Research

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19 pages, 2826 KiB

Open AccessArticle

Mixture of Doxycycline, ML-7 and L-NAME Restores the Pro- and Antioxidant Balance during Myocardial Infarction—In Vivo Pig Model Study

by Iwona Bil-Lula, Wiktor Kuliczkowski, Anna Krzywonos-Zawadzka, Piotr Frydrychowski, Dominika Stygar, Kornela Hałucha and Agnieszka Noszczyk-Nowak

Biomedicines 2024, 12(4), 784; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines12040784 - 02 Apr 2024

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Abstract

The restoration of blood flow to the ischemic myocardium inflicts ischemia/reperfusion (I/R) heart injury (IRI). The main contributors to IRI are increased oxidative stress and subsequent excessive production of ROS, increased expression of NOS and peroxinitate, activation of MMPs, and enhanced posttranslational modifications [...] Read more.

The restoration of blood flow to the ischemic myocardium inflicts ischemia/reperfusion (I/R) heart injury (IRI). The main contributors to IRI are increased oxidative stress and subsequent excessive production of ROS, increased expression of NOS and peroxinitate, activation of MMPs, and enhanced posttranslational modifications of contractile proteins, which make them more susceptible to proteolytic degradation. Since the pathophysiology of IRI is a complex issue, and thus, various therapeutic strategies are required to prevent or reduce IRI and microvascular dysfunction, in the current study we proposed an innovative multi-drug therapy using low concentrations of drugs applied intracoronary to reach microvessels in order to stabilize the pro- and antioxidant balance during a MI in an in vivo pig model. The ability of a mixture of doxycycline (1 μM), ML-7 (0.5 μM), and L-NAME (2 μM) to modulate the pro- and antioxidative balance was tested in the left ventricle tissue and blood samples. Data showed that infusion of a MIX reduced the total oxidative status (TOS), oxidative stress index (OSI), and malondialdehyde (MDA). It also increased the total antioxidant capacity, confirming its antioxidative properties. MIX administration also reduced the activity of MMP-2 and MMP-9, and then decreased the release of MLC1 and BNP-26 into plasma. This study demonstrated that intracoronary administration of low concentrations of doxycycline in combination with ML-7 and L-NAME is incredibly efficient in regulating pro- and antioxidant balance during MI. Full article

(This article belongs to the Special Issue State-of-the-Art Drug Discovery and Development in Poland)

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27 pages, 4412 KiB

Open AccessArticle

Ursolic Acid Formulations Effectively Induce Apoptosis and Limit Inflammation in the Psoriasis Models In Vitro

by Ewa Bielecka, Natalia Zubrzycka, Karolina Marzec, Anna Maksylewicz, Maja Sochalska, Agnieszka Kulawik-Pióro, Elwira Lasoń, Karolina Śliwa, Magdalena Malinowska, Elżbieta Sikora, Krzysztof Nowak, Małgorzata Miastkowska and Tomasz Kantyka

Biomedicines 2024, 12(4), 732; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines12040732 - 25 Mar 2024

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Abstract

Psoriasis, a prevalent inflammatory skin disorder affecting a significant percentage of the global population, poses challenges in its management, necessitating the exploration of novel cost-effective and widely accessible therapeutic options. This study investigates the potential of ursolic acid (UA), a triterpenoid known for [...] Read more.

Psoriasis, a prevalent inflammatory skin disorder affecting a significant percentage of the global population, poses challenges in its management, necessitating the exploration of novel cost-effective and widely accessible therapeutic options. This study investigates the potential of ursolic acid (UA), a triterpenoid known for its anti-inflammatory and pro-apoptotic properties, in addressing psoriasis-related inflammation and keratinocyte hyperproliferation. The research involved in vitro models employing skin and immune cells to assess the effects of UA on psoriasis-associated inflammation. The presented research demonstrates the limiting effects of UA on IL-6 and IL-8 production in response to the inflammatory stimuli and limiting effects on the expression of psoriatic biomarkers S100A7, S100A8, and S100A9. Further, the study reveals promising outcomes, demonstrating UA’s ability to mitigate inflammatory responses and hyperproliferation of keratinocytes by the induction of non-inflammatory apoptosis, as well as a lack of the negative influence on other cell types, including immune cells. Considering the limitations of UA’s poor solubility, hybrid systems were designed to enhance its bioavailability and developed as hybrid nano-emulsion and bi-gel topical systems to enhance bioavailability and effectiveness of UA. One of them in particular–bi-gel–demonstrated high effectiveness in limiting the pathological response of keratinocytes to pro-psoriatic stimulation; this was even more prominent than with ursolic acid alone. Our results indicate that topical formulations of ursolic acid exhibit desirable anti-inflammatory activity in vitro and may be further employed for topical psoriasis treatment. Full article

