergillosis, n = 2). Three patients developed serious adverse events: pneumonia (n = 2), transient agranulocytosis (n = 1) after the third rituximab infusion, and meningitis, caused by Listeria monocytosis, after the first rituximab infusion. Eight patients received antibacterial treatment for different respiratory infections without hospital admissions. Conclusions: Rituximab biosimilar BCD020 showed effectiveness in LN, whereas previous non-biologic treatment was insufficiently effective. Randomized controlled trials are required to evaluate the efficacy and safety of rituximab and evaluate the benefits when compared with conventional SLE treatment. Full article

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

16 pages, 596 KiB

Open AccessArticle

Relationship between Diabetic Nephropathy and Development of Diabetic Macular Edema in Addition to Diabetic Retinopathy

by Yukihisa Suzuki and Motohiro Kiyosawa

Biomedicines 2023, 11(5), 1502; https://doi.org/10.3390/biomedicines11051502 - 22 May 2023

Cited by 4 | Viewed by 1865

Abstract

This study aimed to examine the relationship between diabetic retinopathy (DR) and systemic factors. We evaluated 261 patients (143 men, 118 women, aged 70.1 ± 10.1 years) with type 2 diabetes. All participants underwent a fundus examination, fundus photography using spectral domain optical [...] Read more.

This study aimed to examine the relationship between diabetic retinopathy (DR) and systemic factors. We evaluated 261 patients (143 men, 118 women, aged 70.1 ± 10.1 years) with type 2 diabetes. All participants underwent a fundus examination, fundus photography using spectral domain optical coherence tomography (SD-OCT), and blood tests. For glycated hemoglobin (HbA1c) levels, the average and highest values in the past were used. We observed DR in 127 (70 men and 57 women) of 261 patients. Logistic regression analyses revealed a significant correlation between DR development and the duration of diabetes (OR = 2.40; 95% CI: 1.50), average HbA1c level (OR = 5.57; 95% CI: 1.27, 24.4), highest HbA1c level (OR = 2.46; 95% CI: 1.12, 5.38), and grade of diabetic nephropathy (DN) (OR = 6.23; 95% CI: 2.70, 14.4). Regression analyses revealed a significant correlation between the severity of DR and duration of diabetes (t = –6.66; 95% CI: 0.21, 0.39), average HbA1c level (t = 2.59; 95% CI: 0.14, 1.02), and severity of DN (t = 6.10; 95% CI: 0.49, 0.97). Logistic regression analyses revealed a significant correlation between diabetic macular edema (DME) development and DN grade (OR = 2.22; 95% CI: 1.33, 3.69). DN grade correlates with the development of DR and DME, and decreased renal function predicts the onset of DR. Full article

(This article belongs to the Special Issue Molecular Research and Recent Advances in Diabetic Retinopathy)

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14 pages, 760 KiB

Open AccessArticle

Association between Food/UGT2B7 Polymorphisms and Pharmacokinetics/Pharmacodynamics Properties of Indapamide in Healthy Humans

by Banaz Abbas, Nagwa A. Sabri and Amal A. El-Khouly

Biomedicines 2023, 11(5), 1501; https://doi.org/10.3390/biomedicines11051501 - 22 May 2023

Cited by 2 | Viewed by 1289

Abstract

Indapamide is an effective and safe antihypertensive medication showing a beneficial effect in combination with other antihypertensive agents regarding morbidity and mortality. A comparative study was performed under fasting and fed conditions to investigate the effect of food and selected single nucleotide polymorphisms [...] Read more.

Indapamide is an effective and safe antihypertensive medication showing a beneficial effect in combination with other antihypertensive agents regarding morbidity and mortality. A comparative study was performed under fasting and fed conditions to investigate the effect of food and selected single nucleotide polymorphisms in the uridine diphosphate glucuronyl transferase (UGT2B7) gene on the pharmacokinetics and pharmacodynamics behavior of indapamide 1.5 mg sustained release. Forty-nine healthy volunteers aged 18–55 years were randomized into two groups; 25 volunteers were administered indapamide under fasting conditions and 24 under fed conditions. Genotyping of the UGT2B7 rs7438135 and rs11740316 was done before commencing the study using predesigned TaqMan assays. Results showed that food independently decreased the value of indapamide’ T_max by 5.5 h and increased the value of C_max by 8.7 ng/mL. On the other hand, all genetic variants of both UGT2B7 SNPs had no significant impact on the values of T_max, C_max, and AUC_0–t; however, it was found that rs11740316 variant AG was correlated with a 2.8 h lower MRT_inf. Finally, BMI positively correlated with longer MRT_inf. It was concluded that none of rs7438135, rs11740316, or food had a significant impact on the pharmacodynamic properties. Food had a modest impact on indapamide C_max and T_max values, while there were unremarkable differences in safety and efficacy. Full article

(This article belongs to the Special Issue Pharmacokinetics of Biomedicines: Impact on Pre-clinical Development and Clinical Use)

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29 pages, 480 KiB

Open AccessReview

Mitochondrial Dysfunction in Cardiac Diseases and Therapeutic Strategies

by Yafei Huang and Bingying Zhou

Biomedicines 2023, 11(5), 1500; https://doi.org/10.3390/biomedicines11051500 - 22 May 2023

Cited by 9 | Viewed by 2263

Abstract

Mitochondria are the main site of intracellular synthesis of ATP, which provides energy for various physiological activities of the cell. Cardiomyocytes have a high density of mitochondria and mitochondrial damage is present in a variety of cardiovascular diseases. In this paper, we describe [...] Read more.

Mitochondria are the main site of intracellular synthesis of ATP, which provides energy for various physiological activities of the cell. Cardiomyocytes have a high density of mitochondria and mitochondrial damage is present in a variety of cardiovascular diseases. In this paper, we describe mitochondrial damage in mitochondrial cardiomyopathy, congenital heart disease, coronary heart disease, myocardial ischemia–reperfusion injury, heart failure, and drug-induced cardiotoxicity, in the context of the key roles of mitochondria in cardiac development and homeostasis. Finally, we discuss the main current therapeutic strategies aimed at alleviating mitochondrial impairment-related cardiac dysfunction, including pharmacological strategies, gene therapy, mitochondrial replacement therapy, and mitochondrial transplantation. It is hoped that this will provide new ideas for the treatment of cardiovascular diseases. Full article

(This article belongs to the Special Issue Mitochondrial Function in Biomedicines)

35 pages, 3280 KiB

Open AccessReview

Valproate-Induced Metabolic Syndrome

by Natalia A. Shnayder, Violetta V. Grechkina, Vera V. Trefilova, Ilya S. Efremov, Evgenia A. Dontceva, Ekaterina A. Narodova, Marina M. Petrova, Irina A. Soloveva, Liia E. Tepnadze, Polina A. Reznichenko, Mustafa Al-Zamil, Gulnara I. Altynbekova, Anna I. Strelnik and Regina F. Nasyrova

Biomedicines 2023, 11(5), 1499; https://doi.org/10.3390/biomedicines11051499 - 22 May 2023

Cited by 1 | Viewed by 2133

Abstract

Valproic acid (VPA) and its salts (sodium calcium magnesium and orotic) are psychotropic drugs that are widely used in neurology and psychiatry. The long-term use of VPA increases the risk of developing adverse drug reactions (ADRs), among which metabolic syndrome (MetS) plays a [...] Read more.

