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Frontiers in Immunology 2024Excess dietary fructose consumption has been long proposed as a culprit for the world-wide increase of incidence in metabolic disorders and cancer within the past... (Review)
Review
Excess dietary fructose consumption has been long proposed as a culprit for the world-wide increase of incidence in metabolic disorders and cancer within the past decades. Understanding that cancer cells can gradually accumulate metabolic mutations in the tumor microenvironment, where glucose is often depleted, this raises the possibility that fructose can be utilized by cancer cells as an alternative source of carbon. Indeed, recent research has increasingly identified various mechanisms that show how cancer cells can metabolize fructose to support their proliferating and migrating needs. In light of this growing interest, this review will summarize the recent advances in understanding how fructose can metabolically reprogram different types of cancer cells, as well as how these metabolic adaptations can positively support cancer cells development and malignancy.
Topics: Humans; Fructose; Neoplasms; Tumor Microenvironment; Animals; Cellular Reprogramming; Energy Metabolism; Metabolic Reprogramming
PubMed: 38711514
DOI: 10.3389/fimmu.2024.1375461 -
Cellular Oncology (Dordrecht) Apr 2024Tumor-associated macrophages, as the major immunocytes in solid tumors, show divided loyalty and remarkable plasticity in tumorigenesis. Once the M2-to-M1 repolarization... (Review)
Review
BACKGROUND
Tumor-associated macrophages, as the major immunocytes in solid tumors, show divided loyalty and remarkable plasticity in tumorigenesis. Once the M2-to-M1 repolarization is achieved, they could be switched from the supporters for tumor development into the guardians for host immunity. Meanwhile, Lipid metabolic reprogramming is demonstrated to be one of the most important hallmarks of tumor-associated macrophages, which plays a decisive role in regulating their phenotypes and functions to promote tumorigenesis and immunotherapy resistance. Therefore, targeting the lipid metabolism of TAMs may provide a new direction for anti-tumor strategies.
CONCLUSION
In this review, we first summarized the origins, classifications and general lipid metabolic process of TAMs. Then we discussed the currently available drugs and interventions that target lipid metabolic disorders of TAMs, including those targeting lipid uptake, efflux, lipolysis, FAO and lipid peroxidation. Besides, based on the recent research status, we summarized the present challenges for this cancer immunotherapy, including the precise drug delivery system, the lipid metabolic heterogeneity, and the intricate lipid metabolic interactions in the TME, and we also proposed corresponding possible solutions. Collectively, we hope this review will give researchers a better understanding of the lipid metabolism of TAMs and lead to the development of corresponding anti-tumor therapies in the future.
Topics: Humans; Lipid Metabolism; Immunotherapy; Neoplasms; Tumor-Associated Macrophages; Animals; Tumor Microenvironment; Metabolic Reprogramming
PubMed: 37776422
DOI: 10.1007/s13402-023-00881-y -
Experimental & Molecular Medicine Oct 2023Posttranslational modification of proteins via ubiquitination determines their activation, translocation, dysregulation, or degradation. This process targets a large... (Review)
Review
Posttranslational modification of proteins via ubiquitination determines their activation, translocation, dysregulation, or degradation. This process targets a large number of cellular proteins, affecting all biological pathways involved in the cell cycle, development, growth, and differentiation. Thus, aberrant regulation of ubiquitination is likely associated with several diseases, including various types of metabolic diseases. Among the ubiquitin enzymes, E3 ubiquitin ligases are regarded as the most influential ubiquitin enzymes due to their ability to selectively bind and recruit target substrates for ubiquitination. Continued research on the regulatory mechanisms of E3 ligases and their adaptors in metabolic diseases will further stimulate the discovery of new targets and accelerate the development of therapeutic options for metabolic diseases. In this review, based on recent discoveries, we summarize new insights into the roles of E3 ubiquitin ligases and their adaptors in the pathogenesis of metabolic diseases by highlighting recent evidence obtained in both human and animal model studies.
Topics: Animals; Humans; Ubiquitin-Protein Ligases; Neoplasms; Ubiquitination; Ubiquitin; Metabolic Diseases
PubMed: 37779139
DOI: 10.1038/s12276-023-01087-w -
Journal of Chemical Information and... Nov 2023The metagenome of bacteria colonizing the human intestine is a set of genes that is almost 150 times greater than the set of host genes. Some of these genes encode...
The metagenome of bacteria colonizing the human intestine is a set of genes that is almost 150 times greater than the set of host genes. Some of these genes encode enzymes whose functioning significantly expands the number of potential pathways for xenobiotic metabolism. The resulting metabolites can exhibit activity different from that of the parent compound. This can decrease the efficacy of pharmacotherapy as well as induce undesirable and potentially life-threatening side effects. Thus, analysis of the biotransformation of small drug-like compounds mediated by the gut microbiota is an important step in the development of new pharmaceutical agents and repurposing of the approved drugs. research, the interaction of drug-like compounds with the gut microbiota is a multistep and time-consuming process. Systematic testing of large sets of chemical structures is associated with a number of challenges, including the lack of standardized techniques and significant financial costs to identify the structure of the final metabolites. Estimation of the compounds' ability to be biotransformed by the gut microbiota and prediction of the structures of their metabolites are possible . However, the development of computational approaches is limited by the lack of information about chemical structures metabolized by microbiota enzymes. The aim of this study is to create a database containing information on the metabolism of drug-like compounds by the gut microbiota. We created the data set containing information about 368 structures metabolized and 310 structures not metabolized by the human gut microbiota. The HGMMX database is freely available at https://www.way2drug.com/hgmmx. The information presented will be useful in the development of computational approaches for analyzing the impact of the human microbiota on metabolism of drug-like molecules.
