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Diabetologia Mar 2024Beyond their conventional roles in intracellular energy production, some traditional metabolites also function as extracellular messengers that activate cell-surface... (Review)
Review
Beyond their conventional roles in intracellular energy production, some traditional metabolites also function as extracellular messengers that activate cell-surface G-protein-coupled receptors (GPCRs) akin to hormones and neurotransmitters. These signalling metabolites, often derived from nutrients, the gut microbiota or the host's intermediary metabolism, are now acknowledged as key regulators of various metabolic and immune responses. This review delves into the multi-dimensional aspects of succinate, a dual metabolite with roots in both the mitochondria and microbiome. It also connects the dots between succinate's role in the Krebs cycle, mitochondrial respiration, and its double-edge function as a signalling transmitter within and outside the cell. We aim to provide an overview of the role of the succinate-succinate receptor 1 (SUCNR1) axis in diabetes, discussing the potential use of succinate as a biomarker and the novel prospect of targeting SUCNR1 to manage complications associated with diabetes. We further propose strategies to manipulate the succinate-SUCNR1 axis for better diabetes management; this includes pharmacological modulation of SUCNR1 and innovative approaches to manage succinate concentrations, such as succinate administration and indirect strategies, like microbiota modulation. The dual nature of succinate, both in terms of origins and roles, offers a rich landscape for understanding the intricate connections within metabolic diseases, like diabetes, and indicates promising pathways for developing new therapeutic strategies.
Topics: Humans; Diabetes Mellitus, Type 2; Receptors, G-Protein-Coupled; Signal Transduction; Succinates
PubMed: 38182909
DOI: 10.1007/s00125-023-06063-7 -
Current Opinion in Endocrinology,... Apr 2024Low-density lipoproteins (LDL) cause atherosclerotic cardiovascular disease, a condition associated with significant morbidity and mortality. Statins represent the... (Review)
Review
PURPOSE OF REVIEW
Low-density lipoproteins (LDL) cause atherosclerotic cardiovascular disease, a condition associated with significant morbidity and mortality. Statins represent the cornerstone for preventing cardiovascular events in patients with elevated LDL-cholesterol (LDL-C) levels, however, they are associated with frequent musculoskeletal adverse effects, which lead to drug discontinuation or limit their use to low (and less effective) doses. Bempedoic acid (BA) is a newly approved, safe, cholesterol-lowering agent that inhibits ATP-citrate lyase, an enzyme upstream to 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, the target of statins. Unlike statins, BA is not associated with musculoskeletal side effects, representing a promising drug for statin-intolerant patients. This review aims to summarize the current evidence on the efficacy, safety, and impact on clinical outcomes of BA, to review current indications for its use, and to highlight the ongoing clinical trials that will help deepen our knowledge of this promising compound.
RECENT FINDINGS
BA improves clinical outcomes in statin-intolerant patients. Multiple ongoing studies are evaluating whether BA can be employed in other clinical settings.
SUMMARY
BA safely and effectively reduces the levels of multiple atherogenic markers and can be employed to reach LDL-C targets independently from statin tolerance.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cholesterol, LDL; Hypercholesterolemia; Cholesterol; Atherosclerosis; Biomarkers; Dicarboxylic Acids; Fatty Acids
PubMed: 38095480
DOI: 10.1097/MED.0000000000000853 -
Inflammation Research : Official... Dec 2023Kidney stones commonly occur with a 50% recurrence rate within 5 years, and can elevate the risk of chronic kidney disease. Macrophage-to-myofibroblast transition (MMT)...
OBJECTIVE AND DESIGN
Kidney stones commonly occur with a 50% recurrence rate within 5 years, and can elevate the risk of chronic kidney disease. Macrophage-to-myofibroblast transition (MMT) is a newly discovered mechanism that leads to progressive fibrosis in different forms of kidney disease. In this study, we aimed to investigate the role of MMT in renal fibrosis in glyoxylate-induced kidney stone mice and the mechanism by which signal transducer and activator of transcription 6 (STAT6) regulates MMT.