Valproic acid (VPA) and its salts (sodium calcium magnesium and orotic) are psychotropic drugs that are widely used in neurology and psychiatry. The long-term use of VPA increases the risk of developing adverse drug reactions (ADRs), among which metabolic syndrome (MetS) plays a special role. MetS belongs to a cluster of metabolic conditions such as abdominal obesity, high blood pressure, high blood glucose, high serum triglycerides, and low serum high-density lipoprotein. Valproate-induced MetS (VPA-MetS) is a common ADR that needs an updated multidisciplinary approach to its prevention and diagnosis. In this review, we consider the results of studies of blood (serum and plasma) and the urinary biomarkers of VPA-MetS. These metabolic biomarkers may provide the key to the development of a new multidisciplinary personalized strategy for the prevention and diagnosis of VPA-MetS in patients with neurological diseases, psychiatric disorders, and addiction diseases. Full article

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

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10 pages, 3085 KiB

Open AccessArticle

Impact on Patient Management of a Novel Host Response Test for Distinguishing Bacterial and Viral Infections: Real World Evidence from the Urgent Care Setting

by Boaz Kalmovich, Daniella Rahamim-Cohen and Shirley Shapiro Ben David

Biomedicines 2023, 11(5), 1498; https://doi.org/10.3390/biomedicines11051498 - 22 May 2023

Cited by 1 | Viewed by 2533

Abstract

Antibiotic overuse and underuse are prevalent in urgent care settings, driven in part by diagnostic uncertainty. A host-based test for distinguishing bacterial and viral infections (MeMed BV) has been clinically validated previously. Here we examined how BV impacts antibiotic prescription in a real-world [...] Read more.

Antibiotic overuse and underuse are prevalent in urgent care settings, driven in part by diagnostic uncertainty. A host-based test for distinguishing bacterial and viral infections (MeMed BV) has been clinically validated previously. Here we examined how BV impacts antibiotic prescription in a real-world setting. The intention to treat with antibiotics before the receipt of a BV result was compared with practice after the receipt of a BV result at three urgent care centers. The analysis included 152 patients, 57.9% children and 50.7% female. In total, 131 (86.2%) had a bacterial or viral BV result. Physicians were uncertain about prescription for 38 (29.0%) patients and for 30 (78.9%) of these cases, subsequently acted in accordance with the BV result. Physicians intended to prescribe antibiotics to 39 (29.8%) patients, of whom 17 (43.6%) had bacterial BV results. Among the remaining 22 patients with viral BV results, antibiotic prescriptions were reduced by 40.9%. Overall, the physician prescribed in accordance with BV results in 81.7% of all cases (p < 0.05). In total, the physicians reported that BV supported or altered their decision making in 87.0% of cases (p < 0.05). BV impacts patient management in real-world settings, supporting appropriate antibiotic use. Full article

(This article belongs to the Special Issue Advances and Challenges in the Study of Host-Pathogen Interactions)

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14 pages, 674 KiB

Open AccessPerspective

A Holistic Perspective on How Photobiomodulation May Influence Fatigue, Pain, and Depression in Inflammatory Bowel Disease: Beyond Molecular Mechanisms

by E-Liisa Laakso and Tatjana Ewais

Biomedicines 2023, 11(5), 1497; https://doi.org/10.3390/biomedicines11051497 - 22 May 2023

Cited by 4 | Viewed by 4644

Abstract

Background: Numerous mechanisms, mostly molecular, have been tested and proposed for photobiomodulation. Photobiomodulation is finding a niche in the treatment of conditions that have no gold-standard treatment or only partially effective pharmacological treatment. Many chronic conditions are characterised by symptoms for which there [...] Read more.

Background: Numerous mechanisms, mostly molecular, have been tested and proposed for photobiomodulation. Photobiomodulation is finding a niche in the treatment of conditions that have no gold-standard treatment or only partially effective pharmacological treatment. Many chronic conditions are characterised by symptoms for which there is no cure or control and for which pharmaceuticals may add to the disease burden through side effects. To add quality to life, alternate methods of symptom management need to be identified. Objective: To demonstrate how photobiomodulation, through its numerous mechanisms, may offer an adjunctive therapy in inflammatory bowel disease. Rather than considering only molecular mechanisms, we take an overarching biopsychosocial approach to propose how existing evidence gleaned from other studies may underpin a treatment strategy of potential benefit to people with Crohn’s disease and ulcerative colitis. Main findings: In this paper, the authors have proposed the perspective that photobiomodulation, through an integrated effect on the neuroimmune and microbiome–gut–brain axis, has the potential to be effective in managing the fatigue, pain, and depressive symptoms of people with inflammatory bowel disease. Full article

(This article belongs to the Special Issue Therapeutic Mechanisms of Photobiomodulation)

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12 pages, 995 KiB

Open AccessReview

Checkpoint Inhibitor-Induced Colitis: An Update

by Giuseppe Losurdo, Daniele Angelillo, Nicolas Favia, Maria Chiara Sergi, Alfredo Di Leo, Giacomo Triggiano and Marco Tucci

Biomedicines 2023, 11(5), 1496; https://doi.org/10.3390/biomedicines11051496 - 22 May 2023

Cited by 5 | Viewed by 4768

Abstract

Immunotherapy with immune checkpoint inhibitors (ICIs) nowadays has indications for several solid tumors. The current targets for ICIs are CTLA-4, PD-1, and PD-L1 receptors. Despite the clinical advantages derived from ICIs, a variety of side effects are linked to overstimulation of the immune [...] Read more.

Immunotherapy with immune checkpoint inhibitors (ICIs) nowadays has indications for several solid tumors. The current targets for ICIs are CTLA-4, PD-1, and PD-L1 receptors. Despite the clinical advantages derived from ICIs, a variety of side effects are linked to overstimulation of the immune system. Among these, ICI-related colitis is one of the most common, with a disabling impact on the patient. Diarrhea, abdominal pain, abdominal distension, cramping, and hematochezia are the most common ICI enterocolitis presenting symptoms. The most frequently used grading system for assessment of the severity of ICI enterocolitis is called the Common Terminology Criteria for Adverse Events (CTCAE) grading. With regard to the histological picture, there is no specific feature; however, microscopic damage can be classified into five types: (1) acute active colitis, (2) chronic active colitis, (3) microscopic colitis-like, (4) graft-versus-host disease-like, and (5) other types. Supportive therapy (oral hydration, a bland diet without lactose or caffeine, and anti-diarrheal agents) is indicated in mild colitis. Symptomatic treatment alone or with loperamide, a low-fiber diet, and spasmolytics are recommended for low-grade diarrhea. In more severe cases, corticosteroid treatment is mandatory. In refractory cases, off-label use of biological therapies (infliximab or vedolizumab) was proposed. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series: Utilization of Immune Checkpoint Inhibitors: Past, Present and Future Therapeutics in Cancer)

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28 pages, 3413 KiB

Open AccessSystematic Review

Exploring Sex Differences of Beta-Blockers in the Treatment of Hypertension: A Systematic Review and Meta-Analysis

by Nick Wilmes, Eveline M. van Luik, Esmée W. P. Vaes, Maud A. M. Vesseur, Sophie A. J. S. Laven, Zenab Mohseni-Alsalhi, Daniek A. M. Meijs, Cédric J. R. Dikovec, Sander de Haas, Marc E. A. Spaanderman and Chahinda Ghossein-Doha

Biomedicines 2023, 11(5), 1494; https://doi.org/10.3390/biomedicines11051494 - 22 May 2023

Cited by 2 | Viewed by 2068

Abstract

Aims: In the prevention of cardiovascular morbidity and mortality, early recognition and adequate treatment of hypertension are of leading importance. However, the efficacy of antihypertensives may be depending on sex disparities. Our objective was to evaluate and quantify the sex-diverse effects of beta-blockers [...] Read more.

