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Current Opinion in Structural Biology Jun 2024Protein-protein interactions (PPIs) play a critical role in cellular signaling and represent interesting targets for therapeutic intervention. 14-3-3 proteins integrate... (Review)
Review
Protein-protein interactions (PPIs) play a critical role in cellular signaling and represent interesting targets for therapeutic intervention. 14-3-3 proteins integrate many signaling targets via PPIs and are frequently implicated in disease, making them intriguing drug targets. Here, we review the recent advances in the 14-3-3 field. It will discuss the roles 14-3-3 proteins play within the cell, elucidation of their expansive interactome, and the complex mechanisms that underpin their function. In addition, the review will discuss significant advances in the development of molecular glues that target 14-3-3 PPIs. In particular, it will focus on novel drug discovery and development methodologies that have delivered selective, potent, and drug-like molecules that could open new avenues for the development of precision molecular tools and medicines.
Topics: 14-3-3 Proteins; Humans; Protein Interaction Maps; Protein Binding; Drug Discovery; Signal Transduction; Animals; Protein Interaction Mapping
PubMed: 38685162
DOI: 10.1016/j.sbi.2024.102822 -
Endocrinology and Metabolism (Seoul,... Jun 2024Thyroid cancer is a common endocrine malignancy with increasing incidence globally. Although most cases can be treated effectively, some cases are more aggressive and... (Review)
Review
Thyroid cancer is a common endocrine malignancy with increasing incidence globally. Although most cases can be treated effectively, some cases are more aggressive and have a higher risk of mortality. Inhibiting RET and BRAF kinases has emerged as a potential therapeutic strategy for the treatment of thyroid cancer, particularly in cases of advanced or aggressive disease. However, the development of resistance mechanisms may limit the efficacy of these kinase inhibitors. Therefore, developing precise strategies to target thyroid cancer cell metabolism and overcome resistance is a critical area of research for advancing thyroid cancer treatment. In the field of cancer therapeutics, researchers have explored combinatorial strategies involving dual metabolic inhibition and metabolic inhibitors in combination with targeted therapy, chemotherapy, and immunotherapy to overcome the challenge of metabolic plasticity. This review highlights the need for new therapeutic approaches for thyroid cancer and discusses promising metabolic inhibitors targeting thyroid cancer. It also discusses the challenges posed by metabolic plasticity in the development of effective strategies for targeting cancer cell metabolism and explores the potential advantages of combined metabolic targeting.
Topics: Humans; Thyroid Neoplasms; Protein Kinase Inhibitors; Cellular Reprogramming; Molecular Targeted Therapy; Metabolic Reprogramming
PubMed: 38853437
DOI: 10.3803/EnM.2023.1802 -
Antioxidants & Redox Signaling Jul 2023Protein persulfidation (the formation of RSSH), an evolutionarily conserved oxidative posttranslational modification in which thiol groups in cysteine residues are... (Review)
Review
Protein persulfidation (the formation of RSSH), an evolutionarily conserved oxidative posttranslational modification in which thiol groups in cysteine residues are converted into persulfides, has emerged as one of the main mechanisms through which hydrogen sulfide (HS) conveys its signaling. New methodological advances in persulfide labeling started unraveling the chemical biology of this modification and its role in (patho)physiology. Some of the key metabolic enzymes are regulated by persulfidation. RSSH levels are important for the cellular defense against oxidative injury, and they decrease with aging, leaving proteins vulnerable to oxidative damage. Persulfidation is dysregulated in many diseases. A relatively new field of signaling by protein persulfidation still has many unanswered questions: the mechanism(s) of persulfide formation and transpersulfidation and the identification of "protein persulfidases," the improvement of methods to monitor RSSH changes and identify protein targets, and understanding the mechanisms through which this modification controls important (patho)physiological functions. Deep mechanistic studies using more selective and sensitive RSSH labeling techniques will provide high-resolution structural, functional, quantitative, and spatiotemporal information on RSSH dynamics and help with better understanding how HS-derived protein persulfidation affects protein structure and function in health and disease. This knowledge could pave the way for targeted drug design for a wide variety of pathologies. 39, 19-39.
Topics: Sulfides; Hydrogen Sulfide; Signal Transduction; Oxidative Stress; Oxidation-Reduction; Biology
PubMed: 37288744
DOI: 10.1089/ars.2023.0352 -
International Journal of Molecular... Dec 2023Sphingolipids are involved in cell signaling and metabolic pathways, and their metabolites play a critical role in host defense against intracellular pathogens. Here, we... (Review)
Review
Sphingolipids are involved in cell signaling and metabolic pathways, and their metabolites play a critical role in host defense against intracellular pathogens. Here, we review the known mechanisms of sphingolipids in viral infections and discuss the potential implication of the study of sphingolipid metabolism in vaccine and therapeutic development.
