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Indian Heart Journal Mar 2024Despite numerous improvements in the management of acute coronary syndrome(ACS), it is a major cause of mortality in India. Lipids play a critical role in pathogenesis... (Review)
Review
Despite numerous improvements in the management of acute coronary syndrome(ACS), it is a major cause of mortality in India. Lipids play a critical role in pathogenesis of ACS and reduction of lipid parameters plays a pivotal role in secondary prevention. High total cholesterol and high low-density lipoprotein(LDL) are the major lipid abnormalities globally as well as in Indians. Among all the lipid parameters, LDL is the primary target of lipid-lowering therapies across the globe. High-dose statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, and bempedoic acid are recommended therapies for LDL reduction in ACS patients. Statins have pleiotropic effects on the modulation of thrombogenesis, endothelial dysfunction, and myocardial protection. Multiple randomised controlled trials and meta-analyses have shown that the use of high-dose statin has significant benefits in ACS. LDL reduction goal is < 55 mg/dl or at least 50 % reduction from the baseline regardless of age or gender. Non-fasting LDL should be measured soon after the ACS as it varies minimally with food intake. The first line of therapy after ACS is to advise lifestyle modifications, combination therapy including high-dose statin with ezetimibe, and evaluation after 4-6 weeks of the index event. If the goal is not achieved then PCSK 9 inhibitors or Bempedoic acid should be used in combination with statins and ezetimibe to reduce recurrent ischaemic events. Despite the proven effect of these lipid-lowering therapies, undertreatment is still a big hurdle across the globe. Prohibitive costs, adverse effects, medication non-adherence, variation in health practice in different countries, and clinical inertia to prescribe this medication by physicians are the main reasons for the undertreatment.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Acute Coronary Syndrome; Cholesterol, LDL; Ezetimibe; Dyslipidemias; Anticholesteremic Agents; Proprotein Convertase 9; Dicarboxylic Acids; Fatty Acids
PubMed: 38307382
DOI: 10.1016/j.ihj.2024.01.011 -
Journal of Immunology (Baltimore, Md. :... Sep 2023Annexin A1 is a key anti-inflammatory effector protein that is involved in the anti-inflammatory effects of glucocorticoids. 4-Octyl itaconate (4-OI), a derivative of...
Annexin A1 is a key anti-inflammatory effector protein that is involved in the anti-inflammatory effects of glucocorticoids. 4-Octyl itaconate (4-OI), a derivative of the endogenous metabolite itaconate, which is abundantly produced by LPS-activated macrophages, has recently been identified as a potent anti-inflammatory agent. The anti-inflammatory effects of 4-OI share a significant overlap with those of dimethyl fumarate (DMF), a derivate of another Krebs cycle metabolite fumarate, which is already in use clinically for the treatment of inflammatory diseases. In this study we show that both 4-OI and DMF induce secretion of the 33-kDa form of annexin A1 from murine bone marrow-derived macrophages, an effect that is much more pronounced in LPS-stimulated cells. We also show that this 4-OI- and DMF-driven annexin A1 secretion is NRF2-dependent and that other means of activating NRF2 give rise to the same response. Lastly, we demonstrate that the cholesterol transporter ABCA1, which has previously been implicated in annexin A1 secretion, is required for this process in macrophages. Our findings contribute to the growing body of knowledge on the anti-inflammatory effects of the Krebs cycle metabolite derivatives 4-OI and DMF.
Topics: Mice; Animals; Dimethyl Fumarate; NF-E2-Related Factor 2; Annexin A1; Lipopolysaccharides; Anti-Inflammatory Agents
PubMed: 37578391
DOI: 10.4049/jimmunol.2200848 -
International Journal of Molecular... Nov 2023Oxygen deficiency is an environmental challenge which affects plant growth, the development and distribution in land and aquatic ecosystems, as well as crop yield losses... (Review)
Review
Oxygen deficiency is an environmental challenge which affects plant growth, the development and distribution in land and aquatic ecosystems, as well as crop yield losses worldwide. The capacity to exist in the conditions of deficiency or the complete lack of oxygen depends on a number of anatomic, developmental and molecular adaptations. The lack of molecular oxygen leads to an inhibition of aerobic respiration, which causes energy starvation and the acceleration of glycolysis passing into fermentations. We focus on systemic metabolic alterations revealed with the different approaches of metabolomics. Oxygen deprivation stimulates the accumulation of glucose, pyruvate and lactate, indicating the acceleration of the sugar metabolism, glycolysis and lactic fermentation, respectively. Among the Krebs-cycle metabolites, only the succinate level increases. Amino acids related to glycolysis, including the phosphoglycerate family (Ser and Gly), shikimate family (Phe, Tyr and Trp) and pyruvate family (Ala, Leu and Val), are greatly elevated. Members of the Asp family (Asn, Lys, Met, Thr and Ile), as well as the Glu family (Glu, Pro, Arg and GABA), accumulate as well. These metabolites are important members of the metabolic signature of oxygen deficiency in plants, linking glycolysis with an altered Krebs cycle and allowing alternative pathways of NAD(P)H reoxidation to avoid the excessive accumulation of toxic fermentation products (lactate, acetaldehyde, ethanol). Reoxygenation induces the downregulation of the levels of major anaerobically induced metabolites, including lactate, succinate and amino acids, especially members of the pyruvate family (Ala, Leu and Val), Tyr and Glu family (GABA and Glu) and Asp family (Asn, Met, Thr and Ile). The metabolic profiles during native and environmental hypoxia are rather similar, consisting in the accumulation of fermentation products, succinate, fumarate and amino acids, particularly Ala, Gly and GABA. The most intriguing fact is that metabolic alterations during oxidative stress are very much similar, with plant response to oxygen deprivation but not to reoxygenation.
