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Molecular Medicine (Cambridge, Mass.) Jan 2024In heart failure (HF), mitochondrial dysfunction and metabolic remodeling lead to a reduction in energy productivity and aggravate cardiomyocyte injury. Supplementation...
BACKGROUND
In heart failure (HF), mitochondrial dysfunction and metabolic remodeling lead to a reduction in energy productivity and aggravate cardiomyocyte injury. Supplementation with α-ketoglutarate (AKG) alleviated myocardial hypertrophy and fibrosis in mice with HF and improved cardiac insufficiency. However, the myocardial protective mechanism of AKG remains unclear. We verified the hypothesis that AKG improves mitochondrial function by upregulating NAD levels and activating silent information regulator 2 homolog 1 (SIRT1) in cardiomyocytes.
METHODS
In vivo, 2% AKG was added to the drinking water of mice undergoing transverse aortic constriction (TAC) surgery. Echocardiography and biopsy were performed to evaluate cardiac function and pathological changes. Myocardial metabolomics was analyzed by liquid chromatography‒mass spectrometry (LC‒MS/MS) at 8 weeks after surgery. In vitro, the expression of SIRT1 or PINK1 proteins was inhibited by selective inhibitors and siRNA in cardiomyocytes stimulated with angiotensin II (AngII) and AKG. NAD levels were detected using an NAD test kit. Mitophagy and ferroptosis levels were evaluated by Western blotting, qPCR, JC-1 staining and lipid peroxidation analysis.
RESULTS
AKG supplementation after TAC surgery could alleviate myocardial hypertrophy and fibrosis and improve cardiac function in mice. Metabolites of the malate-aspartate shuttle (MAS) were increased, but the TCA cycle and fatty acid metabolism pathway could be inhibited in the myocardium of TAC mice after AKG supplementation. Decreased NAD levels and SIRT1 protein expression were observed in heart of mice and AngII-treated cardiomyocytes. After AKG treatment, these changes were reversed, and increased mitophagy, inhibited ferroptosis, and alleviated damage in cardiomyocytes were observed. When the expression of SIRT1 was inhibited by a selective inhibitor and siRNA, the protective effect of AKG was suppressed.
CONCLUSION
Supplementation with AKG can improve myocardial hypertrophy, fibrosis and chronic cardiac insufficiency caused by pressure overload. By increasing the level of NAD, the SIRT-PINK1 and SIRT1-GPX4 signaling pathways are activated to promote mitophagy and inhibit ferroptosis in cardiomyocytes, which ultimately alleviates cardiomyocyte damage.
Topics: Angiotensin II; Aortic Valve Stenosis; Chromatography, Liquid; Ferroptosis; Fibrosis; Heart Failure; Hypertrophy; Ketoglutaric Acids; Mitophagy; Myocytes, Cardiac; NAD; Protein Kinases; RNA, Small Interfering; Sirtuin 1; Tandem Mass Spectrometry; Animals; Mice
PubMed: 38254035
DOI: 10.1186/s10020-024-00783-1 -
Advances in Nutrition (Bethesda, Md.) Apr 2024The epithelium lining the intestinal tract serves a multifaceted role. It plays a crucial role in nutrient absorption and immune regulation and also acts as a protective... (Review)
Review
The epithelium lining the intestinal tract serves a multifaceted role. It plays a crucial role in nutrient absorption and immune regulation and also acts as a protective barrier, separating underlying tissues from the gut lumen content. Disruptions in the delicate balance of the gut epithelium trigger inflammatory responses, aggravate conditions such as inflammatory bowel disease, and potentially lead to more severe complications such as colorectal cancer. Maintaining intestinal epithelial homeostasis is vital for overall health, and there is growing interest in identifying nutraceuticals that can strengthen the intestinal epithelium. α-Ketoglutarate, a metabolite of the tricarboxylic acid cycle, displays a variety of bioactive effects, including functioning as an antioxidant, a necessary cofactor for epigenetic modification, and exerting anti-inflammatory effects. This article presents a comprehensive overview of studies investigating the potential of α-ketoglutarate supplementation in preventing dysfunction of the intestinal epithelium.