Aims: In the prevention of cardiovascular morbidity and mortality, early recognition and adequate treatment of hypertension are of leading importance. However, the efficacy of antihypertensives may be depending on sex disparities. Our objective was to evaluate and quantify the sex-diverse effects of beta-blockers (BB) on hypertension and cardiac function. We focussed on comparing hypertensive female versus male individuals. Methods and results: A systematic search was performed for studies on BBs from inception to May 2020. A total of 66 studies were included that contained baseline and follow up measurements on blood pressure (BP), heart rate (HR), and cardiac function. Data also had to be stratified for sex. Mean differences were calculated using a random-effects model. In females as compared to males, BB treatment decreased systolic BP 11.1 mmHg (95% CI, −14.5; −7.8) vs. 11.1 mmHg (95% CI, −14.0; −8.2), diastolic BP 8.0 mmHg (95% CI, −10.6; −5.3) vs. 8.0 mmHg (95% CI, −10.1; −6.0), and HR 10.8 beats per minute (bpm) (95% CI, −17.4; −4.2) vs. 9.8 bpm (95% CI, −11.1; −8.4)), respectively, in both sexes’ absolute and relative changes comparably. Left ventricular ejection fraction increased only in males (3.7% (95% CI, 0.6; 6.9)). Changes in left ventricular mass and cardiac output (CO) were only reported in males and changed −20.6 g (95% CI, −56.3; 15.1) and −0.1 L (95% CI, −0.5; 0.2), respectively. Conclusions: BBs comparably lowered BP and HR in both sexes. The lack of change in CO in males suggests that the reduction in BP is primarily due to a decrease in vascular resistance. Furthermore, females were underrepresented compared to males. We recommend that future research should include more females and sex-stratified data when researching the treatment effects of antihypertensives. Full article

(This article belongs to the Special Issue Advances in Cardiovascular Pharmacology: The Era of Targeted Therapies in Cardiology 2.0)

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15 pages, 4268 KiB

Open AccessArticle

Design of a Novel and Potent Multi-Epitope Chimeric Vaccine against Human Papillomavirus (HPV): An Immunoinformatics Approach

by Muhammad Shahab, Dejia Guo, Guojun Zheng and Yening Zou

Biomedicines 2023, 11(5), 1493; https://doi.org/10.3390/biomedicines11051493 - 22 May 2023

Cited by 2 | Viewed by 1668

Abstract

In the current era, our experience is full of pandemic infectious agents that no longer threaten the major local source but the whole globe. One such infectious agent is HPV, a sexually transmitted disease that can cause various clinical disorders, including benign lesions [...] Read more.

In the current era, our experience is full of pandemic infectious agents that no longer threaten the major local source but the whole globe. One such infectious agent is HPV, a sexually transmitted disease that can cause various clinical disorders, including benign lesions and cervical cancer. Since available vaccines still need further improvements in order to enhance efficacy, our goal was to design a chimeric vaccine against HPV using an immunoinformatics approach. For designing the vaccine, the sequence of HPV was retrieved, and then phylogenetic analysis was performed. Several CTL epitopes, HTL epitopes, and LBL epitopes were all predicted using bioinformatics tools. After checking the antigenicity, allergenicity, and toxicity scores, the best epitopes were selected for vaccine construction, and then physicochemical and immunological properties were analyzed. Subsequently, vaccine 3D structure prediction, refinement, and validation were performed. Molecular docking and dynamics simulation techniques were used to explore the interactions between the Toll-like receptor 2 and the modeled vaccine construct. To ensure the vaccine protein was expressed at a higher level, the construct was computationally cloned into the pET28a (+) plasmid. The molecular docking and simulation results showed that our designed vaccine is stable, of immunogenic quality, and has considerable solubility. Through in silico immune simulation, it was predicted that the designed polypeptide vaccine construct would trigger both humoral and cellular immune responses. The developed vaccine showed significant affinity for the TLR2 receptor molecule. However, additional laboratory research is required to evaluate its safety and efficacy. Full article

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

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19 pages, 869 KiB

Open AccessSystematic Review

Evaluating the Adipose Tissue Depth as a Predictor Factor for Gestational Diabetes in Later Pregnancy—A Systematic Review

by Bianca-Margareta Salmen, Valeria-Anca Pietrosel, Cristiana-Elena Durdu, Teodor Salmen, Cosmina Theodora Diaconu, Ioana-Cristina Bica, Claudia Gabriela Potcovaru, Florentina Gherghiceanu, Roxana-Adriana Stoica and Anca Pantea Stoian

Biomedicines 2023, 11(5), 1492; https://doi.org/10.3390/biomedicines11051492 - 22 May 2023

Cited by 2 | Viewed by 1490

Abstract

The increasing prevalence of gestational diabetes mellitus (GDM) requires non-invasive and precise techniques for evaluating the predisposing risk factors such as visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). According to PRISMA, we developed a systematic review and searched after “visceral adipose [...] Read more.

The increasing prevalence of gestational diabetes mellitus (GDM) requires non-invasive and precise techniques for evaluating the predisposing risk factors such as visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). According to PRISMA, we developed a systematic review and searched after “visceral adipose tissue AND gestational diabetes” and identified 221 articles on the MEDLINE and Word of Science databases. After assessing them for inclusion criteria and two researchers screened them, 11 relevant articles were included. Although evidence is conflicting, more studies favor using US-determined VAT in GDM prediction. VAT may be more valuable than body mass index or SAT in predicting GDM. VAT can represent an additive factor to the prediction tool of the risk of developing GDM when used in conjunction with other anthropometric or biological parameters or maternal risk factors. US measurements are heterogeneous given different evaluation techniques, cut-off values and inter-operator variation. A significant limitation is the lack of a gold standard to identify GDM confidently. Pregnant women may benefit from early monitoring and preventive care if classified as high risk for GDM early in the gestational period. US-measured VAT during the first trimester of pregnancy seems a valuable and inexpensive screening approach to predict GDM development later in pregnancy, either by itself or if used in conjunction with other clinical and biological parameters. Full article

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

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13 pages, 2600 KiB

Open AccessArticle

Synthesis and Characterization of PCL-Idebenone Nanoparticles for Potential Nose-to-Brain Delivery

by Radka Boyuklieva, Asya Hristozova and Bissera Pilicheva

Biomedicines 2023, 11(5), 1491; https://doi.org/10.3390/biomedicines11051491 - 22 May 2023

Cited by 2 | Viewed by 1324

Abstract

The present work is focused on the preparation of an optimal model of poly-ε-caprolactone nanoparticles as potential carriers for nasal administration of idebenone. A solvent/evaporation technique was used for nanoparticle preparation. Poly-ε-caprolactone with different molecular weights (14,000 and 80,000 g/mol) was used. Polysorbate [...] Read more.

The present work is focused on the preparation of an optimal model of poly-ε-caprolactone nanoparticles as potential carriers for nasal administration of idebenone. A solvent/evaporation technique was used for nanoparticle preparation. Poly-ε-caprolactone with different molecular weights (14,000 and 80,000 g/mol) was used. Polysorbate 20 and Poloxamer 407, alone and in combination, were used as emulsifiers at different concentrations to obtain a stable formulation. The nanoparticles were characterized using dynamic light scattering, SEM, TEM, and FTIR. The resulting structures were spherical in shape and their size distribution depended on the type of emulsifier. The average particle size ranged from 188 to 628 nm. The effect of molecular weight and type of emulsifier was established. Optimal models of appropriate size for nasal administration were selected for inclusion of idebenone. Three models of idebenone-loaded nanoparticles were developed and the effect of molecular weight on the encapsulation efficiency was investigated. Increased encapsulation efficiency was found when poly-ε-caprolactone with lower molecular weight was used. The molecular weight also affected the drug release from the nanostructures. Dissolution study data were fitted into various kinetic models and the Korsmeyer–Peppas model was found to be indicative of the release mechanism of idebenone. Full article

(This article belongs to the Special Issue Advanced Research in Drug Delivery across the Blood–Brain Barrier (BBB))

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14 pages, 4225 KiB

Open AccessArticle

DCLK1 Drives EGFR-TKI-Acquired Resistance in Lung Adenocarcinoma by Remodeling the Epithelial–Mesenchymal Transition Status

by Rui Yan, Xuying Huang, Heshu Liu, Zeru Xiao, Jian Liu, Guangyu An and Yang Ge

Biomedicines 2023, 11(5), 1490; https://doi.org/10.3390/biomedicines11051490 - 22 May 2023

Cited by 1 | Viewed by 1463

Abstract

Objective: Epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR-TKI) is a first-line treatment for lung adenocarcinoma with EGFR-sensitive mutations, but acquired resistance to EGFR-TKIs remains a problem in clinical practice. The development of epithelial–mesenchymal transition (EMT) is a critical mechanism that induces acquired resistance [...] Read more.