(This article belongs to the Special Issue State-of-the-Art Drug Discovery and Development in Poland)

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13 pages, 2369 KiB

Open AccessArticle

In Vivo Study on Doxycycline Protective Mechanisms during Myocardial Ischemia Injury in Rats

by Anna Krzywonos-Zawadzka, Agnieszka Olejnik, Grzegorz Sawicki and Iwona Bil-Lula

Biomedicines 2024, 12(3), 634; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines12030634 - 13 Mar 2024

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Abstract

Background: The fact that during myocardial ischemia/reperfusion (I/R) injury, myosin light chain 1 (MLC1) and troponin I (TnI) are degraded by matrix metalloproteases activity has already been well established in both in vitro and ex vivo studies. However, I/R injury is a complex [...] Read more.

Background: The fact that during myocardial ischemia/reperfusion (I/R) injury, myosin light chain 1 (MLC1) and troponin I (TnI) are degraded by matrix metalloproteases activity has already been well established in both in vitro and ex vivo studies. However, I/R injury is a complex issue based on several overlapping mechanisms. Increased activity of myosin light chain kinase and nitric oxide synthase due to oxidative stress leads to post-translational modifications of MLC1, thus leading to the increased degradation of these proteins. Methods: Wistar rats were subjected to left anterior descending coronary artery occlusion. To measure the pharmacological effect of doxycycline, transthoracic echocardiography as well as biochemical tests, concentrations of TnI, LDH, MLC1, MMP-2 and MMP-9 were performed. Gelatinize activity and cytotoxicity level were also assessed; Results: I.p., administration of doxycycline before LAD occlusion surgery increased TnI and LDH content in the heart and decreased cytotoxicity. A reduction of MMP-2 and MMP-9 concentration and MMP-2 activity after administration of Doxy was also observed, as well as improvement in echocardiographic parameters just 7 days after surgery. Conclusions: Inhibition of MMPs by doxycycline, in vivo, may serve as a protective agent in future therapy. Full article

(This article belongs to the Special Issue State-of-the-Art Drug Discovery and Development in Poland)

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17 pages, 1283 KiB

Open AccessArticle

ADMET and Solubility Analysis of New 5-Nitroisatine-Based Inhibitors of CDK2 Enzymes

by Przemysław Czeleń, Tomasz Jeliński, Agnieszka Skotnicka, Beata Szefler and Kamil Szupryczyński

Biomedicines 2023, 11(11), 3019; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11113019 - 10 Nov 2023

Cited by 1 | Viewed by 904

Abstract

The development of new substances with the ability to interact with a biological target is only the first stage in the process of the creation of new drugs. The 5-nitroisatin derivatives considered in this study are new inhibitors of cyclin-dependent kinase 2 (CDK2) [...] Read more.

The development of new substances with the ability to interact with a biological target is only the first stage in the process of the creation of new drugs. The 5-nitroisatin derivatives considered in this study are new inhibitors of cyclin-dependent kinase 2 (CDK2) intended for anticancer therapy. The research, carried out based on the ADMET (absorption, distribution, metabolism, excretion, toxicity) methods, allowed a basic assessment of the physicochemical parameters of the tested drugs to be made. The collected data clearly showed the good oral absorption, membrane permeability, and bioavailability of the tested substances. The analysis of the metabolite activity and toxicity of the tested drugs did not show any critical hazards in terms of the toxicity of the tested substances. The substances’ low solubility in water meant that extended studies tested compounds were required, which helped to select solvents with a high dissolving capacity of the examined substances, such as DMSO or NMP. The use of aqueous binary mixtures based on these two solvents allowed a relatively high solubility with significantly reduced toxicity and environmental index compared to pure solvents to be maintained, which is important in the context of the search for green solvents for pharmaceutical use. Full article

(This article belongs to the Special Issue State-of-the-Art Drug Discovery and Development in Poland)

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25 pages, 5766 KiB

Open AccessArticle

Synthesis, Cytotoxicity and Molecular Docking of New Hybrid Compounds by Combination of Curcumin with Oleanolic Acid

by Katarzyna Sowa-Kasprzak, Ewa Totoń, Jacek Kujawski, Dorota Olender, Natalia Lisiak, Lucjusz Zaprutko, Błażej Rubiś, Mariusz Kaczmarek and Anna Pawełczyk

Biomedicines 2023, 11(6), 1506; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11061506 - 23 May 2023

Cited by 1 | Viewed by 1324

Abstract

Curcumin and oleanolic acid are natural compounds with high potential in medicinal chemistry. These products have been widely studied for their pharmacological properties and have been structurally modified to improve their bioavailability and therapeutic value. In the present study, we discuss how these [...] Read more.