Topics: Humans; Oxygen; Ecosystem; Amino Acids; Hypoxia; Lactates; Pyruvates; Succinates; gamma-Aminobutyric Acid; Peptide Fragments; Trypsin
PubMed: 38003412
DOI: 10.3390/ijms242216222 -
Postepy Dermatologii I Alergologii Dec 2023Azelaic acid (AZA) is a naturally occurring saturated dicarboxylic acid whose topical application has found multiple uses in dermatology. Its anti-inflammatory,... (Review)
Review
Azelaic acid (AZA) is a naturally occurring saturated dicarboxylic acid whose topical application has found multiple uses in dermatology. Its anti-inflammatory, antioxidant and antimicrobial properties against Propionibacterium acne are currently used in the treatment of various types of acne such as rosacea and acne vulgaris. AZA is an inhibitor of tyrosinase, mitochondrial respiratory chain enzymes and DNA synthesis, and is a scavenger of harmful free radicals and inhibits the production of reactive oxygen species by neutrophils. Interestingly, AZA also has anti-proliferative and cytotoxic effects on various cancer cells. To date, its inhibitory effect on melanocytes has been mainly used, making it widely used in the treatment of hyperpigmentation disorders such as melasma and post-inflammatory hyperpigmentation. Commercially available topical formulations with cosmetic and drug status contain 5% to 20% AZA in the form of gels and creams. The use of liposomal technology allows greater control over the pharmacokinetics and pharmacodynamics of the formulations. When applied topically, AZA is well tolerated, and side effects are limited to generally mild and transient local skin irritation. Importantly, liposomal technology has enabled the drug to penetrate all layers of the skin while maintaining a very high accumulation of the active ingredient. This solution could be revolutionary for the treatment of skin cancer, where until now the main obstacle was poor absorption through the skin, making the treatment require multiple applications to maintain long-term activity levels. In this review, we will present the mechanism of action and pharmacokinetics of AZA. We will summarize its use in the treatment of dermatoses and its potential in skin cancer therapy. We will provide an overview of the preparations available on the market, taking into consideration technologies used.
PubMed: 38282869
DOI: 10.5114/ada.2023.133955 -
Neurology(R) Neuroimmunology &... Sep 2023Despite accumulating evidence of intrathecal inflammation in patients with primary progressive multiple sclerosis (PPMS), immunomodulatory and suppressive treatment... (Observational Study)
Observational Study
BACKGROUND AND OBJECTIVE
Despite accumulating evidence of intrathecal inflammation in patients with primary progressive multiple sclerosis (PPMS), immunomodulatory and suppressive treatment strategies have proven unsuccessful. With this study, we investigated the involvement of CD20 T cells and the effect of dimethyl fumarate on CD20 T cells in PPMS.
METHODS
The main outcomes in this observational, case-control study were flow cytometry assessments of blood and CSF CD20 T cells and ELISA measurements of myelin basic protein and neurofilament light chain in untreated patients with PPMS and patients treated for 48 weeks with dimethyl fumarate or placebo. MRI measures included new and enlarging T2-weighted lesions over 48 weeks and lesion, normal-appearing white matter, cortical, and thalamic volume.
RESULTS
Assessing CD20 T cells in patients with PPMS and controls showed an increased percentage of CD20 T cells in the blood of untreated patients and a strong enrichment in the CSF. In addition, a higher frequency of CD8CD20 T cells in the CSF correlated with a higher concentration of myelin basic protein and T2-weighted lesion volume and with a lower normal-appearing white matter and thalamus volume. Furthermore, CD8CD20 T cells were associated with the development of new T2 lesions. After 48 weeks of treatment with dimethyl fumarate, total T cells in CSF were reduced; however, CD20 T cells were unaffected.