Objective: Epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR-TKI) is a first-line treatment for lung adenocarcinoma with EGFR-sensitive mutations, but acquired resistance to EGFR-TKIs remains a problem in clinical practice. The development of epithelial–mesenchymal transition (EMT) is a critical mechanism that induces acquired resistance to TKIs. Reversing acquired resistance to EGFR-TKIs through targeting the key molecules driving EMT provides an alternative choice for patients. We, therefore, aimed to explore the role of doublecortin-like kinase 1 (DCLK1) as an EMT driver gene in the acquired resistance of lung adenocarcinoma to EGFR-TKIs. Methods: The IC₅₀ of Gefitinib or Osimertinib in PC9/HCC827 cells was measured using a cell counting kit-8 (CCK8) assay. The expression levels of EMT-related genes in PC9 and HCC827 cells were detected using RT-PCR and Western blot. Cell migration and invasion abilities were assessed via a transwell assay. For the in vivo experiments, PC9 cells were subcutaneously injected into BALB/c nude mice to form tumors. Upon harvesting, tumor tissues were retained for RT-PCR, Western blot, and polychromatic fluorescence staining to detect biomarker changes in the EMT process. Results: Gefitinib-resistant PC9 (PC9/GR) and Osimertinib-resistant HCC827 (HCC827/OR) cells showed remarkable activation of EMT and enhanced migration and invasion abilities compared to TKI-sensitive cells. In addition, DCLK1 expression was markedly increased in EGFR-TKI-resistant lung adenocarcinoma cells. The targeted knockout of DCLK1 effectively reversed the EMT phenotype in TKI-resistant cells and improved EGFR-TKI sensitivity, which was further validated by the in vivo experiments. Conclusions: DCLK1 facilitates acquired resistance to EGFR-TKI in lung adenocarcinoma by inducting EMT and accelerating the migration and invasion abilities of TKI-resistant cells. Full article

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

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13 pages, 2773 KiB

Open AccessArticle

Decreased MARCKS Protein Expression in Kidney Cortex Membrane Fractions of Cathepsin B Knockout Mice Is Associated with Reduced Lysophosphatidylcholine and Protein Kinase C Activity

by Tamim Kawakibi, Niharika Bala, Lauren P. Liu, Louis A. Searcy, Nancy D. Denslow and Abdel A. Alli

Biomedicines 2023, 11(5), 1489; https://doi.org/10.3390/biomedicines11051489 - 20 May 2023

Viewed by 1347

Abstract

Cathpesin B is a multi-functional protease that plays numerous roles in physiology and pathophysiology. We hypothesized that actin cytoskeleton proteins that are substrates of cathepsin B, various lipids, and kinases that are regulated by lipids would be down-regulated in the kidney of cathepsin [...] Read more.

Cathpesin B is a multi-functional protease that plays numerous roles in physiology and pathophysiology. We hypothesized that actin cytoskeleton proteins that are substrates of cathepsin B, various lipids, and kinases that are regulated by lipids would be down-regulated in the kidney of cathepsin B knockout mice. Here, we show by Western blot and densitometric analysis that the expression and proteolysis of the actin cytoskeleton proteins myristoylated alanine-rich C-kinase substrate (MARCKS) and spectrin are significantly reduced in kidney cortex membrane fractions of cathepsin B knockout mice compared to C57B6 wild-type control mice. Lipidomic results show that specific lipids are increased while other lipids, including lysophosphatidylcholine (LPC) species LPC (16:0), LPC (18:0), LPC (18:1), and LPC (18:2), are significantly decreased in membrane fractions of the kidney cortex from Cathepsin B null mice. Protein Kinase C (PKC) activity is significantly lower in the kidney cortex of cathepsin B knockout mice compared to wild-type mice, while calcium/calmodulin-dependent protein kinase II (CaMKII) activity and phospholipase D (PLD) activity are comparable between the two groups. Together, these results provide the first evidence of altered actin cytoskeleton organization, membrane lipid composition, and PKC activity in the kidneys of mice lacking cathepsin B. Full article

(This article belongs to the Special Issue Acute Kidney Injury and Chronic Kidney Disease: Pathophysiology and New Therapeutic Strategies)

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17 pages, 2717 KiB

Open AccessArticle

Influence of Chronic Fatigue Syndrome Codiagnosis on the Relationship between Perceived and Objective Psychoneuro-Immunoendocrine Disorders in Women with Fibromyalgia

by Eduardo Otero, Isabel Gálvez, Eduardo Ortega and María Dolores Hinchado

Biomedicines 2023, 11(5), 1488; https://doi.org/10.3390/biomedicines11051488 - 20 May 2023

Cited by 2 | Viewed by 2945

Abstract

Although the predominant symptom in fibromyalgia (FM) is muscle pain, and fatigue in chronic fatigue syndrome (CFS), differential diagnosis is very difficult. This research investigates the psychoneuroimmunoendocrine disorders of FM patients and ascertains whether a previous CFS diagnosis affected them. Through accelerometry objective [...] Read more.

Although the predominant symptom in fibromyalgia (FM) is muscle pain, and fatigue in chronic fatigue syndrome (CFS), differential diagnosis is very difficult. This research investigates the psychoneuroimmunoendocrine disorders of FM patients and ascertains whether a previous CFS diagnosis affected them. Through accelerometry objective parameters, physical activity/sedentarism levels in relation to fatigue are studied, as well as whether perceived levels of stress, anxiety, and pain correspond to objective biomarkers, all of these with respect to a reference group (RG) of women without FM. FM patients have a worse psychological state and perceived quality of life than those with RG. These perceived outcomes are consistent with impaired objective levels of a sedentary lifestyle, higher systemic levels of cortisol and noradrenaline, and lower levels of serotonin. However, FM patients with a previous CFS diagnosis had lower systemic levels of IL-8, cortisol, oxytocin, and higher levels of adrenaline and serotonin than FM patients without diagnosed CFS. In conclusion, while perceived health parameters do not detect differences, when objective neuroimmunoendocrine parameters related to stress, inflammation, pain, and fatigue are used, people with CFS could be overdiagnosed with FM. This reinforces the need for objective biomarker assessment of these patients for better diagnostic discrimination between both syndromes. Full article

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

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17 pages, 1556 KiB

Open AccessReview

Novel Technologies for Exosome and Exosome-like Nanovesicle Procurement and Enhancement

by Andrés Martínez-Santillán and José González-Valdez

Biomedicines 2023, 11(5), 1487; https://doi.org/10.3390/biomedicines11051487 - 19 May 2023

Cited by 3 | Viewed by 2174

Abstract

Exosomes are extracellular nanovesicles commonly produced by mammalian cells that in recent years have risen as a novel strategy for drug delivery systems and cancer therapy because of their innate specificity and high bioavailability. However, there are limitations that undermine their potential. Among [...] Read more.

