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FASEB Journal : Official Publication of... Aug 2023Metabolic diseases are considered the primary culprit for physical and mental health of individuals. Although the diagnosis of these diseases is relatively easy, more... (Review)
Review
Metabolic diseases are considered the primary culprit for physical and mental health of individuals. Although the diagnosis of these diseases is relatively easy, more effective and convenient potent drugs are still being explored. Ca across the inner mitochondrial membrane is a vital intracellular messenger that regulates energy metabolism and cellular Ca homeostasis and is involved in cell death. Mitochondria rely on a selective mitochondrial Ca unidirectional transport complex (MCU complex) in their inner membrane for Ca uptake. We found that the channel contains several subunits and undergoes dramatic transformations in various pathological processes, especially in metabolic diseases. In this way, we believe that the MCU complex becomes a target with significant potential for these diseases. However, there is no review linking the two factors, thus hindering the possibility of new drug production. Here, we highlight the connection between MCU complex-related Ca transport and the pathophysiology of metabolic diseases, adding understanding and insight at the molecular level to provide new insights for targeting MCU to reverse metabolism-related diseases.
Topics: Humans; Mitochondria; Biological Transport; Cell Death; Energy Metabolism; Metabolic Diseases
PubMed: 37389546
DOI: 10.1096/fj.202300218R -
Nanoscale Feb 2024PROteolysis TArgeting Chimeras (PROTACs), as a recently identified technique in the field of new drug development, provide new concepts for disease treatment and are... (Review)
Review
PROteolysis TArgeting Chimeras (PROTACs), as a recently identified technique in the field of new drug development, provide new concepts for disease treatment and are expected to revolutionize drug discovery. With high specificity and flexibility, PROTACs serve as an innovative research tool to target and degrade disease-relevant proteins that are not currently pharmaceutically vulnerable to eliminating their functions by hijacking the ubiquitin-proteasome system. To date, PROTACs still face the challenges of low solubility, poor permeability, off-target effects, and metabolic instability. The combination of nanotechnology and PROTACs has been explored to enhance the performance of PROTACs regarding overcoming these challenging hurdles. In this review, we summarize the latest advancements in the building-block design of PROTAC prodrug nanoparticles and provide an overview of existing/potential delivery systems and loading approaches for PROTAC drugs. Furthermore, we discuss the current status and prospects of the split-and-mix approach for PROTAC drug optimization. Additionally, the advantages and translational potentials of carrier-free nano-PROTACs and their combinational therapeutic effects are highlighted. This review aims to foster a deeper understanding of this rapidly evolving field and facilitate the progress of nano-PROTACs that will continue to push the boundaries of achieving selectivity and controlled release of PROTAC drugs.
Topics: Proteolysis; Proteolysis Targeting Chimera; Proteasome Endopeptidase Complex; Proteins; Drug Discovery
PubMed: 38305466
DOI: 10.1039/d3nr06059d -
Biomolecules Mar 2024Diabetes and its associated complications have increasingly become major challenges for global healthcare. The current therapeutic strategies involve insulin replacement... (Review)
Review
Diabetes and its associated complications have increasingly become major challenges for global healthcare. The current therapeutic strategies involve insulin replacement therapy for type 1 diabetes (T1D) and small-molecule drugs for type 2 diabetes (T2D). Despite these advances, the complex nature of diabetes necessitates innovative clinical interventions for effective treatment and complication prevention. Accumulative evidence suggests that protein post-translational modifications (PTMs), including glycosylation, phosphorylation, acetylation, and SUMOylation, play important roles in diabetes and its pathological consequences. Therefore, the investigation of these PTMs not only sheds important light on the mechanistic regulation of diabetes but also opens new avenues for targeted therapies. Here, we offer a comprehensive overview of the role of several PTMs in diabetes, focusing on the most recent advances in understanding their functions and regulatory mechanisms. Additionally, we summarize the pharmacological interventions targeting PTMs that have advanced into clinical trials for the treatment of diabetes. Current challenges and future perspectives are also provided.