DISCUSSION
This study shows an association between intrathecal CD8CD20 T cells, white matter injury, and thalamic atrophy in PPMS, suggesting a role of CD8CD20 T cells in the immunopathogenesis of PPMS. The results also suggest that limited efficacy of dimethyl fumarate in PPMS may, at least partly, be a consequence of failure to suppress CD8CD20 T cells in CSF.
Topics: Humans; Case-Control Studies; CD8-Positive T-Lymphocytes; Dimethyl Fumarate; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Myelin Basic Protein; T-Lymphocytes
PubMed: 37369602
DOI: 10.1212/NXI.0000000000200140 -
International Journal of Molecular... Oct 2023Altered hepatic mitochondrial fatty acid β-oxidation and associated tricarboxylic acid (TCA) cycle activity contributes to lifestyle-related diseases, and circulating...
Altered hepatic mitochondrial fatty acid β-oxidation and associated tricarboxylic acid (TCA) cycle activity contributes to lifestyle-related diseases, and circulating biomarkers reflecting these changes could have disease prognostic value. This study aimed to determine hepatic and systemic changes in TCA-cycle-related metabolites upon the selective pharmacologic enhancement of mitochondrial fatty acid β-oxidation in the liver, and to elucidate the mechanisms and potential markers of hepatic mitochondrial activity. Male Wistar rats were treated with 3-thia fatty acids (e.g., tetradecylthioacetic acid (TTA)), which target mitochondrial biogenesis, mitochondrial fatty acid β-oxidation, and ketogenesis predominantly in the liver. Hepatic and plasma concentrations of TCA cycle intermediates and anaplerotic substrates (LC-MS/MS), plasma ketones (colorimetric assay), and acylcarnitines (HPLC-MS/MS), along with associated TCA-cycle-related gene expression (qPCR) and enzyme activities, were determined. TTA-induced hepatic fatty acid β-oxidation resulted in an increased ratio of plasma ketone bodies/nonesterified fatty acid (NEFA), lower plasma malonyl-CoA levels, and a higher ratio of plasma acetylcarnitine/palmitoylcarnitine (C2/C16). These changes were associated with decreased hepatic and increased plasma pyruvate concentrations, and increased plasma concentrations of succinate, malate, and 2-hydroxyglutarate. Expression of several genes encoding TCA cycle enzymes and the malate-oxoglutarate carrier (), glutamate dehydrogenase (), and malic enzyme ( and ) were significantly increased. In conclusion, the induction of hepatic mitochondrial fatty acid β-oxidation by 3-thia fatty acids lowered hepatic pyruvate while increasing plasma pyruvate, as well as succinate, malate, and 2-hydroxyglutarate.
Topics: Rats; Animals; Male; Rats, Wistar; Malates; Pyruvic Acid; Chromatography, Liquid; Tandem Mass Spectrometry; Liver; Fatty Acids; Oxidation-Reduction; Ketone Bodies; Succinates
PubMed: 37958519
DOI: 10.3390/ijms242115536 -
Science Advances Aug 2023Host-derived succinate accumulates in the airways during bacterial infection. Here, we show that luminal succinate activates murine tracheal brush (tuft) cells through a...
Host-derived succinate accumulates in the airways during bacterial infection. Here, we show that luminal succinate activates murine tracheal brush (tuft) cells through a signaling cascade involving the succinate receptor 1 (SUCNR1), phospholipase Cβ2, and the cation channel transient receptor potential channel subfamily M member 5 (TRPM5). Stimulated brush cells then trigger a long-range Ca wave spreading radially over the tracheal epithelium through a sequential signaling process. First, brush cells release acetylcholine, which excites nearby cells via muscarinic acetylcholine receptors. From there, the Ca wave propagates through gap junction signaling, reaching also distant ciliated and secretory cells. These effector cells translate activation into enhanced ciliary activity and Cl secretion, which are synergistic in boosting mucociliary clearance, the major innate defense mechanism of the airways. Our data establish tracheal brush cells as a central hub in triggering a global epithelial defense program in response to a danger-associated metabolite.