Exosomes are extracellular nanovesicles commonly produced by mammalian cells that in recent years have risen as a novel strategy for drug delivery systems and cancer therapy because of their innate specificity and high bioavailability. However, there are limitations that undermine their potential. Among them is the lack of mass production capacity with the current available sources and the failure to reach the intended therapeutic effect because of their insufficient uptake or their rapid clearance once administered. This review aims to show the current advances in overcoming these limitations by presenting, firstly, reported strategies to improve exosome and exosome-like nanovesicle extraction from possible novel eukaryotic sources, including animals, plants, and protozoa; and secondly, alternative modification methods that functionalize exosomes by conferring them higher targeting capacity and protection from organism defenses, which results in an increase in the attachment of ligands and cellular uptake of inorganic materials. However, even when these strategies might address some of the obstacles in their procurement and therapeutic use, there are still several aspects that need to be addressed, so several perspectives of the matter are also presented and analyzed throughout this work. Full article

(This article belongs to the Special Issue Extracellular Vesicles in Drug Delivery System)

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10 pages, 1374 KiB

Open AccessArticle

Development of a Non-Peptide Angiotensin II Type 1 Receptor Ligand by Structural Modification of Olmesartan as a Biased Agonist

by Yoshino Matsuo, Yasunori Suematsu, Hidetaka Morita and Shin-ichiro Miura

Biomedicines 2023, 11(5), 1486; https://doi.org/10.3390/biomedicines11051486 - 19 May 2023

Viewed by 1439

Abstract

As a biased agonist, peptide angiotensin II (Ang II) type 1 (AT₁) receptor ligand antagonizes Ang II-stimulated G protein signaling but stimulates several kinase pathways. Here, we developed a non-peptide AT₁ receptor compound as a biased ligand. We synthesized three [...] Read more.

As a biased agonist, peptide angiotensin II (Ang II) type 1 (AT₁) receptor ligand antagonizes Ang II-stimulated G protein signaling but stimulates several kinase pathways. Here, we developed a non-peptide AT₁ receptor compound as a biased ligand. We synthesized three non-peptide AT₁ receptor ligands (R239470, R781253, and R794847) as candidates of biased ligands. Extracellular signal-regulated kinase (ERK) 1/2 activation and inositol phosphate (IP) production were measured using a cell system that overexpressed AT₁ receptors (wild-type, L112A, Q257A, Y292A, and N295A receptors). We also examined the modes of receptor–ligand binding using a competition binding study. The K_d values of R239470, R781253, and R794847 for the AT₁ wild-type receptor were 0.8, 21, and 48 nM, respectively, as assessed in a competition binding study. Those of R239470, R781253, and R794847 for the L112A receptor were 37, 23, and 31 nM, respectively. R781253 and R794847 decreased and increased IP production, respectively, whereas R239470 did not change IP production. R781253 and R794847, but not R239470, activated ERK1/2. In conclusion, R239470, R781253, and R794847 act as a neutral antagonist, an inverse agonist, and an agonist with regard to IP production, respectively. On the other hand, R781253 and R794847, but not R239470, are agonists toward ERK1/2 activation. Thus, we developed a non-peptide AT₁ receptor compound as a biased ligand. Full article

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

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19 pages, 2327 KiB

Open AccessArticle

Developing In Vitro Models to Define the Role of Direct Mitochondrial Toxicity in Frequently Reported Drug-Induced Rhabdomyolysis

by Faten F. Bin Dayel, Ana Alfirevic and Amy E. Chadwick

Biomedicines 2023, 11(5), 1485; https://doi.org/10.3390/biomedicines11051485 - 19 May 2023

Cited by 1 | Viewed by 1388

Abstract

The United States Food and Drug Administration Adverse Event Reporting System (FAERS) logged 27,140 rhabdomyolysis cases from 2004 to 31 March 2020. We used FAERS to identify 14 drugs frequently reported in 6583 rhabdomyolysis cases and to investigate whether mitochondrial toxicity is a [...] Read more.

The United States Food and Drug Administration Adverse Event Reporting System (FAERS) logged 27,140 rhabdomyolysis cases from 2004 to 31 March 2020. We used FAERS to identify 14 drugs frequently reported in 6583 rhabdomyolysis cases and to investigate whether mitochondrial toxicity is a common pathway of drug-induced rhabdomyolysis by these drugs. Preliminary screening for mitochondrial toxicity was performed using the acute metabolic switch assay, which is adapted here for use in murine L6 cells. Fenofibrate, risperidone, pregabalin, propofol, and simvastatin lactone drugs were identified as mitotoxic and underwent further investigation, using real-time respirometry (Seahorse Technology) to provide more detail on the mechanism of mitochondrial-induced toxicity. To confirm the human relevance of the findings, fenofibrate and risperidone were evaluated in primary human skeletal muscle-derived cells (HSKMDC), using the acute metabolic switch assay and real-time respirometry, which confirmed this designation, although the toxic effects on the mitochondria were more pronounced in HSKMDC. Overall, these studies demonstrate that the L6 model of acute modification may find utility as an initial, cost-effective screen for identifying potential myotoxicants with relevance to humans and, importantly, that drug-induced mitochondrial dysfunction may be a common mechanism shared by some drugs that induce myotoxicity. Full article

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

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14 pages, 3202 KiB

Open AccessArticle

Comparative Evaluation of the Cytotoxicity of Doxorubicin in BT-20 Triple-Negative Breast Carcinoma Monolayer and Spheroid Cultures

by Keith N. Ncube, Tamarin Jurgens, Vanessa Steenkamp, Allan D. Cromarty, Iman van den Bout and Werner Cordier

Biomedicines 2023, 11(5), 1484; https://doi.org/10.3390/biomedicines11051484 - 19 May 2023

Cited by 2 | Viewed by 1944

Abstract

Three-dimensional cell culture models are increasingly adopted as preferred pre-clinical drug testing platforms, as they circumvent limitations associated with traditional monolayer cell cultures. However, many of these models are not fully characterized. This study aimed to characterize a BT-20 triple-negative breast carcinoma spheroid [...] Read more.

Three-dimensional cell culture models are increasingly adopted as preferred pre-clinical drug testing platforms, as they circumvent limitations associated with traditional monolayer cell cultures. However, many of these models are not fully characterized. This study aimed to characterize a BT-20 triple-negative breast carcinoma spheroid model and assess its susceptibility to doxorubicin in comparison to a monolayer model. Spheroids were developed using the liquid overlay method. Phenotypic attributes were analyzed by characterizing changes in size, gross morphology, protein content, metabolic activity, hypoxic status, and cell–cell junctions. The cytotoxic range of doxorubicin in monolayers was determined using the sulforhodamine B assay, and the comparative effect of toxic and sub-toxic concentrations was assessed in both spheroids and monolayers. Similar to the in vivo microenvironment, spheroids had a heterogeneous spatial cytoarchitecture, inherent hypoxia and strong adherens junctions. Doxorubicin induced dose-dependent cytotoxicity in monolayers (IC₂₅: 130 nM, IC₅₀: 320 nM and IC₇₅: 1580 nM); however, these concentrations did not alter the spheroid size or acid phosphatase activity. Only concentrations ≥6 µM had any effect on spheroid integrity. In comparison to monolayers, the BT-20 spheroid model has decreased sensitivity to doxorubicin and could serve as a better model for susceptibility testing in triple-negative breast cancer. Full article

(This article belongs to the Special Issue Breast Cancer: From Pathophysiology to Therapeutic Strategies)

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10 pages, 3348 KiB

Open AccessArticle

Histologic Analysis of Idiopathic Pulmonary Fibrosis by Morphometric and Fractal Analysis

by Massimiliano Mancini, Lavinia Bargiacchi, Claudia De Vitis, Michela D’Ascanio, Chiara De Dominicis, Mohsen Ibrahim, Erino Angelo Rendina, Alberto Ricci, Arianna Di Napoli, Rita Mancini and Andrea Vecchione

Biomedicines 2023, 11(5), 1483; https://doi.org/10.3390/biomedicines11051483 - 19 May 2023