Topics: Humans; Diabetes Mellitus, Type 2; Protein Processing, Post-Translational; Phosphorylation; Glycosylation; Sumoylation
PubMed: 38540730
DOI: 10.3390/biom14030310 -
International Journal of Molecular... Aug 2023Nonalcoholic fatty liver disease (NAFLD, including nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH)) is a high-prevalence disorder, affecting... (Review)
Review
Nonalcoholic fatty liver disease (NAFLD, including nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH)) is a high-prevalence disorder, affecting about 1 billion people, which can evolve to more severe conditions like cirrhosis or hepatocellular carcinoma. NAFLD is often concomitant with conditions of the metabolic syndrome, such as central obesity and insulin-resistance, but a specific drug able to revert NAFL and prevent its evolution towards NASH is still lacking. With the liver being a key organ in metabolic processes, the potential therapeutic strategies are many, and range from directly targeting the lipid metabolism to the prevention of tissue inflammation. However, side effects have been reported for the drugs tested up to now. In this review, different approaches to the treatment of NAFLD are presented, including newer therapies and ongoing clinical trials. Particular focus is placed on the reverse cholesterol transport system and on the agonists for nuclear factors like PPAR and FXR, but also drugs initially developed for other conditions such as incretins and thyromimetics along with validated natural compounds that have anti-inflammatory potential. This work provides an overview of the different therapeutic strategies currently being tested for NAFLD, other than, or along with, the recommendation of weight loss.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Lipid Metabolism; Biological Transport; Liver Neoplasms
PubMed: 37628929
DOI: 10.3390/ijms241612748 -
Expert Opinion on Drug Metabolism &... 2024Pregnane X receptor (PXR) is a master xenobiotic sensor that transcriptionally controls drug metabolism and disposition pathways. PXR activation by pharmaceutical drugs,... (Review)
Review
INTRODUCTION
Pregnane X receptor (PXR) is a master xenobiotic sensor that transcriptionally controls drug metabolism and disposition pathways. PXR activation by pharmaceutical drugs, natural products, environmental toxins, etc. may decrease drug efficacy and increase drug-drug interactions and drug toxicity, indicating a therapeutic value for PXR antagonists. However, PXR's functions in physiological events, such as intestinal inflammation, indicate that PXR activators may be useful in certain disease contexts.
AREAS COVERED
We review the reported roles of PXR in various physiological and pathological processes including drug metabolism, cancer, inflammation, energy metabolism, and endobiotic homeostasis. We then highlight specific cellular and chemical routes that modulate PXR activity and discuss the functional consequences. Databases searched and inclusive dates: PubMed, 1 January 1980 to 10 January 2024.
EXPERT OPINION
Knowledge of PXR's drug metabolism function has helped drug developers produce small molecules without PXR-mediated metabolic liabilities, and further understanding of PXR's cellular functions may offer drug development opportunities in multiple disease settings.
Topics: Humans; Pregnane X Receptor; Receptors, Steroid; Inactivation, Metabolic; Inflammation
PubMed: 38251638
DOI: 10.1080/17425255.2024.2309212 -
Drug Metabolism and Disposition: the... Oct 2023
Topics: Inactivation, Metabolic; Metabolic Clearance Rate
PubMed: 37709358
DOI: 10.1124/dmd.123.001480 -
Molecules (Basel, Switzerland) Sep 2023Glycomimetics, which are synthetic molecules designed to mimic the structures and functions of natural carbohydrates, have been developed to overcome the limitations... (Review)
Review
Glycomimetics, which are synthetic molecules designed to mimic the structures and functions of natural carbohydrates, have been developed to overcome the limitations associated with natural carbohydrates. The fluorination of carbohydrates has emerged as a promising solution to dramatically enhance the metabolic stability, bioavailability, and protein-binding affinity of natural carbohydrates. In this review, the fluorination methods used to prepare the fluorinated carbohydrates, the effects of fluorination on the physical, chemical, and biological characteristics of natural sugars, and the biological activities of fluorinated sugars are presented.