METHODS
We collected non-functioning kidneys from patients with stones, established glyoxylate-induced calcium oxalate stone mice model and treated AS1517499 every other day in the treatment group, and constructed a STAT6-knockout RAW264.7 cell line. We first screened the enrichment pathway of the model by transcriptome sequencing; detected renal injury and fibrosis by hematoxylin eosin staining, Von Kossa staining and Sirius red staining; detected MMT levels by multiplexed immunofluorescence and flow cytometry; and verified the binding site of STAT6 at the PPARα promoter by chromatin immunoprecipitation. Fatty acid oxidation (FAO) and fibrosis-related genes were detected by western blot and real-time quantitative polymerase chain reaction.
RESULTS
In this study, we found that FAO was downregulated, macrophages converted to myofibroblasts, and STAT6 expression was elevated in stone patients and glyoxylate-induced kidney stone mice. The promotion of FAO in macrophages attenuated MMT and upregulated fibrosis-related genes induced by calcium oxalate treatment. Further, inhibition of peroxisome proliferator-activated receptor-α (PPARα) eliminated the effect of STAT6 deletion on FAO and fibrosis-associated protein expression. Pharmacological inhibition of STAT6 also prevented the development of renal injury, lipid accumulation, MMT, and renal fibrosis. Mechanistically, STAT6 transcriptionally represses PPARα and FAO through cis-inducible elements located in the promoter region of the gene, thereby promoting MMT and renal fibrosis.
CONCLUSIONS
These findings establish a role for STAT6 in kidney stone injury-induced renal fibrosis, and suggest that STAT6 may be a therapeutic target for progressive renal fibrosis in patients with nephrolithiasis.
Topics: Animals; Humans; Mice; Calcium Oxalate; Fatty Acids; Fibrosis; Glyoxylates; Kidney; Kidney Calculi; Macrophages; Myofibroblasts; Oxalates; PPAR alpha; STAT6 Transcription Factor
PubMed: 37924395
DOI: 10.1007/s00011-023-01803-2 -
Bioorganic Chemistry Feb 2024Antibody-Drug Conjugates (ADC) are a new class of anticancer therapeutics with immense potential. They have been rapidly advancing in the last two decades. This fast... (Review)
Review
Antibody-Drug Conjugates (ADC) are a new class of anticancer therapeutics with immense potential. They have been rapidly advancing in the last two decades. This fast speed of development has become possible due to several new technologies and methods. One of them is Click Chemistry, an approach that was created only two decades ago, but already is actively utilized for bioconjugation, material science and drug discovery. In this review, we researched the impact of Click Chemistry reactions on the synthesis and development of ADCs. The information about the most frequently utilized reactions, such as Michael's addition, Copper-catalyzed azide-alkyne [3+2] cycloaddition (CuAAC), Strain-promoted azide-alkyne [3+2] cycloaddition (SPAAC), oxime bond formation, hydrazine-iso-Pictet-Spengler Ligation (HIPS), Diels-Alder reactions have been summarized. The implementation of thiol-maleimide Click Chemistry reaction in the synthesis of numerous FDA-approved Antibody-Drug Conjugates has been reported. The data amassed in the present review provides better understanding of the importance of Click Chemistry in the synthesis, development and improvement of the Antibody-Drug Conjugates and it will be helpful for further researches related to ADCs.
Topics: Click Chemistry; Azides; Alkynes; Cycloaddition Reaction; Copper; Maleimides; Sulfhydryl Compounds
PubMed: 37995642
DOI: 10.1016/j.bioorg.2023.106982 -
Journal of Agricultural and Food... Mar 2024Mid-to-long-chain dicarboxylic acids (DCA, ≥ 6) are organic compounds in which two carboxylic acid functional groups are present at the terminal position of the... (Review)
Review
Mid-to-long-chain dicarboxylic acids (DCA, ≥ 6) are organic compounds in which two carboxylic acid functional groups are present at the terminal position of the carbon chain. These acids find important applications as structural components and intermediates across various industrial sectors, including organic compound synthesis, food production, pharmaceutical development, and agricultural manufacturing. However, conventional petroleum-based DCA production methods cause environmental pollution, making sustainable development challenging. Hence, the demand for eco-friendly processes and renewable raw materials for DCA production is rising. Owing to advances in systems metabolic engineering, new tools from systems biology, synthetic biology, and evolutionary engineering can now be used for the sustainable production of energy-dense biofuels. Here, we explore systems metabolic engineering strategies for DCA synthesis in various chassis via the conversion of different raw materials into mid-to-long-chain DCAs. Subsequently, we discuss the future challenges in this field and propose synthetic biology approaches for the efficient production and successful commercialization of these acids.