Topics: Humans; Sphingolipids; Virus Diseases; Signal Transduction; Lipid Metabolism; Metabolic Networks and Pathways; Sphingosine
PubMed: 38139132
DOI: 10.3390/ijms242417303 -
Biomedicine & Pharmacotherapy =... Dec 2023Triple-negative breast cancer (TNBC), the most aggressive form of breast cancer, presents severe threats to women's health. Therefore, it is critical to find novel... (Review)
Review
Triple-negative breast cancer (TNBC), the most aggressive form of breast cancer, presents severe threats to women's health. Therefore, it is critical to find novel treatment approaches. Ferroptosis, a newly identified form of programmed cell death, is marked by the buildup of lipid reactive oxygen species (ROS) and high iron concentrations. According to previous studies, ferroptosis sensitivity can be controlled by a number of metabolic events in cells, such as amino acid metabolism, iron metabolism, and lipid metabolism. Given that TNBC tumors are rich in iron and lipids, inducing ferroptosis in these tumors is a potential approach for TNBC treatment. Notably, the metabolic adaptability of cancer cells allows them to coordinate an attack on one or more metabolic pathways to initiate ferroptosis, offering a novel perspective to improve the high drug resistance and clinical therapy of TNBC. However, a clear picture of ferroptosis in TNBC still needs to be completely revealed. In this review, we provide an overview of recent advancements regarding the connection between ferroptosis and amino acid, iron, and lipid metabolism in TNBC. We also discuss the probable significance of ferroptosis as an innovative target for chemotherapy, radiotherapy, immunotherapy, nanotherapy and natural product therapy in TNBC, highlighting its therapeutic potential and application prospects.
Topics: Female; Humans; Triple Negative Breast Neoplasms; Ferroptosis; Lipid Metabolism; Amino Acids; Iron; Cell Line, Tumor
PubMed: 37951026
DOI: 10.1016/j.biopha.2023.115866 -
Bone Research Dec 2023Although aging has traditionally been viewed as the most important risk factor for osteoarthritis (OA), an increasing amount of epidemiological evidence has highlighted... (Review)
Review
Although aging has traditionally been viewed as the most important risk factor for osteoarthritis (OA), an increasing amount of epidemiological evidence has highlighted the association between metabolic abnormalities and OA, particularly in younger individuals. Metabolic abnormalities, such as obesity and type II diabetes, are strongly linked to OA, and they affect both weight-bearing and non-weight-bearing joints, thus suggesting that the pathogenesis of OA is more complicated than the mechanical stress induced by overweight. This review aims to explore the recent advances in research on the relationship between metabolic abnormalities and OA risk, including the impact of abnormal glucose and lipid metabolism, the potential pathogenesis and targeted therapeutic strategies.
Topics: Humans; Diabetes Mellitus, Type 2; Osteoarthritis; Obesity; Risk Factors; Lipid Metabolism
PubMed: 38052778
DOI: 10.1038/s41413-023-00301-9 -
Clinical and Translational Medicine Jan 2024One-carbon (1C) metabolism is a metabolic network that plays essential roles in biological reactions. In 1C metabolism, a series of nutrients are used to fuel metabolic... (Review)
Review
BACKGROUND
One-carbon (1C) metabolism is a metabolic network that plays essential roles in biological reactions. In 1C metabolism, a series of nutrients are used to fuel metabolic pathways, including nucleotide metabolism, amino acid metabolism, cellular redox defence and epigenetic maintenance. At present, 1C metabolism is considered the hallmark of cancer. The 1C units obtained from the metabolic pathways increase the proliferation rate of cancer cells. In addition, anticancer drugs, such as methotrexate, which target 1C metabolism, have long been used in the clinic. In terms of immunotherapy, 1C metabolism has been used to explore biomarkers connected with immunotherapy response and immune-related adverse events in patients.
METHODS
We collected numerous literatures to explain the roles of one-carbon metabolism in cancer immunotherapy.
RESULTS
In this review, we focus on the important pathways in 1C metabolism and the function of 1C metabolism enzymes in cancer immunotherapy. Then, we summarise the inhibitors acting on 1C metabolism and their potential application on cancer immunotherapy. Finally, we provide a viewpoint and conclusion regarding the opportunities and challenges of targeting 1C metabolism for cancer immunotherapy in clinical practicability in the future.
