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18 pages, 11094 KiB

Open AccessArticle

Composite of KLVFF-Transthyretin-Penetratin and Manganese Dioxide Nanoclusters: A Multifunctional Agent against Alzheimer’s β-Amyloid Fibrillogenesis

by Haitao Lan, Ying Wang, Wei Liu, Xiaoyan Dong and Yan Sun

Molecules 2024, 29(6), 1405; https://doi.org/10.3390/molecules29061405 - 21 Mar 2024

Viewed by 873

Abstract

Design of amyloid β-protein (Aβ) inhibitors is considered an effective strategy for the prevention and treatment of Alzheimer’s disease (AD). However, the limited blood–brain barrier (BBB) penetration and poor Aβ-targeting capability restricts the therapeutic efficiency of candidate drugs. Herein, we have proposed to [...] Read more.

Design of amyloid β-protein (Aβ) inhibitors is considered an effective strategy for the prevention and treatment of Alzheimer’s disease (AD). However, the limited blood–brain barrier (BBB) penetration and poor Aβ-targeting capability restricts the therapeutic efficiency of candidate drugs. Herein, we have proposed to engineer transthyretin (TTR) by fusion of the Aβ-targeting peptide KLVFF and cell-penetrating peptide Penetratin to TTR, and derived a fusion protein, KLVFF-TTR-Penetratin (KTP). Moreover, to introduce the scavenging activity for reactive oxygen species (ROS), a nanocomposite of KTP and manganese dioxide nanoclusters (KTP@MnO₂) was fabricated by biomineralization. Results revealed that KTP@MnO₂ demonstrated significantly enhanced inhibition on Aβ aggregation as compared to TTR. The inhibitory effect was increased from 18%, 33%, and 49% (10, 25, and 50 μg/mL TTR, respectively) to 52%, 81%, and 100% (10, 25, and 50 μg/mL KTP@MnO₂). In addition, KTP@MnO₂ could penetrate the BBB and target amyloid plaques. Moreover, multiple ROS, including hydroxyl radicals, superoxide radicals, hydrogen peroxide, and Aβ-induced-ROS, which cannot be scavenged by TTR, were scavenged by KTP@MnO₂, thus resulting in the mitigation of cellular oxidative damages. More importantly, cell culture and in vivo experiments with AD nematodes indicated that KTP@MnO₂ at 50 μg/mL increased the viability of Aβ-treated cells from 66% to more than 95%, and completely cleared amyloid plaques in AD nematodes and extended their lifespan by 7 d. Overall, despite critical aspects such as the stability, metabolic distribution, long-term biotoxicity, and immunogenicity of the nanocomposites in mammalian models remaining to be investigated, this work has demonstrated the multifunctionality of KTP@MnO₂ for targeting Aβ in vivo, and provided new insights into the design of multifunctional nanocomposites of protein–metal clusters against AD. Full article

(This article belongs to the Special Issue Breakthroughs and Challenges in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes)

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21 pages, 3230 KiB

Open AccessArticle

Development of Pleiotropic TrkB and 5-HT₄ Receptor Ligands as Neuroprotective Agents

by Mirjana Antonijevic, Despoina Charou, Audrey Davis, Thomas Curel, Maria Valcarcel, Isbaal Ramos, Patricia Villacé, Sylvie Claeysen, Patrick Dallemagne, Achille Gravanis, Ioannis Charalampopoulos and Christophe Rochais

Molecules 2024, 29(2), 515; https://doi.org/10.3390/molecules29020515 - 19 Jan 2024

Cited by 1 | Viewed by 962

Abstract

One common event that is the most detrimental in neurodegenerative disorders, even though they have a complex pathogenesis, is the increased rate of neuronal death. Endogenous neurotrophins consist of the major neuroprotective factors, while brain-derived neurotrophic factor (BDNF) and its high-affinity tyrosine kinase [...] Read more.