Topics: Humans; Gastrointestinal Microbiome; Xenobiotics; Microbiota; Biotransformation; Databases, Factual
PubMed: 37871298
DOI: 10.1021/acs.jcim.3c00837 -
MBio Aug 2023Polyphenols are abundant in nature, and their anaerobic biodegradation by gut and soil bacteria is a topic of great interest. The O requirement of phenol oxidases is...
Polyphenols are abundant in nature, and their anaerobic biodegradation by gut and soil bacteria is a topic of great interest. The O requirement of phenol oxidases is thought to explain the microbial inertness of phenolic compounds in anoxic environments, such as peatlands, termed the enzyme latch hypothesis. A caveat of this model is that certain phenols are known to be degraded by strict anaerobic bacteria, although the biochemical basis for this process is incompletely understood. Here, we report the discovery and characterization of a gene cluster in the environmental bacterium for the degradation phloroglucinol (1,3,5-trihydroxybenzene), a key intermediate in the anaerobic degradation of flavonoids and tannins, which constitute the most abundant polyphenols in nature. The gene cluster encodes the key C-C cleavage enzyme dihydrophloroglucinol cyclohydrolase, as well as ()-3-hydroxy-5-oxo-hexanoate dehydrogenase and triacetate acetoacetate-lyase, which enable phloroglucinol to be utilized as a carbon and energy source. Bioinformatics studies revealed the presence of this gene cluster in phylogenetically and metabolically diverse gut and environmental bacteria, with potential impacts on human health and carbon preservation in peat soils and other anaerobic environmental niches. IMPORTANCE This study provides novel insights into the microbiota's anaerobic metabolism of phloroglucinol, a critical intermediate in the degradation of polyphenols in plants. Elucidation of this anaerobic pathway reveals enzymatic mechanisms for the degradation of phloroglucinol into short-chain fatty acids and acetyl-CoA, which are used as a carbon and energy source for bacterium growth. Bioinformatics studies suggested the prevalence of this pathway in phylogenetically and metabolically diverse gut and environmental bacteria, with potential impacts on carbon preservation in peat soils and human gut health.
Topics: Humans; Phloroglucinol; Anaerobiosis; Bacteria; Bacteria, Anaerobic; Phenols; Polyphenols; Soil
PubMed: 37341492
DOI: 10.1128/mbio.01099-23 -
World Journal of Surgical Oncology Oct 2023Lung cancer is a highly prevalent malignancy characterized by significant metabolic alterations. Understanding the metabolic rewiring in lung cancer is crucial for the... (Review)
Review
Lung cancer is a highly prevalent malignancy characterized by significant metabolic alterations. Understanding the metabolic rewiring in lung cancer is crucial for the development of effective therapeutic strategies. The hexosamine biosynthesis pathway (HBP) is a metabolic pathway that plays a vital role in cellular metabolism and has been implicated in various cancers, including lung cancer. Abnormal activation of HBP is involved in the proliferation, progression, metastasis, and drug resistance of tumor cells. In this review, we will discuss the function and regulation of metabolic enzymes related to HBP in lung cancer. Furthermore, the implications of targeting the HBP for lung cancer treatment are also discussed, along with the challenges and future directions in this field. This review provides a comprehensive understanding of the role and intervention of HBP in lung cancer. Future research focusing on the HBP in lung cancer is essential to uncover novel treatment strategies and improve patient outcomes.
Topics: Humans; Lung Neoplasms; Hexosamines; Biosynthetic Pathways
PubMed: 37880766
DOI: 10.1186/s12957-023-03226-z -
Genome Biology Oct 2023Xenobiotics are primarily metabolized by hepatocytes in the liver, and primary human hepatocytes are the gold standard model for the assessment of drug efficacy, safety,...
BACKGROUND
Xenobiotics are primarily metabolized by hepatocytes in the liver, and primary human hepatocytes are the gold standard model for the assessment of drug efficacy, safety, and toxicity in the early phases of drug development. Recent advances in single-cell genomics demonstrate liver zonation and ploidy as main drivers of cellular heterogeneity. However, little is known about the impact of hepatocyte specialization on liver function upon metabolic challenge, including hepatic metabolism, detoxification, and protein synthesis.