Topics: Humans; Ketoglutaric Acids; Inflammatory Bowel Diseases; Intestinal Mucosa
PubMed: 38438107
DOI: 10.1016/j.advnut.2024.100200 -
Cardiovascular Research Mar 2024Chronic low-degree inflammation is a hallmark of atherosclerotic cardiovascular (CV) disease. To assess the effect of lipid-lowering therapies on C-reactive protein... (Meta-Analysis)
Meta-Analysis
Chronic low-degree inflammation is a hallmark of atherosclerotic cardiovascular (CV) disease. To assess the effect of lipid-lowering therapies on C-reactive protein (CRP), a biomarker of inflammation, we conducted a meta-analysis according to the PRISMA guidelines. Databases were searched from inception to July 2023. Inclusion criteria were: (i) randomized controlled trials (RCTs) in human, Phase II, III, or IV; (ii) English language; (iii) comparing the effect of lipid-lowering drugs vs. placebo; (iv) reporting the effects on CRP levels; (v) with intervention duration of more than 3 weeks; (vi) and sample size (for both intervention and control group) over than 100 subjects. The between-group (treatment-placebo) CRP absolute mean differences and 95% confidence intervals were calculated for each drug class separately. A total of 171 668 subjects from 53 RCTs were included. CRP levels (mg/L) were significantly decreased by statins [-0.65 (-0.87 to -0.43), bempedoic acid; -0.43 (-0.67 to -0.20), ezetimibe; -0.28 (-0.48 to -0.08)], and omega-3 fatty acids [omega3FAs, -0.27 (-0.52 to -0.01)]. CRP was reduced by -0.40 (-1.17 to 0.38) with fibrates, although not statistically significant. A slight increase of CRP concentration was observed for proprotein convertase subtilisin/kexin type 9 inhibitors [0.11 (0.07-0.14)] and cholesteryl-ester transfer protein inhibitors [0.10 (0.00-0.21)], the latter being not statistically significant. Meta-regression analysis did not show a significant correlation between changes in CRP and LDL cholesterol (LDL-C) or triglycerides. Statins, bempedoic acid, ezetimibe, and omega3FAs significantly reduce serum CRP concentration, independently of LDL-C reductions. The impact of this anti-inflammatory effect in terms of CV prevention needs further investigation.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Anticholesteremic Agents; Cholesterol, LDL; C-Reactive Protein; Cardiovascular Diseases; Randomized Controlled Trials as Topic; Ezetimibe; Atherosclerosis; Inflammation; Dicarboxylic Acids; Fatty Acids
PubMed: 38373008
DOI: 10.1093/cvr/cvae034 -
Semergen 2024Monacolin K is the major active component in red yeast rice (RYR) which is structurally identical to lovastatin and has the most powerful effect, in terms of reducing... (Review)
Review
Monacolin K is the major active component in red yeast rice (RYR) which is structurally identical to lovastatin and has the most powerful effect, in terms of reducing blood cholesterol levels. This review aimed to examine the effect and safety of different doses of monacolin K on blood cholesterol levels. PubMed and Cochrane were searched for articles published between 2012 and 2023 for clinical-trials and randomized-controlled-trials. Eligible studies included participants>18-years-old, of any gender and ethnicity. The intervention/exposure of interest was monacolin K. Hypercholesterolemia was considered the outcome of interest defined as the elevated total or low-density-lipoprotein (LDL) cholesterol levels. 12 randomized-controlled-trials were eligible for inclusion in the analysis including 769 participants>18-years-old. 11 out of 12 studies were assessed with high methodological quality and one study with low methodological quality. Monacolin K supplementation varied between 2mg and 10mg per day and the maximum period of supplementation was 12 weeks. All studies indicated a beneficial effect of monacolin supplementation on LDL and total cholesterol levels (p<0.05) regardless the dose and period of supplementation. Also, 3 of the included studies reported adverse side effects after treatment with monacolin K. Low doses of monacolin K equal to 3mg/day exert potential cholesterol-lowering effects although the number of relative studies is limited. Regarding the safety of monacolin K supplementation, findings seem to be more controversial and therefore, it is suggested for all patients treated with monacolin K to be routinely monitored regardless the dose of supplementation.
Topics: Humans; Hypercholesterolemia; Dietary Supplements; Randomized Controlled Trials as Topic; Lovastatin; Anticholesteremic Agents; Cholesterol, LDL; Dose-Response Relationship, Drug; Cholesterol; Biological Products; Dicarboxylic Acids; Fatty Acids
PubMed: 38310834
DOI: 10.1016/j.semerg.2023.102156 -
JCI Insight Sep 2023Lung contusion and gastric aspiration (LC and GA) are major risk factors for developing acute respiratory distress following trauma. Hypoxia from lung injury is mainly...
Lung contusion and gastric aspiration (LC and GA) are major risk factors for developing acute respiratory distress following trauma. Hypoxia from lung injury is mainly regulated by hypoxia-inducible factor 1α (HIF-1α). Published data from our group indicate that HIF-1α regulation in airway epithelial cells (AEC) drives the acute inflammatory response following LC and GA. Metabolomic profiling and metabolic flux of Type II AEC following LC revealed marked increases in glycolytic and TCA intermediates in vivo and in vitro that were HIF-1α dependent. GLUT-1/4 expression was also increased in HIF-1α+/+ mice, suggesting that increased glucose entry may contribute to increased intermediates. Importantly, lactate incubation in vitro on Type II cells did not significantly increase the inflammatory byproduct IL-1β. Contrastingly, succinate had a direct proinflammatory effect on human small AEC by IL-1β generation in vitro. This effect was reversed by dimethylmalonate, suggesting an important role for succinate dehydrogenase in mediating HIF-1α effects. We confirmed the presence of the only known receptor for succinate binding, SUCNR1, on Type II AEC. These results support the hypothesis that succinate drives HIF-1α-mediated airway inflammation following LC. This is the first report to our knowledge of direct proinflammatory activation of succinate in nonimmune cells such as Type II AEC in direct lung injury models.