One common event that is the most detrimental in neurodegenerative disorders, even though they have a complex pathogenesis, is the increased rate of neuronal death. Endogenous neurotrophins consist of the major neuroprotective factors, while brain-derived neurotrophic factor (BDNF) and its high-affinity tyrosine kinase receptor TrkB are described in a number of studies for their important neuronal effects. Normal function of this receptor is crucial for neuronal survival, differentiation, and synaptic function. However, studies have shown that besides direct activation, the TrkB receptor can be transactivated via GPCRs. It has been proven that activation of the 5-HT₄ receptor and transactivation of the TrkB receptor have a positive influence on neuronal differentiation (total dendritic length, number of primary dendrites, and branching index). Because of that and based on the main structural characteristics of LM22A-4, a known activator of the TrkB receptor, and RS67333, a partial 5-HT₄ receptor agonist, we have designed and synthesized a small data set of novel compounds with potential dual activities in order to not only prevent neuronal death, but also to induce neuronal differentiation in neurodegenerative disorders. Full article

(This article belongs to the Special Issue Breakthroughs and Challenges in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes)

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22 pages, 3295 KiB

Open AccessArticle

Glucuronidation Pathways of 5- and 7-Hydroxypropranolol: Determination of Glucuronide Structures and Enzyme Selectivity

by Fan Yang, Maxi Wenzel, Matthias Bureik and Maria Kristina Parr

Molecules 2023, 28(23), 7783; https://doi.org/10.3390/molecules28237783 - 26 Nov 2023

Viewed by 878

Abstract

Propranolol, a non-selective beta-blocker medication, has been utilized in the treatment of cardiovascular diseases for several decades. Its hydroxynaphthyl metabolites have been recognized to possess varying degrees of beta-blocker activity due to the unaltered side-chain. This study achieved the successful separation and identification [...] Read more.

Propranolol, a non-selective beta-blocker medication, has been utilized in the treatment of cardiovascular diseases for several decades. Its hydroxynaphthyl metabolites have been recognized to possess varying degrees of beta-blocker activity due to the unaltered side-chain. This study achieved the successful separation and identification of diastereomeric glucuronic metabolites derived from 4-, 5-, and 7-hydroxypropranolol (4-OHP, 5-OHP, and 7-OHP) in human urine. Subsequently, reaction phenotyping of 5- and 7-hydroxypropranolol by different uridine 5’-diphospho-glucuronosyltransferases (UGTs) was carried out, with a comparison to the glucuronidation of 4-hydroxypropranolol (4-OHP). Among the 19 UGT enzymes examined, UGT1A1, UGT1A3, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2A1, and UGT2A2 were found to be involved in the glucuronidation of 5-OHP. Furthermore, UGT1A6 exhibited glucuronidation activity towards 7-OHP, along with the aforementioned eight UGTs. Results obtained by glucuronidation of corresponding methoxypropranolols and MS/MS analysis of 1,2-dimethylimidazole-4-sulfonyl (DMIS) derivatives of hydroxypropranolol glucuronides suggest that both the aromatic and aliphatic hydroxy groups of the hydroxypropranolols may be glucuronidated in vitro. However, the analysis of human urine samples collected after the administration of propranolol leads us to conclude that aromatic-linked glucuronidation is the preferred pathway under physiological conditions. Full article

(This article belongs to the Special Issue Breakthroughs and Challenges in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes)

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22 pages, 8141 KiB

Open AccessArticle

Discovery of Novel Biphenyl Carboxylic Acid Derivatives as Potent URAT1 Inhibitors

by Xianxin Hou, Yongcheng Wang, Yajun Yang and Zhiyan Xiao

Molecules 2023, 28(21), 7415; https://doi.org/10.3390/molecules28217415 - 03 Nov 2023

Viewed by 1002

Abstract

Urate transporter 1 (URAT1) is a clinically validated target for the treatment of hyperuricemia and gout. Due to the absence of protein structures, the molecular design of new URAT1 inhibitors generally resorts to ligand-based approaches. Two series of biphenyl carboxylic acids were designed [...] Read more.