Curcumin and oleanolic acid are natural compounds with high potential in medicinal chemistry. These products have been widely studied for their pharmacological properties and have been structurally modified to improve their bioavailability and therapeutic value. In the present study, we discuss how these compounds are utilized to develop bioactive hybrid compounds that are intended to target cancer cells. Using a bifunctional linker, succinic acid, to combine curcumin and triterpenoic oleanolic acid, several hybrid compounds were prepared. Their cytotoxicity against different cancer cell lines was evaluated and compared with the activity of curcumin (the IC50 value (24 h), for MCF7, HeLaWT and HT-29 cancer cells for KS5, KS6 and KS8 compounds was in the range of 20.6–94.4 µM, in comparison to curcumin 15.6–57.2 µM). Additionally, in silico studies were also performed. The computations determined the activity of the tested compounds towards proteins selected due to their similar binding modes and the nature of hydrogen bonds formed within the cavity of ligand−protein complexes. Overall, the curcumin-triterpene hybrids represent an important class of compounds for the development of effective anticancer agents also without the diketone moiety in the curcumin molecule. Moreover, some structural modifications in keto-enol moiety have led to obtaining more information about different chemical and biological activities. Results obtained may be of interest for further research into combinations of curcumin and oleanolic acid derivatives. Full article

(This article belongs to the Special Issue State-of-the-Art Drug Discovery and Development in Poland)

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Review

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16 pages, 324 KiB

Open AccessReview

Abnormalities in the KRAS Gene and Treatment Options for NSCLC Patients with the G12C Mutation in This Gene—A Literature Review and Single-Center Experience

by Anna K. Rekowska, Piotr Rola, Agnieszka Kwiatkowska, Magdalena Wójcik-Superczyńska, Michał Gil, Paweł Krawczyk and Janusz Milanowski

Biomedicines 2024, 12(2), 325; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines12020325 - 31 Jan 2024

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Abstract

Mutations in the KRAS gene are among the most common mutations observed in cancer cells, but they have only recently become an achievable goal for targeted therapies. Two KRAS inhibitors, sotorasib and adagrasib, have recently been approved for the treatment of patients with [...] Read more.

Mutations in the KRAS gene are among the most common mutations observed in cancer cells, but they have only recently become an achievable goal for targeted therapies. Two KRAS inhibitors, sotorasib and adagrasib, have recently been approved for the treatment of patients with advanced non-small cell lung cancer with the KRAS G12C mutation, while studies on their efficacy are still ongoing. In this work, we comprehensively analyzed RAS gene mutations’ molecular background, mutation testing, KRAS inhibitors’ effectiveness with an emphasis on non-small cell lung cancer, the impact of KRAS mutations on immunotherapy outcomes, and drug resistance problems. We also summarized ongoing trials and analyzed emerging perspectives on targeting KRAS in cancer patients. Full article

(This article belongs to the Special Issue State-of-the-Art Drug Discovery and Development in Poland)

34 pages, 863 KiB

Open AccessReview

GLP-1 Analogs, SGLT-2, and DPP-4 Inhibitors: A Triad of Hope for Alzheimer’s Disease Therapy

by Magdalena Złotek, Antonina Kurowska, Mariola Herbet and Iwona Piątkowska-Chmiel

Biomedicines 2023, 11(11), 3035; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11113035 - 12 Nov 2023

Cited by 1 | Viewed by 2077

Abstract

Alzheimer’s is a prevalent, progressive neurodegenerative disease marked by cognitive decline and memory loss. The disease’s development involves various pathomechanisms, including amyloid-beta accumulation, neurofibrillary tangles, oxidative stress, inflammation, and mitochondrial dysfunction. Recent research suggests that antidiabetic drugs may enhance neuronal survival and cognitive [...] Read more.