RESULTS
Here, we investigate the metabolic capacity of individual human hepatocytes in vitro. We assess how chronic accumulation of lipids enhances cellular heterogeneity and impairs the metabolisms of drugs. Using a phenotyping five-probe cocktail, we identify four functional subgroups of hepatocytes responding differently to drug challenge and fatty acid accumulation. These four subgroups display differential gene expression profiles upon cocktail treatment and xenobiotic metabolism-related specialization. Notably, intracellular fat accumulation leads to increased transcriptional variability and diminishes the drug-related metabolic capacity of hepatocytes.
CONCLUSIONS
Our results demonstrate that, upon a metabolic challenge such as exposure to drugs or intracellular fat accumulation, hepatocyte subgroups display different and heterogeneous transcriptional responses.
Topics: Humans; Hepatocytes; Liver; Fatty Acids
PubMed: 37848949
DOI: 10.1186/s13059-023-03075-9 -
Advanced Science (Weinheim,... Jan 2024Increasing numbers of studies have shown that tumor cells prefer fermentative glycolysis over oxidative phosphorylation to provide a vast amount of energy for fast... (Review)
Review
Increasing numbers of studies have shown that tumor cells prefer fermentative glycolysis over oxidative phosphorylation to provide a vast amount of energy for fast proliferation even under oxygen-sufficient conditions. This metabolic alteration not only favors tumor cell progression and metastasis but also increases lactate accumulation in solid tumors. In addition to serving as a byproduct of glycolytic tumor cells, lactate also plays a central role in the construction of acidic and immunosuppressive tumor microenvironment, resulting in therapeutic tolerance. Recently, targeted drug delivery and inherent therapeutic properties of nanomaterials have attracted great attention, and research on modulating lactate metabolism based on nanomaterials to enhance antitumor therapy has exploded. In this review, the advanced tumor therapy strategies based on nanomaterials that interfere with lactate metabolism are discussed, including inhibiting lactate anabolism, promoting lactate catabolism, and disrupting the "lactate shuttle". Furthermore, recent advances in combining lactate metabolism modulation with other therapies, including chemotherapy, immunotherapy, photothermal therapy, and reactive oxygen species-related therapies, etc., which have achieved cooperatively enhanced therapeutic outcomes, are summarized. Finally, foreseeable challenges and prospective developments are also reviewed for the future development of this field.
Topics: Humans; Prospective Studies; Neoplasms; Glycolysis; Lactates; Nanostructures; Tumor Microenvironment
PubMed: 37941489
DOI: 10.1002/advs.202305662 -
Journal of Controlled Release :... Aug 2023Oral administration of pharmaceuticals is the most preferred route of administration for patients, but it is challenging to effectively deliver active ingredients (APIs)... (Review)
Review
Oral administration of pharmaceuticals is the most preferred route of administration for patients, but it is challenging to effectively deliver active ingredients (APIs) that i) have extremely high or low solubility in intestinal fluids, ii) are large in size, iii) are subject to digestive and/or metabolic enzymes present in the gastrointestinal tract (GIT), brush border, and liver, and iv) are P-glycoprotein substrates. Over the past decades, efforts to increase the oral bioavailability of APIs have led to the development of nanoparticles (NPs) with non-specific uptake pathways (M cells, mucosal, and tight junctions) and target-specific uptake pathways (FcRn, vitamin B12, and bile acids). However, voluminous findings from preclinical models of different species rarely meet practical standards when translated to humans, and API concentrations in NPs are not within the adequate therapeutic window. Various NP oral delivery approaches studied so far show varying bioavailability impacted by a range of factors, such as species, GIT physiology, age, and disease state. This may cause difficulty in obtaining similar oral delivery efficacy when research results in animal models are translated into humans. This review describes the selection of parameters to be considered for translational potential when designing and developing oral NPs.
Topics: Animals; Humans; Pharmaceutical Preparations; Nanoparticles; Administration, Oral; Biological Availability; Biological Transport; Intestinal Absorption; Drug Carriers
PubMed: 37348679
DOI: 10.1016/j.jconrel.2023.06.024 -
The Pharmacogenomics Journal Nov 2023Codeine is metabolized by the CYP2D6 enzyme, and individuals with certain genetic variations of the CYP2D6 gene may metabolize codeine differently, leading to variable... (Review)
Review
Codeine is metabolized by the CYP2D6 enzyme, and individuals with certain genetic variations of the CYP2D6 gene may metabolize codeine differently, leading to variable efficacy and toxicity. Drug-drug interactions can also affect the metabolism of codeine. A tool to adjust codeine dose based on these factors does not currently exist. Healthcare providers should use their clinical judgment and reference different established dosing guidelines to determine the appropriate dose of codeine for individual patients. The study provides a tool that assists prescribers in adjusting codeine dose based on CYP2D6 gene-pair polymorphisms and drug-drug interactions. Highlighted is the need to consider pharmacogenetics and drug-drug interactions when determining the appropriate dosing of codeine and provide a framework for implementing individualized dosing based on these factors.
Topics: Humans; Codeine; Cytochrome P-450 CYP2D6; Analgesics, Opioid; Polymorphism, Genetic; Drug Interactions; Software
PubMed: 37940650
DOI: 10.1038/s41397-023-00318-7