Cited by 2 | Viewed by 1272

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disorder, ultimately leading to respiratory failure and death. Despite great research advances in understanding the mechanisms underlying the disease, its diagnosis, and its treatment, IPF still remains idiopathic without known biological or histological [...] Read more.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disorder, ultimately leading to respiratory failure and death. Despite great research advances in understanding the mechanisms underlying the disease, its diagnosis, and its treatment, IPF still remains idiopathic without known biological or histological markers able to predict disease progression or response to treatment. The histologic hallmark of IPF is usual interstitial pneumonia (UIP), with its intricate architectural distortion and temporal inhomogeneity. We hypothesize that normal lung alveolar architecture can be compared to fractals, such as the Pythagoras tree with its fractal dimension (D_f), and every pathological insult, distorting the normal lung structure, could result in D_f variations. In this study, we aimed to assess the UIP histologic fractal dimension in relationship to other morphometric parameters in newly diagnosed IPF patients and its possible role in the prognostic stratification of the disease. Clinical data and lung tissue specimens were obtained from twelve patients with IPF, twelve patients with non-specific interstitial pneumonia (NSIP), and age-matched “healthy” control lung tissue from patients undergoing lung surgery for other causes. Histology and histomorphometry were performed to evaluate D_f and lacunarity measures, using the box counting method on the FracLac ImageJ plugin. The results showed that D_f was significantly higher in IPF patients compared to controls and fibrotic NSIP patients, indicating greater architectural distortion in IPF. Additionally, high D_f values were associated with higher fibroblastic foci density and worse prognostic outcomes in IPF, suggesting that D_f may serve as a potential novel prognostic marker for IPF. The scalability of D_f measurements was demonstrated through repeated measurements on smaller portions from the same surgical biopsies, which were selected to mimic a cryobiopsy. Our study provides further evidence to support the use of fractal morphometry as a tool for quantifying and determining lung tissue remodeling in IPF, and we demonstrated a significant correlation between histological and radiological D_f in UIP pattern, as well as a significant association between D_f and FF density. Furthermore, our study demonstrates the scalability and self-similarity of D_f measurements across different biopsy types, including surgical and smaller specimens. Full article

(This article belongs to the Special Issue Phenotypes and Endotypes in Interstitial Lung Diseases)

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24 pages, 3844 KiB

Open AccessArticle

Brain-Derived Neurotrophic Factor (BDNF) in Mechanisms of Autistic-like Behavior in BTBR Mice: Crosstalk with the Dopaminergic Brain System

by Tatiana Ilchibaeva, Anton Tsybko, Marina Lipnitskaya, Dmitry Eremin, Kseniya Milutinovich, Vladimir Naumenko and Nina Popova

Biomedicines 2023, 11(5), 1482; https://doi.org/10.3390/biomedicines11051482 - 19 May 2023

Cited by 2 | Viewed by 1775

Abstract

Disturbances in neuroplasticity undoubtedly play an important role in the development of autism spectrum disorders (ASDs). Brain neurotransmitters and brain-derived neurotrophic factor (BDNF) are known as crucial players in cerebral and behavioral plasticity. Such an important neurotransmitter as dopamine (DA) is involved in [...] Read more.

Disturbances in neuroplasticity undoubtedly play an important role in the development of autism spectrum disorders (ASDs). Brain neurotransmitters and brain-derived neurotrophic factor (BDNF) are known as crucial players in cerebral and behavioral plasticity. Such an important neurotransmitter as dopamine (DA) is involved in the behavioral inflexibility of ASD. Additionally, much evidence from human and animal studies implicates BDNF in ASD pathogenesis. Nonetheless, crosstalk between BDNF and the DA system has not been studied in the context of an autistic-like phenotype. For this reason, the aim of our study was to compare the effects of either the acute intracerebroventricular administration of a recombinant BDNF protein or hippocampal adeno-associated-virus–mediated BDNF overexpression on autistic-like behavior and expression of key DA-related and BDNF-related genes in BTBR mice (a widely recognized model of autism). The BDNF administration failed to affect autistic-like behavior but downregulated Comt mRNA in the frontal cortex and hippocampus; however, COMT protein downregulation in the hippocampus and upregulation in the striatum were insignificant. BDNF administration also reduced the receptor TrkB level in the frontal cortex and midbrain and the BDNF/proBDNF ratio in the striatum. In contrast, hippocampal BDNF overexpression significantly diminished stereotypical behavior and anxiety; these alterations were accompanied only by higher hippocampal DA receptor D1 mRNA levels. The results indicate an important role of BDNF in mechanisms underlying anxiety and repetitive behavior in ASDs and implicates BDNF–DA crosstalk in the autistic-like phenotype of BTBR mice. Full article

(This article belongs to the Special Issue BDNF in Brain Disorders: From Pathogenesis to Treatment)

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14 pages, 1739 KiB

Open AccessArticle

Cognitive and Cellular Effects of Combined Organophosphate Toxicity and Mild Traumatic Brain Injury

by Dor Freidin, Meirav Har-Even, Vardit Rubovitch, Kathleen E. Murray, Nicola Maggio, Efrat Shavit-Stein, Lee Keidan, Bruce A. Citron and Chaim G. Pick

Biomedicines 2023, 11(5), 1481; https://doi.org/10.3390/biomedicines11051481 - 19 May 2023

Viewed by 1333

Abstract

Traumatic brain injury (TBI) is considered the most common neurological disorder among people under the age of 50. In modern combat zones, a combination of TBI and organophosphates (OP) can cause both fatal and long-term effects on the brain. We utilized a mouse [...] Read more.

Traumatic brain injury (TBI) is considered the most common neurological disorder among people under the age of 50. In modern combat zones, a combination of TBI and organophosphates (OP) can cause both fatal and long-term effects on the brain. We utilized a mouse closed-head TBI model induced by a weight drop device, along with OP exposure to paraoxon. Spatial and visual memory as well as neuron loss and reactive astrocytosis were measured 30 days after exposure to mild TBI (mTBI) and/or paraoxon. Molecular and cellular changes were assessed in the temporal cortex and hippocampus. Cognitive and behavioral deficits were most pronounced in animals that received a combination of paraoxon exposure and mTBI, suggesting an additive effect of the insults. Neuron survival was reduced in proximity to the injury site after exposure to paraoxon with or without mTBI, whereas in the dentate gyrus hilus, cell survival was only reduced in mice exposed to paraoxon prior to sustaining a mTBI. Neuroinflammation was increased in the dentate gyrus in all groups exposed to mTBI and/or to paraoxon. Astrocyte morphology was significantly changed in mice exposed to paraoxon prior to sustaining an mTBI. These results provide further support for assumptions concerning the effects of OP exposure following the Gulf War. This study reveals additional insights into the potentially additive effects of OP exposure and mTBI, which may result in more severe brain damage on the modern battlefield. Full article

(This article belongs to the Special Issue Brain Injury and Neurodegeneration: Molecular, Functional, and Translational Approach 2.0)

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14 pages, 1882 KiB

Open AccessArticle

TRPM4 Blocking Antibody Protects Cerebral Vasculature in Delayed Stroke Reperfusion

by Bo Chen, Shunhui Wei, See Wee Low, Charlene Priscilla Poore, Andy Thiam-Huat Lee, Bernd Nilius and Ping Liao

Biomedicines 2023, 11(5), 1480; https://doi.org/10.3390/biomedicines11051480 - 19 May 2023

Cited by 7 | Viewed by 1485

Abstract

Reperfusion therapy for acute ischemic stroke aims to restore the blood flow of occluded blood vessels. However, successful recanalization is often associated with disruption of the blood-brain barrier, leading to reperfusion injury. Delayed recanalization increases the risk of severe reperfusion injury, including severe [...] Read more.