Alzheimer’s is a prevalent, progressive neurodegenerative disease marked by cognitive decline and memory loss. The disease’s development involves various pathomechanisms, including amyloid-beta accumulation, neurofibrillary tangles, oxidative stress, inflammation, and mitochondrial dysfunction. Recent research suggests that antidiabetic drugs may enhance neuronal survival and cognitive function in diabetes. Given the well-documented correlation between diabetes and Alzheimer’s disease and the potential shared mechanisms, this review aimed to comprehensively assess the potential of new-generation anti-diabetic drugs, such as GLP-1 analogs, SGLT-2 inhibitors, and DPP-4 inhibitors, as promising therapeutic approaches for Alzheimer’s disease. This review aims to comprehensively assess the potential therapeutic applications of novel-generation antidiabetic drugs, including GLP-1 analogs, SGLT-2 inhibitors, and DPP-4 inhibitors, in the context of Alzheimer’s disease. In our considered opinion, antidiabetic drugs offer a promising avenue for groundbreaking developments and have the potential to revolutionize the landscape of Alzheimer’s disease treatment. Full article

(This article belongs to the Special Issue State-of-the-Art Drug Discovery and Development in Poland)

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27 pages, 987 KiB

Open AccessReview

Quality by Design (QbD) and Design of Experiments (DOE) as a Strategy for Tuning Lipid Nanoparticle Formulations for RNA Delivery

by Lidia Gurba-Bryśkiewicz, Wioleta Maruszak, Damian A. Smuga, Krzysztof Dubiel and Maciej Wieczorek

Biomedicines 2023, 11(10), 2752; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11102752 - 11 Oct 2023

Cited by 1 | Viewed by 2885

Abstract

The successful development of nonviral delivery systems for nucleic acids has been reported extensively over the past years. Increasingly employed to improve the delivery efficiency and therapeutic efficacy of RNA are lipid nanoparticles (LNPs). Many of the various critical formulation parameters can affect [...] Read more.

The successful development of nonviral delivery systems for nucleic acids has been reported extensively over the past years. Increasingly employed to improve the delivery efficiency and therapeutic efficacy of RNA are lipid nanoparticles (LNPs). Many of the various critical formulation parameters can affect the quality attributes and effectiveness of these nano-formulations. Therefore, the systematic drug development approach (QbD) and multivariate design and statistical analysis (DOE) can be very helpful and recommended for the optimization of the composition and production of RNA–LNPs. This review addresses the concepts and applications of QbD and/or DOE for the development of lipid nanoparticles for the delivery of different types of RNA, reporting examples published in the ten recent years presenting the latest trends and regulatory requirements as well as the modern mathematical and statistical design methods. As the topic explored in this review is a novel approach, the full QbD has been described in only a few papers, and a few refer only to some aspects of QbD. In contrast, the DOE approach has been used in most of the optimization works. Different approaches and innovations in DOE have been observed. Traditional statistical tests and modeling (ANOVA, regression analysis) are slowly being replaced by artificial intelligence and machine learning methods. Full article

(This article belongs to the Special Issue State-of-the-Art Drug Discovery and Development in Poland)

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22 pages, 1635 KiB

Open AccessReview

Recent Advances in the Polish Research on Polysaccharide-Based Nanoparticles in the Context of Various Administration Routes

by Mateusz Młynek, Jakub Waldemar Trzciński and Tomasz Ciach

Biomedicines 2023, 11(5), 1307; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11051307 - 28 Apr 2023

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Abstract

Polysaccharides are the most abundant polymers in nature. They exhibit robust biocompatibility, reliable non-toxicity, and biodegradable character; thus, they are employed in multiple biomedical applications. The presence of chemically accessible functional groups on the backbone of biopolymers (amine, carboxyl, hydroxyl, etc.) makes them [...] Read more.

Polysaccharides are the most abundant polymers in nature. They exhibit robust biocompatibility, reliable non-toxicity, and biodegradable character; thus, they are employed in multiple biomedical applications. The presence of chemically accessible functional groups on the backbone of biopolymers (amine, carboxyl, hydroxyl, etc.) makes them suitable materials for chemical modification or drug immobilisation. Among different drug delivery systems (DDSs), nanoparticles have been of great interest in scientific research in the last decades. In the following review, we want to address the issue of rational design of nanoparticle (NP)-based drug delivery systems in reference to the specificity of the medication administration route and resulting requirements. In the following sections, readers can find a comprehensive analysis of the articles published by authors with Polish affiliations in the last few years (2016–2023). The article emphasises NP administration routes and synthetic approaches, followed by in vitro and in vivo attempts toward pharmacokinetic (PK) studies. The ‘Future Prospects’ section was constructed to address the critical observations and gaps found in the screened studies, as well as to indicate good practices for polysaccharide-based nanoparticle preclinical evaluation. Full article

(This article belongs to the Special Issue State-of-the-Art Drug Discovery and Development in Poland)

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