Urate transporter 1 (URAT1) is a clinically validated target for the treatment of hyperuricemia and gout. Due to the absence of protein structures, the molecular design of new URAT1 inhibitors generally resorts to ligand-based approaches. Two series of biphenyl carboxylic acids were designed based on the structures of URAT1 inhibitors Epaminurad and Telmisartan via a strategy of pharmacophore fusion. Fifty-one novel compounds were synthesized and most of them showed obvious inhibition against human URAT1. A1 and B21 were identified as the most potent URAT1 inhibitors in series A and B, respectively. They exhibited IC₅₀ values of 0.93 μM and 0.17 μM, which were comparable or superior to the clinical uricosuric drug benzbromarone. The results confirmed the effectiveness of ligand-based approaches in identifying novel and potent URAT1 inhibitors. Full article

(This article belongs to the Special Issue Breakthroughs and Challenges in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes)

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11 pages, 1455 KiB

Open AccessArticle

Investigation of the Impact of L-Phenylalanine and L-Tyrosine Pre-Treatment on the Uptake of 4-Borono-L-Phenylalanine in Cancerous and Normal Cells Using an Analytical Approach Based on SC-ICP-MS

by Emilia Balcer, Joanna Giebułtowicz, Małgorzata Sochacka, Anna Ruszczyńska, Magdalena Muszyńska and Ewa Bulska

Molecules 2023, 28(18), 6552; https://doi.org/10.3390/molecules28186552 - 10 Sep 2023

Viewed by 1494

Abstract

Boron has gained significant attention in medical research due to its B-10 isotope’s high cross section for the reaction with thermal neutrons, generating ionizing particles that can eliminate cancer cells, propelling the development of boron neutron capture therapy (BNCT) for cancer treatment. The [...] Read more.

Boron has gained significant attention in medical research due to its B-10 isotope’s high cross section for the reaction with thermal neutrons, generating ionizing particles that can eliminate cancer cells, propelling the development of boron neutron capture therapy (BNCT) for cancer treatment. The compound 4-borono-L-phenylalanine (BPA) has exhibited potential in BNCT clinical trials. Enhancing BPA uptake in cells involves proposing L-amino acid preloading. This study introduces a novel analytical strategy utilizing ICP-MS and single cell ICP-MS (SC-ICP-MS) to assess the effectiveness of L-tyrosine and L-phenylalanine preloading on human non-small cell lung carcinoma (A549) and normal Chinese hamster lung fibroblast (V79-4) models, an unexplored context. ICP-MS outcomes indicated that L-tyrosine and L-phenylalanine pre-treatment increased BPA uptake in V79-4 cells by 2.04 ± 0.74-fold (p = 0.000066) and 1.46 ± 0.06-fold (p = 0.000016), respectively. Conversely, A549 cells manifested heightened BPA uptake solely with L-tyrosine preloading, with a factor of 1.24 ± 0.47 (p = 0.028). BPA uptake remained higher in A549 compared to V79-4 regardless of preloading. SC-ICP-MS measurements showcased noteworthy boron content heterogeneity within A549 cells, signifying diverse responses to BPA exposure, including a subset with notably high BPA uptake. This study underscores SC-ICP-MS’s utility in precise cellular boron quantification, validating cellular BPA uptake’s heterogeneity. Full article

(This article belongs to the Special Issue Breakthroughs and Challenges in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes)

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Review

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28 pages, 3771 KiB

Open AccessReview

Skin Pigmentation Types, Causes and Treatment—A Review

by Amin Mahmood Thawabteh, Alaa Jibreen, Donia Karaman, Alà Thawabteh and Rafik Karaman

Molecules 2023, 28(12), 4839; https://doi.org/10.3390/molecules28124839 - 18 Jun 2023

Cited by 10 | Viewed by 15305

Abstract

Human skin pigmentation and melanin synthesis are incredibly variable, and are impacted by genetics, UV exposure, and some drugs. Patients’ physical appearance, psychological health, and social functioning are all impacted by a sizable number of skin conditions that cause pigmentary abnormalities. Hyperpigmentation, where [...] Read more.