Topics: Metabolic Engineering; Dicarboxylic Acids; Acids; Biofuels; Organic Chemicals
PubMed: 38442481
DOI: 10.1021/acs.jafc.4c00002 -
Endocrinology and Metabolism (Seoul,... Aug 2023Hepatic stellate cells (HSCs) are the major cells which play a pivotal role in liver fibrosis. During injury, extracellular stimulators can induce HSCs...
BACKGRUOUND
Hepatic stellate cells (HSCs) are the major cells which play a pivotal role in liver fibrosis. During injury, extracellular stimulators can induce HSCs transdifferentiated into active form. Phloretin showed its ability to protect the liver from injury, so in this research we would like to investigate the effect of phloretin on succinate-induced HSCs activation in vitro and liver fibrosis in vivo study.
METHODS
In in vitro, succinate was used to induce HSCs activation, and then the effect of phloretin on activated HSCs was examined. In in vivo, succinate was used to generated liver fibrosis in mouse and phloretin co-treated to check its protection on the liver.
RESULTS
Phloretin can reduce the increase of fibrogenic markers and inhibits the proliferation, migration, and contraction caused by succinate in in vitro experiments. Moreover, an upregulation of proteins associated with aerobic glycolysis occurred during the activation of HSCs, which was attenuated by phloretin treatment. In in vivo experiments, intraperitoneal injection of phloretin decreased expression of fibrotic and glycolytic markers in the livers of mice with sodium succinate diet-induced liver fibrosis. These results suggest that aerobic glycolysis plays critical role in activation of HSCs and succinate can induce liver fibrosis in mice, whereas phloretin has therapeutic potential for treating hepatic fibrosis.
CONCLUSION
Intraperitoneal injection of phloretin attenuated succinate-induced hepatic fibrosis and alleviates the succinate-induced HSCs activation.
Topics: Mice; Animals; Succinic Acid; Phloretin; Hepatic Stellate Cells; Liver Cirrhosis
PubMed: 37533177
DOI: 10.3803/EnM.2023.1661 -
Current Microbiology Apr 2024Dicarboxylic acid (DCA) is a multifaceted chemical intermediate, recoursed to produce many industrially important products such as adhesives, plasticizers, lubricants,... (Review)
Review
Dicarboxylic acid (DCA) is a multifaceted chemical intermediate, recoursed to produce many industrially important products such as adhesives, plasticizers, lubricants, polymers, etc. To bypass the shortcomings of the chemical methods of synthesis of DCA and to reduce fossil fuel footprints, bio-based synthesis is gaining attention. In pursuit of an eco-friendly sustainable alternative method of DCA production, microbial cell factories, and renewable organic resources are gaining popularity. Among the plethora of microbial communities, yeast is being favored industrially compared to bacterial fermentation due to its hyperosmotic and low pH tolerance and flexibility for gene manipulations. By application of rapidly evolving genetic manipulation techniques, the bio-based DCA production could be made more precise and economical. To bridge the gap between supply and demand of DCA, many strategies are employed to improve the fermentation. This review briefly outlines the advancements in DCA production using yeast cell factories with the exemplification of strain improvement strategies.