Reperfusion therapy for acute ischemic stroke aims to restore the blood flow of occluded blood vessels. However, successful recanalization is often associated with disruption of the blood-brain barrier, leading to reperfusion injury. Delayed recanalization increases the risk of severe reperfusion injury, including severe cerebral edema and hemorrhagic transformation. The TRPM4-blocking antibody M4P has been shown to alleviate reperfusion injury and improve functional outcomes in animal models of early stroke reperfusion. In this study, we examined the role of M4P in a clinically relevant rat model of delayed stroke reperfusion in which the left middle cerebral artery was occluded for 7 h. To mimic the clinical scenario, M4P or control IgG was administered 1 h before recanalization. Immunostaining showed that M4P treatment improved vascular morphology after stroke. Evans blue extravasation demonstrated attenuated vascular leakage following M4P treatment. With better vascular integrity, cerebral perfusion was improved, leading to a reduction of infarct volume and animal mortality rate. Functional outcome was evaluated by the Rotarod test. As more animals with severe injuries died during the test in the control IgG group, we observed no difference in functional outcomes in the surviving animals. In conclusion, we identified the potential of TRPM4 blocking antibody M4P to ameliorate vascular injury during delayed stroke reperfusion. If combined with reperfusion therapy, M4P has the potential to improve current stroke management. Full article

(This article belongs to the Special Issue Genetic, Epigenetic, Environmental, and Pharmacological Models for Neuroscience, Neurologic Diseases, and Psychiatric Disorders: Advancement in Bench-to-Bedside Translational Research)

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16 pages, 5667 KiB

Open AccessArticle

A Deep Learning Approach for Prognostic Evaluation of Lung Adenocarcinoma Based on Cuproptosis-Related Genes

by Pengchen Liang, Jianguo Chen, Lei Yao, Zezhou Hao and Qing Chang

Biomedicines 2023, 11(5), 1479; https://doi.org/10.3390/biomedicines11051479 - 19 May 2023

Cited by 3 | Viewed by 1628

Abstract

Lung adenocarcinoma represents a significant global health challenge. Despite advances in diagnosis and treatment, the prognosis remains poor for many patients. In this study, we aimed to identify cuproptosis-related genes and to develop a deep neural network model to predict the prognosis of [...] Read more.

Lung adenocarcinoma represents a significant global health challenge. Despite advances in diagnosis and treatment, the prognosis remains poor for many patients. In this study, we aimed to identify cuproptosis-related genes and to develop a deep neural network model to predict the prognosis of lung adenocarcinoma. We screened differentially expressed genes from The Cancer Genome Atlas data through differential analysis of cuproptosis-related genes. We then used this information to establish a prognostic model using a deep neural network, which we validated using data from the Gene Expression Omnibus. Our deep neural network model incorporated nine cuproptosis-related genes and achieved an area under the curve of 0.732 in the training set and 0.646 in the validation set. The model effectively distinguished between distinct risk groups, as evidenced by significant differences in survival curves (p < 0.001), and demonstrated significant independence as a standalone prognostic predictor (p < 0.001). Functional analysis revealed differences in cellular pathways, the immune microenvironment, and tumor mutation burden between the risk groups. Furthermore, our model provided personalized survival probability predictions with a concordance index of 0.795 and identified the drug candidate BMS-754807 as a potentially sensitive treatment option for lung adenocarcinoma. In summary, we presented a deep neural network prognostic model for lung adenocarcinoma, based on nine cuproptosis-related genes, which offers independent prognostic capabilities. This model can be used for personalized predictions of patient survival and the identification of potential therapeutic agents for lung adenocarcinoma, which may ultimately improve patient outcomes. Full article

(This article belongs to the Special Issue Research and Application of Artificial Intelligence in Assisting Disease Diagnosis and Treatment)

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15 pages, 4268 KiB

Open AccessArticle

Neuroprotective Effect of a Nutritional Supplement Containing Spearmint Extract, Forskolin, Homotaurine and Group B Vitamins in a Mouse Model of Transient Ocular Hypertension

by Andrea Satriano, Maria Luisa Laganà, Ester Licastro, Carlo Nucci, Giacinto Bagetta, Rossella Russo and Annagrazia Adornetto

Biomedicines 2023, 11(5), 1478; https://doi.org/10.3390/biomedicines11051478 - 18 May 2023

Cited by 1 | Viewed by 1676

Abstract

Glaucoma is one of the most common sight-threatening eye disorders and one of the main causes of irreversible blindness worldwide. The current therapies focusing on reducing intraocular pressure (IOP) are often insufficient to prevent the progression of the disease, so the therapeutic management [...] Read more.

Glaucoma is one of the most common sight-threatening eye disorders and one of the main causes of irreversible blindness worldwide. The current therapies focusing on reducing intraocular pressure (IOP) are often insufficient to prevent the progression of the disease, so the therapeutic management of glaucoma remains a challenge. The aim of this study was to evaluate the neuroprotective, IOP-lowering independent effects of a nutritional supplement containing forskolin, homotaurine, spearmint extract and vitamins of the B group in a model of acute glaucoma developed in mice. Glaucoma was induced in adult wild-type C57BL/6J mice by transient elevation of IOP. The dietary supplement, branded as Gangliomix^® (125 mg/kg/day), was administered by oral gavage for 17 days and ocular hypertension was induced on the 10th day of treatment. A histological analysis of the retinas was performed and RGC survival was evaluated with fluorogold labeling and Brn3a immunostaining on wholemount and retinal sections. Expression of alpha-spectrin, caspase-3, PARP-1 and GFAP was studied with western blotting or immunofluorescence. A significant increase in RGC survival was reported in the retina of mice treated with the dietary supplement as compared to vehicle-treated animals. The observed neuroprotection was associated with a calpain activity decrease, reduction in caspase-3 and PARP-1 activation, and prevention of GFAP upregulation. These effects were independent from the hypotensive effects of the supplement. Altogether, our data suggest that the dietary supplementation with forskolin, homotaurine, spearmint extract and vitamins of the B group supports RGC survival and may offer beneficial effects in glaucoma patients in combination with the currently used IOP-lowering therapy. Full article

(This article belongs to the Special Issue State-of-the-Art Neurologic Disease in Italy)

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19 pages, 1348 KiB

Open AccessReview

Air Pollution: A Silent Key Driver of Dementia

by Pawel Serafin, Malgorzata Zaremba, Dorota Sulejczak and Patrycja Kleczkowska

Biomedicines 2023, 11(5), 1477; https://doi.org/10.3390/biomedicines11051477 - 18 May 2023

Cited by 2 | Viewed by 2047

Abstract

In 2017, the Lancet Commission on Dementia Prevention, Intervention, and Care included air pollution in its list of potential risk factors for dementia; in 2018, the Lancet Commission on Pollution concluded that the evidence for a causal relationship between fine particulate matter (PM) [...] Read more.

In 2017, the Lancet Commission on Dementia Prevention, Intervention, and Care included air pollution in its list of potential risk factors for dementia; in 2018, the Lancet Commission on Pollution concluded that the evidence for a causal relationship between fine particulate matter (PM) and dementia is encouraging. However, few interventions exist to delay or prevent the onset of dementia. Air quality data are becoming increasingly available, and the science underlying the associated health effects is also evolving rapidly. Recent interest in this area has led to the publication of population-based cohort studies, but these studies have used different approaches to identify cases of dementia. The purpose of this article is to review recent evidence describing the association between exposure to air pollution and dementia with special emphasis on fine particulate matter of 2.5 microns or less. We also summarize here the proposed detailed mechanisms by which air pollutants reach the brain and activate the innate immune response. In addition, the article also provides a short overview of existing limitations in the treatment of dementia. Full article

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

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17 pages, 3074 KiB

Open AccessArticle

Rapid Generation of Pulmonary Organoids from Induced Pluripotent Stem Cells by Co-Culturing Endodermal and Mesodermal Progenitors for Pulmonary Disease Modelling

by Adam Mitchell, Chaowen Yu, Xiangjun Zhao, Laurence Pearmain, Rajesh Shah, Karen Piper Hanley, Timothy Felton and Tao Wang

Biomedicines 2023, 11(5), 1476; https://doi.org/10.3390/biomedicines11051476 - 18 May 2023

Cited by 1 | Viewed by 1869

Abstract

Differentiation of induced pluripotent stem cells to a range of target cell types is ubiquitous in monolayer culture. To further improve the phenotype of the cells produced, 3D organoid culture is becoming increasingly prevalent. Mature organoids typically require the involvement of cells from [...] Read more.