Human skin pigmentation and melanin synthesis are incredibly variable, and are impacted by genetics, UV exposure, and some drugs. Patients’ physical appearance, psychological health, and social functioning are all impacted by a sizable number of skin conditions that cause pigmentary abnormalities. Hyperpigmentation, where pigment appears to overflow, and hypopigmentation, where pigment is reduced, are the two major classifications of skin pigmentation. Albinism, melasma, vitiligo, Addison’s disease, and post-inflammatory hyperpigmentation, which can be brought on by eczema, acne vulgaris, and drug interactions, are the most common skin pigmentation disorders in clinical practice. Anti-inflammatory medications, antioxidants, and medications that inhibit tyrosinase, which prevents the production of melanin, are all possible treatments for pigmentation problems. Skin pigmentation can be treated orally and topically with medications, herbal remedies, and cosmetic products, but a doctor should always be consulted before beginning any new medicine or treatment plan. This review article explores the numerous types of pigmentation problems, their causes, and treatments, as well as the 25 plants, 4 marine species, and 17 topical and oral medications now on the market that have been clinically tested to treat skin diseases. Full article

(This article belongs to the Special Issue Breakthroughs and Challenges in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes)

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22 pages, 2674 KiB

Open AccessReview

Endoplasmic Reticulum Stress and Mitochondrial Stress in Drug-Induced Liver Injury

by Sisi Pu, Yangyang Pan, Qian Zhang, Ting You, Tao Yue, Yuxing Zhang and Meng Wang

Molecules 2023, 28(7), 3160; https://doi.org/10.3390/molecules28073160 - 02 Apr 2023

Cited by 10 | Viewed by 2842

Abstract

Drug-induced liver injury (DILI) is a widespread and harmful disease closely linked to mitochondrial and endoplasmic reticulum stress (ERS). Globally, severe drug-induced hepatitis, cirrhosis, and liver cancer are the primary causes of liver-related morbidity and mortality. A hallmark of DILI is ERS and [...] Read more.

Drug-induced liver injury (DILI) is a widespread and harmful disease closely linked to mitochondrial and endoplasmic reticulum stress (ERS). Globally, severe drug-induced hepatitis, cirrhosis, and liver cancer are the primary causes of liver-related morbidity and mortality. A hallmark of DILI is ERS and changes in mitochondrial morphology and function, which increase the production of reactive oxygen species (ROS) in a vicious cycle of mutually reinforcing stress responses. Several pathways are maladapted to maintain homeostasis during DILI. Here, we discuss the processes of liver injury caused by several types of drugs that induce hepatocyte stress, focusing primarily on DILI by ERS and mitochondrial stress. Importantly, both ERS and mitochondrial stress are mediated by the overproduction of ROS, destruction of Ca²⁺ homeostasis, and unfolded protein response (UPR). Additionally, we review new pathways and potential pharmacological targets for DILI to highlight new possibilities for DILI treatment and mitigation. Full article

(This article belongs to the Special Issue Breakthroughs and Challenges in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes)

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30 pages, 3143 KiB

Open AccessReview

Potential Therapeutic Value of the STING Inhibitors

by Shangran Zhang, Runan Zheng, Yanhong Pan and Hongbin Sun

Molecules 2023, 28(7), 3127; https://doi.org/10.3390/molecules28073127 - 31 Mar 2023

Cited by 5 | Viewed by 5044

Abstract

The stimulator of interferon genes (STING) is a critical protein in the activation of the immune system in response to DNA. It can participate the inflammatory response process by modulating the inflammation-preferred translation program through the STING-PKR-like endoplasmic reticulum kinase (PERK)-eIF2α pathway or [...] Read more.

The stimulator of interferon genes (STING) is a critical protein in the activation of the immune system in response to DNA. It can participate the inflammatory response process by modulating the inflammation-preferred translation program through the STING-PKR-like endoplasmic reticulum kinase (PERK)-eIF2α pathway or by inducing the secretion of type I interferons (IFNs) and a variety of proinflammatory factors through the recruitment of TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) or the regulation of the nuclear factor kappa-B (NF-κB) pathway. Based on the structure, location, function, genotype, and regulatory mechanism of STING, this review summarizes the potential value of STING inhibitors in the prevention and treatment of infectious diseases, psoriasis, systemic lupus erythematosus, non-alcoholic fatty liver disease, and other inflammatory and autoimmune diseases. Full article

(This article belongs to the Special Issue Breakthroughs and Challenges in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes)

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