Topics: Humans; Animals; Mice; Succinic Acid; Lung Injury; Succinates; Respiratory Distress Syndrome; Epithelial Cells; Hypoxia; Inflammation; Lung
PubMed: 37737265
DOI: 10.1172/jci.insight.166860 -
Human Reproduction (Oxford, England) Nov 2023Is the abundance of certain biochemical compounds in human cumulus cells (CCs) related to oocyte quality?
STUDY QUESTION
Is the abundance of certain biochemical compounds in human cumulus cells (CCs) related to oocyte quality?
SUMMARY ANSWER
Malonate, 5-oxyproline, and erythronate were positively associated with pregnancy potential.
WHAT IS KNOWN ALREADY
CCs are removed and discarded prior to ICSI, thereby constituting an interesting biological material on which to perform molecular analysis aimed to predict oocyte developmental competence. Mitochondrial DNA content and transcriptional analyses in CC have been shown to provide a poor predictive value of oocyte competence, but the untargeted analysis of biochemical compounds (metabolomics) has been unexplored.
STUDY DESIGN, SIZE, DURATION
CCs were obtained from three groups of cumulus-oocyte complexes (COCs) of known developmental potential: oocytes not developing to blastocyst following ICSI (Bl-); oocytes developing to blastocyst but failing to establish pregnancy following embryo transfer (P-); and oocytes developing to blastocyst able to establish a pregnancy (P+). Metabolomics analyses were performed on 12 samples per group, each sample comprising the CC recovered from a single COC.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Human CC samples were obtained from IVF treatments. Only unfrozen oocytes and embryos not submitted to preimplantation genetic testing were included in the analysis. Metabolomics analysis was performed by ultra-high performance liquid chromatography-tandem mass spectroscopy.
MAIN RESULTS AND THE ROLE OF CHANCE
The analysis identified 98 compounds, five of which were differentially abundant (P < 0.05) between groups: asparagine, proline, and malonate were less abundant in P- compared to Bl-, malonate and 5-oxoproline were less abundant in P- group compared to P+, and erythronate was less abundant in Bl- group compared to P+. No significant association between the abundance of the compounds identified and donor age or BMI was noted.
LIMITATIONS, REASONS FOR CAUTION
Data dispersion and the lack of coherence between developmental groups preclude the direct use of metabolic markers in clinical practice, where the uterine environment plays a major role in pregnancy outcome. The abundance of other compounds not detected by the analysis may be associated with oocyte competence. As donors were lean (only two with BMI > 30 kg/m2) and young (<34 years old), a possible effect of obesity or advanced age on the CC metabolome could not be determined.
WIDER IMPLICATIONS OF THE FINDINGS
The abundance of malonate, 5-oxyproline, and erythronate in CC was significantly higher in COCs ultimately establishing pregnancy, providing clues on the pathways required for oocyte competence. The untargeted analysis uncovered the presence of compounds that were not expected in CC, such as β-citrylglutamate and the neurotransmitter N-acetyl-aspartyl-glutamate, which may play roles in chromatin remodeling and signaling, respectively.
STUDY FUNDING/COMPETING INTEREST(S)
Research was supported by the Industrial Doctorate Project IND2017/BIO-7748 funded by Madrid Region Government. The authors declare no competing interest.
TRIAL REGISTRATION NUMBER
N/A.
Topics: Female; Humans; Pregnancy; Adult; Cumulus Cells; Hydroxyproline; Oocytes; Oogenesis; Malonates
PubMed: 37697661
DOI: 10.1093/humrep/dead181 -
Journal of Clinical Lipidology 2024Patients with heterozygous familial hypercholesterolemia (HeFH) often cannot reach guideline-recommended low-density lipoprotein cholesterol (LDL-C) goals despite... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Patients with heterozygous familial hypercholesterolemia (HeFH) often cannot reach guideline-recommended low-density lipoprotein cholesterol (LDL-C) goals despite multidrug therapy.
OBJECTIVE
To evaluate the efficacy and safety of bempedoic acid as an add-on therapy for lowering LDL-C in patients with HeFH.