Differentiation of induced pluripotent stem cells to a range of target cell types is ubiquitous in monolayer culture. To further improve the phenotype of the cells produced, 3D organoid culture is becoming increasingly prevalent. Mature organoids typically require the involvement of cells from multiple germ layers. The aim of this study was to produce pulmonary organoids from defined endodermal and mesodermal progenitors. Endodermal and mesodermal progenitors were differentiated from iPSCs and then combined in 3D Matrigel hydrogels and differentiated for a further 14 days to produce pulmonary organoids. The organoids expressed a range of pulmonary cell markers such as SPA, SPB, SPC, AQP5 and T1α. Furthermore, the organoids expressed ACE2 capable of binding SARS-CoV-2 spike proteins, demonstrating the physiological relevance of the organoids produced. This study presented a rapid production of pulmonary organoids using a multi-germ-layer approach that could be used for studying respiratory-related human conditions. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Induced Pluripotent Stem Cells: 15 Years after the Discovery)

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23 pages, 5763 KiB

Open AccessArticle

Anisotropy and Frequency Dependence of Signal Propagation in the Cerebellar Circuit Revealed by High-Density Multielectrode Array Recordings

by Anita Monteverdi, Danila Di Domenico, Egidio D’Angelo and Lisa Mapelli

Biomedicines 2023, 11(5), 1475; https://doi.org/10.3390/biomedicines11051475 - 18 May 2023

Cited by 1 | Viewed by 1496

Abstract

The cerebellum is one of the most connected structures of the central nervous system and receives inputs over an extended frequency range. Nevertheless, the frequency dependence of cerebellar cortical processing remains elusive. In this work, we characterized cerebellar cortex responsiveness to mossy fibers [...] Read more.

The cerebellum is one of the most connected structures of the central nervous system and receives inputs over an extended frequency range. Nevertheless, the frequency dependence of cerebellar cortical processing remains elusive. In this work, we characterized cerebellar cortex responsiveness to mossy fibers activation at different frequencies and reconstructed the spread of activity in the sagittal and coronal planes of acute mouse cerebellar slices using a high-throughput high-density multielectrode array (HD-MEA). The enhanced spatiotemporal resolution of HD-MEA revealed the frequency dependence and spatial anisotropy of cerebellar activation. Mossy fiber inputs reached the Purkinje cell layer even at the lowest frequencies, but the efficiency of transmission increased at higher frequencies. These properties, which are likely to descend from the topographic organization of local inhibition, intrinsic electroresponsiveness, and short-term synaptic plasticity, are critical elements that have to be taken into consideration to define the computational properties of the cerebellar cortex and its pathological alterations. Full article

(This article belongs to the Special Issue Synaptic Transmission: From Molecular to Neural Network Levels)

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20 pages, 1328 KiB

Open AccessReview

Acute Kidney Injury in Kidney Transplant Patients in Intensive Care Unit: From Pathogenesis to Clinical Management

by Marco Fiorentino, Francesca Bagagli, Annamaria Deleonardis, Alessandra Stasi, Rossana Franzin, Francesca Conserva, Barbara Infante, Giovanni Stallone, Paola Pontrelli and Loreto Gesualdo

Biomedicines 2023, 11(5), 1474; https://doi.org/10.3390/biomedicines11051474 - 18 May 2023

Cited by 5 | Viewed by 2555

Abstract

Kidney transplantation is the first-choice treatment for end-stage renal disease (ESRD). Kidney transplant recipients (KTRs) are at higher risk of experiencing a life-threatening event requiring intensive care unit (ICU) admission, mainly in the late post-transplant period (more than 6 months after transplantation). Urosepsis [...] Read more.

Kidney transplantation is the first-choice treatment for end-stage renal disease (ESRD). Kidney transplant recipients (KTRs) are at higher risk of experiencing a life-threatening event requiring intensive care unit (ICU) admission, mainly in the late post-transplant period (more than 6 months after transplantation). Urosepsis and bloodstream infections account for almost half of ICU admissions in this population; in addition, potential side effects related to immunosuppressive treatment should be accounted for cytotoxic and ischemic changes induced by calcineurin inhibitor (CNI), sirolimus/CNI-induced thrombotic microangiopathy and posterior reversible encephalopathy syndrome. Throughout the ICU stay, Acute Kidney Injury (AKI) incidence is common and ranges from 10% to 80%, and up to 40% will require renal replacement therapy. In-hospital mortality can reach 30% and correlates with acute illness severity and admission diagnosis. Graft survival is subordinated to baseline estimated glomerular filtration rate (eGFR), clinical presentation, disease severity and potential drug nephrotoxicity. The present review aims to define the impact of AKI events on short- and long-term outcomes in KTRs, focusing on the epidemiologic data regarding AKI incidence in this subpopulation; the pathophysiological mechanisms underlying AKI development and potential AKI biomarkers in kidney transplantation, graft and patients’ outcomes; the current diagnostic work up and management of AKI; and the modulation of immunosuppression in ICU-admitted KTRs. Full article

(This article belongs to the Special Issue Acute Kidney Injury and Chronic Kidney Disease: Pathophysiology and New Therapeutic Strategies)

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11 pages, 573 KiB

Open AccessArticle

New Opportunities for Preoperative Diagnosis of Medullary Thyroid Carcinoma

by Sergei A. Lukyanov, Sergei V. Sergiyko, Sergei E. Titov, Dmitry G. Beltsevich, Yulia A. Veryaskina, Vladimir E. Vanushko, Liliya S. Urusova, Alexander A. Mikheenkov, Evgeniya S. Kozorezova, Sergey L. Vorobyov and Ilya V. Sleptsov

Biomedicines 2023, 11(5), 1473; https://doi.org/10.3390/biomedicines11051473 - 18 May 2023

Cited by 2 | Viewed by 1419

Abstract

The preoperative diagnostics of medullary thyroid carcinoma (MTC), including the measuring of the blood calcitonin level, has a number of limitations. Particular focus has recently been placed on the role of miRNAs in the development of various malignant tumors; a comparative analysis of [...] Read more.

The preoperative diagnostics of medullary thyroid carcinoma (MTC), including the measuring of the blood calcitonin level, has a number of limitations. Particular focus has recently been placed on the role of miRNAs in the development of various malignant tumors; a comparative analysis of accuracy of the existing methods for MTC diagnosis with a novel diagnosis method, evaluation of the miRNA-375 expression level, was performed in this study. The expression level of miRNA-375 in cytology samples from 555 patients with the known histological diagnosis, including 41 patients with confirmed postoperative diagnosis of MTC, was assessed. The diagnostic parameters of the basal calcitonin level, calcitonin in wash-out fluid from the FNAB needle, and miRNA-375 were compared. An assessment of the miRNA-375 expression level made it possible to detect all the MTC samples with a 100% accuracy among all the 555 cytology specimens, as well as in non-informative FNAB specimens, and specimens from the ipsilateral thyroid lobe. Parameters such as sensitivity, specificity, PPV, and NPV were 100%. The miRNA-375 level, unlike calcitonin, does not correlate with tumor volume, so it does not have the so-called “gray zone”. An assessment of the miRNA-375 expression allows one to accurately distinguish MTC from other malignant and benign thyroid tumors. Full article

(This article belongs to the Special Issue Cancer Heterogeneity: Biomarkers and Targeted Therapies)

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Biomedicines, Volume 11, Issue 5 (May 2023) – 266 articles

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