Topics: Mice; Animals; Trachea; Acetylcholine; Signal Transduction; Succinates; Epithelium
PubMed: 37531421
DOI: 10.1126/sciadv.adg8842 -
World Journal of Microbiology &... Apr 2024Oxalic acid and oxalates are secondary metabolites secreted to the surrounding environment by fungi, bacteria, and plants. Oxalates are linked to a variety of processes... (Review)
Review
Oxalic acid and oxalates are secondary metabolites secreted to the surrounding environment by fungi, bacteria, and plants. Oxalates are linked to a variety of processes in soil, e.g. nutrient availability, weathering of minerals, or precipitation of metal oxalates. Oxalates are also mentioned among low-molecular weight compounds involved indirectly in the degradation of the lignocellulose complex by fungi, which are considered to be the most effective degraders of wood. The active regulation of the oxalic acid concentration is linked with enzymatic activities; hence, the biochemistry of microbial biosynthesis and degradation of oxalic acid has also been presented. The potential of microorganisms for oxalotrophy and the ability of microbial enzymes to degrade oxalates are important factors that can be used in the prevention of kidney stone, as a diagnostic tool for determination of oxalic acid content, as an antifungal factor against plant pathogenic fungi, or even in efforts to improve the quality of edible plants. The potential role of fungi and their interaction with bacteria in the oxalate-carbonate pathway are regarded as an effective way for the transfer of atmospheric carbon dioxide into calcium carbonate as a carbon reservoir.
Topics: Oxalic Acid; Fungi; Bacteria; Biotechnology; Plants; Oxalates; Lignin
PubMed: 38662173
DOI: 10.1007/s11274-024-03973-5 -
Journal of Translational Medicine Nov 2023Epilepsy affects over 65 million people worldwide and significantly burdens patients, caregivers, and society. Drug-resistant epilepsy occurs in approximately 30% of...
BACKGROUND
Epilepsy affects over 65 million people worldwide and significantly burdens patients, caregivers, and society. Drug-resistant epilepsy occurs in approximately 30% of patients and growing evidence indicates that oxidative stress contributes to the development of such epilepsies. Activation of the Nrf2 pathway, which is involved in cellular defense, offers a potential strategy for reducing oxidative stress and epilepsy treatment. Dimethyl fumarate (DMF), an Nrf2 activator, exhibits antioxidant and anti-inflammatory effects and is used to treat multiple sclerosis.
METHODS
The expression of Nrf2 and its related genes in vehicle or DMF treated rats were determined via RT-PCR and Western blot analysis. Neuronal cell death was evaluated by immunohistochemical staining. The effects of DMF in preventing the onset of epilepsy and modifying the disease were investigated in the kainic acid-induced status epilepticus model of temporal lobe epilepsy in rats. The open field, elevated plus maze and T-Maze spontaneous alteration tests were used for behavioral assessments.
RESULTS
We demonstrate that administration of DMF following status epilepticus increased Nrf2 activity, attenuated status epilepticus-induced neuronal cell death, and decreased seizure frequency and the total number of seizures compared to vehicle-treated animals. Moreover, DMF treatment reversed epilepsy-induced behavioral deficits in the treated rats. Moreover, DMF treatment even when initiated well after the diagnosis of epilepsy, reduced symptomatic seizures long after the drug was eliminated from the body.
CONCLUSIONS
Taken together, these findings suggest that DMF, through the activation of Nrf2, has the potential to serve as a therapeutic target for preventing epileptogenesis and modifying epilepsy.
Topics: Humans; Rats; Animals; Dimethyl Fumarate; NF-E2-Related Factor 2; Drug Repositioning; Epilepsy; Seizures; Status Epilepticus; Disease Models, Animal
PubMed: 37940957
DOI: 10.1186/s12967-023-04695-2 -
Clinical and Experimental Immunology Feb 2024Macrophage activation results in the accumulation of endogenous metabolites capable of adopting immunomodulatory roles; one such bioactive metabolite is itaconate. After... (Review)
Review
Macrophage activation results in the accumulation of endogenous metabolites capable of adopting immunomodulatory roles; one such bioactive metabolite is itaconate. After macrophage stimulation, the TCA-cycle intermediate cis-aconitate is converted to itaconate (by aconitate decarboxylase-1, ACOD1) in the mitochondrial matrix. Recent studies have highlighted the potential of targeting itaconate as a therapeutic strategy for lung diseases such as asthma, idiopathic pulmonary fibrosis (IPF), and respiratory infections. This review aims to bring together evidence which highlights a role for itaconate in chronic lung diseases (such as asthma and pulmonary fibrosis) and respiratory infections (such as SARS-CoV-2, influenza and Mycobacterium tuberculosis infection). A better understanding of the role of itaconate in lung disease could pave the way for novel therapeutic interventions and improve patient outcomes in respiratory disorders.
Topics: Humans; Succinates; Lung Diseases; Respiratory Tract Infections; Asthma
PubMed: 38018224
DOI: 10.1093/cei/uxad127