METHODS
Pooled data from two 52-week phase 3 clinical trials of patients with atherosclerotic cardiovascular disease and/or HeFH receiving maximally tolerated statin therapy (randomized 2:1 to bempedoic acid or placebo) were analyzed by HeFH status. Endpoints included changes from baseline to week 12 (and up to week 52) in LDL-C and other lipid parameters, achievement of LDL-C goals, and safety.
RESULTS
A total of 217 (bempedoic acid, 146; placebo, 71) patients with HeFH and 2,792 (bempedoic acid, 1,864; placebo, 928) without HeFH were included (mean baseline LDL-C, 172.8 mg/dL and 102.6 mg/dL, respectively). Bempedoic acid significantly lowered LDL-C at week 12 vs. placebo regardless of HeFH status (with HeFH, -21.2%; without HeFH, -18.2% [both P<0.0001]). Bempedoic acid significantly reduced other lipid parameters and high-sensitivity C-reactive protein vs. placebo regardless of HeFH status (all P≤0.01). Among patients with HeFH treated with bempedoic acid, 32% and 27% achieved LDL-C <100 mg/dL at weeks 12 and 52, respectively. Overall treatment-emergent adverse event incidence was comparable across all four groups (74.7-77.5%).
CONCLUSION
Bempedoic acid significantly lowered LDL-C levels vs. placebo and was generally well tolerated in all patients, with no new safety findings in patients with HeFH, despite more intensive lipid-lowering therapy in patients with vs. without HeFH.
Topics: Humans; Dicarboxylic Acids; Hyperlipoproteinemia Type II; Male; Cholesterol, LDL; Fatty Acids; Middle Aged; Female; Heterozygote; Adult; Treatment Outcome; Clinical Trials, Phase III as Topic; Aged
PubMed: 38341323
DOI: 10.1016/j.jacl.2023.12.005 -
Nature Metabolism Oct 2023
Topics: Glutarates; T-Lymphocytes
PubMed: 37605056
DOI: 10.1038/s42255-023-00878-9 -
Biomaterials Oct 2023Succinate is an important metabolite that modulates metabolism of immune cells and cancer cells in the tumor microenvironment (TME). Herein, we report that polyethylene...
Succinate is an important metabolite that modulates metabolism of immune cells and cancer cells in the tumor microenvironment (TME). Herein, we report that polyethylene succinate (PES) microparticles (MPs) biomaterial mediated controlled delivery of succinate in the TME modulates macrophage responses. Administering PES MPs locally with or without a BRAF inhibitor systemically in an immune-defective aging mice with clinically relevant BRAF mutated YUMM1.1 melanoma decreased tumor volume three-fold. PES MPs in the TME also led to maintenance of M1 macrophages with up-regulation of TSLP and type 1 interferon pathway. Impressively, this led to generation of pro-inflammatory adaptive immune responses in the form of increased T helper type 1 and T helper type 17 cells in the TME. Overall, our findings from this challenging tumor model suggest that immunometabolism-modifying PES MP strategies provide an approach for developing robust cancer immunotherapies.
Topics: Animals; Mice; Succinic Acid; Tumor-Associated Macrophages; Tumor Microenvironment; Proto-Oncogene Proteins B-raf; Succinates; Melanoma
PubMed: 37643489
DOI: 10.1016/j.biomaterials.2023.122292 -
Journal of the American Chemical Society Sep 2023Structural transformation of metal nanoclusters (NCs) is of great ongoing interest regarding their synthesis, stability, and reactivity. Although sporadic examples of...
Structural transformation of metal nanoclusters (NCs) is of great ongoing interest regarding their synthesis, stability, and reactivity. Although sporadic examples of cluster transformations have been reported, neither the underlying transformation mechanism nor the intermediates are unambiguous. Herein, we have synthesized a flexible 54-nuclei silver cluster () by combining soft (BuC≡C) and hard (PrCOO) ligands. The existence of weakly coordinated PrCOO enhances the reactivity of , thus facilitating the dicarboxylic acid to induce structural transformation. X-ray structural analyses reveal that transforms to Ag cluster-based 2D networks ( and ) induced by Hsuc (succinic acid) and Hglu (glutaric acid), whereas with Hpda (2,2'-(1,2-phenylene)diacetic acid), a discrete Ag cluster () is isolated. The key intermediate that emerges during the self-dissociation of was isolated by using cryogenic recrystallization and characterized by X-ray crystallography. The "tandem transformation" mechanism for the structure evolution from to is established by time-dependent electrospray ionization mass spectrometry (ESI-MS) and UV-vis spectroscopy. In addition, the catalytic activity in the 4-nitrophenol reduction follows the sequence > > > due to more bare silver sites on the surface of the Ag cluster unit. Our findings not only open new avenues to the synthesis of silver NCs but also shed light on a better understanding of the structural transformation mechanism from one cluster to another or cluster-based metal-organic networks induced by dicarboxylates.
PubMed: 37646485
DOI: 10.1021/jacs.3c01119