CONCLUSION
Targeting one-carbon metabolism is useful for cancer immunotherapy.
Topics: Humans; Neoplasms; Antineoplastic Agents; Metabolic Networks and Pathways; Carbon
PubMed: 38279895
DOI: 10.1002/ctm2.1521 -
Clinical and Translational Medicine Nov 2023The study and synthesis of membrane organelles are becoming increasingly important, not only as simplified cellular models for corresponding molecular and metabolic... (Review)
Review
BACKGROUND
The study and synthesis of membrane organelles are becoming increasingly important, not only as simplified cellular models for corresponding molecular and metabolic studies but also for applications in synthetic biology of artificial cells and drug delivery vehicles. Lipid droplets (LDs) are central organelles in cellular lipid metabolism and are involved in almost all metabolic processes. Multiple studies have also demonstrated a high correlation between LDs and metabolic diseases. During these processes, LDs reveal a highly dynamic character, with their lipid fraction, protein composition and subcellular localisation constantly changing in response to metabolic demands. However, the molecular mechanisms underlying these functions have not been fully understood due to the limitations of cell biology approaches. Fortunately, developments in synthetic biology have provided a huge breakthrough for metabolism research, and methods for in vitro synthesis of LDs have been successfully established, with great advances in protein binding, lipid function, membrane dynamics and enzymatic reactions.
AIMS AND METHODS
In this review, we provide a comprehensive overview of the assembly and function of endogenous LDs, from the generation of lipid molecules to how they are assembled into LDs in the endoplasmic reticulum. In particular, we highlight two major classes of synthetic LD models for fabrication techniques and their recent advances in biology and explore their roles and challenges in achieving real applications of artificial LDs in the future.
Topics: Humans; Lipid Droplets; Lipid Metabolism; Endoplasmic Reticulum; Lipids; Metabolic Diseases
PubMed: 37997538
DOI: 10.1002/ctm2.1441 -
Biomedicine & Pharmacotherapy =... Sep 2023Cardiovascular diseases are the main killers threatening human health. Many studies have shown that abnormal energy metabolism plays a key role in the occurrence and... (Review)
Review
Cardiovascular diseases are the main killers threatening human health. Many studies have shown that abnormal energy metabolism plays a key role in the occurrence and development of acute and chronic cardiovascular diseases. Regulating cardiac energy metabolism is a frontier topic in the treatment of cardiovascular diseases. However, we are not very clear about the choice of different substrates, the specific mechanism of energy metabolism participating in the course of cardiovascular disease, and how to develop appropriate drugs to regulate energy metabolism to treat cardiovascular disease. Therefore, this paper reviews how energy metabolism participates in cardiovascular pathophysiological processes and potential drugs aimed at interfering energy metabolism.It is expected to provide good suggestions for promoting the clinical prevention and treatment of cardiovascular diseases from the perspective of energy metabolism.
Topics: Humans; Cardiovascular Diseases; Energy Metabolism
PubMed: 37544284
DOI: 10.1016/j.biopha.2023.115271 -
Biomedicine & Pharmacotherapy =... May 2024Ferroptosis, distinct from apoptosis, necrosis, autophagy, and other types of cell death, is a novel iron-dependent regulated cell death characterized by the... (Review)
Review
Ferroptosis, distinct from apoptosis, necrosis, autophagy, and other types of cell death, is a novel iron-dependent regulated cell death characterized by the accumulation of lipid peroxides and redox imbalance with distinct morphological, biochemical, and genetic features. Dysregulation of iron homeostasis, the disruption of antioxidative stress pathways and lipid peroxidation are crucial in ferroptosis. Ferroptosis is involved in the pathogenesis of several cardiovascular diseases, including atherosclerosis, cardiomyopathy, myocardial infarction, ischemia-reperfusion injury, abdominal aortic aneurysm, aortic dissection, and heart failure. Therefore, a comprehensive understanding of the mechanisms that regulate ferroptosis in cardiovascular diseases will enhance the prevention and treatment of these diseases. This review discusses the latest findings on the molecular mechanisms of ferroptosis and its regulation in cardiovascular diseases, the application of ferroptosis modulators in cardiovascular diseases, and the role of traditional Chinese medicines in ferroptosis regulation to provide a comprehensive understanding of the pathogenesis of cardiovascular diseases and identify new prevention and treatment options.
Topics: Ferroptosis; Humans; Cardiovascular Diseases; Animals; Iron; Lipid Peroxidation; Oxidative Stress
PubMed: 38518600
DOI: 10.1016/j.biopha.2024.116457