Topics: Saccharomyces cerevisiae; Fermentation; Dicarboxylic Acids; Metabolic Engineering
PubMed: 38642080
DOI: 10.1007/s00284-024-03654-4 -
International Journal of Molecular... Mar 2024Kidney stone disease (KSD) is one of the most common urological diseases. The incidence of kidney stones has increased dramatically in the last few decades. Kidney... (Review)
Review
Kidney stone disease (KSD) is one of the most common urological diseases. The incidence of kidney stones has increased dramatically in the last few decades. Kidney stones are mineral deposits in the calyces or the pelvis, free or attached to the renal papillae. They contain crystals and organic components, and they are made when urine is supersaturated with minerals. Calcium-containing stones are the most common, with calcium oxalate as the main component of most stones. However, many of these form on a calcium phosphate matrix called Randall's plaque, which is found on the surface of the kidney papilla. The etiology is multifactorial, and the recurrence rate is as high as 50% within 5 years after the first stone onset. There is a great need for recurrence prevention that requires a better understanding of the mechanisms involved in stone formation to facilitate the development of more effective drugs. This review aims to understand the pathophysiology and the main molecular mechanisms known to date to prevent recurrences, which requires behavioral and nutritional interventions, as well as pharmacological treatments that are specific to the type of stone.
Topics: Humans; Kidney Calculi; Kidney Medulla; Calcium Oxalate; Minerals; Body Fluids
PubMed: 38474319
DOI: 10.3390/ijms25053075 -
Current Opinion in Cardiology Jul 2024To study the effect of bempedoic acid on markers of inflammation and lipoprotein (a) to help determine if the drug would be useful to treat patients with elevated... (Review)
Review
PURPOSE OF REVIEW
To study the effect of bempedoic acid on markers of inflammation and lipoprotein (a) to help determine if the drug would be useful to treat patients with elevated cardiovascular risks and residual cardiovascular risk despite optimal low-density lipoprotein cholesterol (LDL-C) levels.
RECENT FINDINGS
Bempedoic acid is found to cause significant reduction in LDL-C and high-sensitivity C-reactive protein (hs-CRP) in various randomized clinical trials. Multiple meta-analyses have also found that bempedoic acid therapy leads to reduction in non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC) and apolipoprotein B (ApoB) levels. However, it has minimal effect on lipoprotein (a) (Lp(a)) level.
SUMMARY
Bempedoic acid is a new lipid-lowering agent that inhibits enzyme ATP-citrate lyase in the cholesterol biosynthesis pathway. Major risk of cardiovascular events and its associated morbidity and mortality are proportional to LDL-C and inflammatory markers levels. It was found that bempedoic acid significantly lowers LDL-C, hs-CRP and other inflammatory markers levels. This drug could potentially be used in patients with elevated cardiovascular risk, in patients with residual cardiovascular risk despite attaining LDL-C goal and in statin intolerant patients.
Topics: Humans; Dicarboxylic Acids; Lipoprotein(a); Biomarkers; Inflammation; Cardiovascular Diseases; Fatty Acids; C-Reactive Protein; Cholesterol, LDL; Hypolipidemic Agents
PubMed: 38456474
DOI: 10.1097/HCO.0000000000001137 -
Nature Communications Dec 2023Succinic acid (SA) is an important C4-dicarboxylic acid. Microbial production of SA at low pH results in low purification costs and hence good overall process economics....
Succinic acid (SA) is an important C4-dicarboxylic acid. Microbial production of SA at low pH results in low purification costs and hence good overall process economics. However, redox imbalances limited SA biosynthesis from glucose via the reductive tricarboxylic acid (TCA) cycle in yeast. Here, we engineer the strictly aerobic yeast Yarrowia lipolytica for efficient SA production without pH control. Introduction of the reductive TCA cycle into the cytosol of a succinate dehydrogenase-disrupted yeast strain causes arrested cell growth. Although adaptive laboratory evolution restores cell growth, limited NADH supply restricts SA production. Reconfiguration of the reductive SA biosynthesis pathway in the mitochondria through coupling the oxidative and reductive TCA cycle for NADH regeneration results in improved SA production. In pilot-scale fermentation, the engineered strain produces 111.9 g/L SA with a yield of 0.79 g/g glucose within 62 h. This study paves the way for industrial production of biobased SA.
Topics: Yarrowia; Succinic Acid; NAD; Citric Acid Cycle; Fermentation; Glucose; Metabolic Engineering
PubMed: 38123538
DOI: 10.1038/s41467-023-44245-4