Topics: Fluorine; Drug Discovery; Carbohydrates; Sugars; Biological Availability; Halogenation
PubMed: 37764416
DOI: 10.3390/molecules28186641 -
Molecules (Basel, Switzerland) Dec 2023Drug bioavailability is a crucial aspect of pharmacology, affecting the effectiveness of drug therapy. Understanding how drugs are absorbed, distributed, metabolized,... (Review)
Review
Drug bioavailability is a crucial aspect of pharmacology, affecting the effectiveness of drug therapy. Understanding how drugs are absorbed, distributed, metabolized, and eliminated in patients' bodies is essential to ensure proper and safe treatment. This publication aims to highlight the relevance of drug bioavailability research and its importance in therapy. In addition to biochemical activity, bioavailability also plays a critical role in achieving the desired therapeutic effects. This may seem obvious, but it is worth noting that a drug can only produce the expected effect if the proper level of concentration can be achieved at the desired point in a patient's body. Given the differences between patients, drug dosages, and administration forms, understanding and controlling bioavailability has become a priority in pharmacology. This publication discusses the basic concepts of bioavailability and the factors affecting it. We also looked at various methods of assessing bioavailability, both in the laboratory and in the clinic. Notably, the introduction of new technologies and tools in this field is vital to achieve advances in drug bioavailability research. This publication also discusses cases of drugs with poorly described bioavailability, providing a deeper understanding of the complex challenges they pose to medical researchers and practitioners. Simultaneously, the article focuses on the perspectives and trends that may shape the future of research regarding bioavailability, which is crucial to the development of modern pharmacology and drug therapy. In this context, the publication offers an essential, meaningful contribution toward understanding and highlighting bioavailability's role in reliable patient treatment. The text also identifies areas that require further research and exploration.
Topics: Humans; Pharmaceutical Preparations; Biological Availability
PubMed: 38138529
DOI: 10.3390/molecules28248038 -
Ageing Research Reviews Jun 2024Cellular senescence is a kind of cellular state triggered by endogenous or exogenous stimuli, which is mainly characterized by stable cell cycle arrest and complex... (Review)
Review
Cellular senescence is a kind of cellular state triggered by endogenous or exogenous stimuli, which is mainly characterized by stable cell cycle arrest and complex senescence-associated secretory phenotype (SASP). Once senescent cells accumulate in tissues, they may eventually accelerate the progression of age-related diseases, such as atherosclerosis, osteoarthritis, chronic lung diseases, cancers, etc. Recent studies have shown that the disorders of lipid metabolism are not only related to age-related diseases, but also regulate the cellular senescence process. Based on existing research evidences, the changes in lipid metabolism in senescent cells are mainly concentrated in the metabolic processes of phospholipids, fatty acids and cholesterol. Obviously, the changes in lipid-metabolizing enzymes and proteins involved in these pathways play a critical role in senescence. However, the link between cellular senescence, changes in lipid metabolism and age-related disease remains to be elucidated. Herein, we summarize the lipid metabolism changes in senescent cells, especially the senescent cells that promote age-related diseases, as well as focusing on the role of lipid-related enzymes or proteins in senescence. Finally, we explore the prospect of lipids in cellular senescence and their potential as drug targets for preventing and delaying age-related diseases.
Topics: Humans; Cellular Senescence; Lipid Metabolism; Aging; Animals; Lipids
PubMed: 38583577
DOI: 10.1016/j.arr.2024.102294 -
Molecules (Basel, Switzerland) Jul 2023The kidney is critical in the human body's excretion of drugs and their metabolites. Renal transporters participate in actively secreting substances from the proximal... (Review)
Review
The kidney is critical in the human body's excretion of drugs and their metabolites. Renal transporters participate in actively secreting substances from the proximal tubular cells and reabsorbing them in the distal renal tubules. They can affect the clearance rates (CLr) of drugs and their metabolites, eventually influence the clinical efficiency and side effects of drugs, and may produce drug-drug interactions (DDIs) of clinical significance. Renal transporters and renal transporter-mediated DDIs have also been studied by many researchers. In this article, the main types of in vitro research models used for the study of renal transporter-mediated DDIs are membrane-based assays, cell-based assays, and the renal slice uptake model. In vivo research models include animal experiments, gene knockout animal models, positron emission tomography (PET) technology, and studies on human beings. In addition, in vitro-in vivo extrapolation (IVIVE), ex vivo kidney perfusion (EVKP) models, and, more recently, biomarker methods and in silico models are included. This article reviews the traditional research methods of renal transporter-mediated DDIs, updates the recent progress in the development of the methods, and then classifies and summarizes the advantages and disadvantages of each method. Through the sorting work conducted in this paper, it will be convenient for researchers at different learning stages to choose the best method for their own research based on their own subject's situation when they are going to study DDIs mediated by renal transporters.
Topics: Animals; Humans; Kidney; Membrane Transport Proteins; Drug Interactions; Biological Transport; Metabolic Clearance Rate; Pharmaceutical Preparations
PubMed: 37446913
DOI: 10.3390/molecules28135252