Substrate Metabolism Research Articles

The effects of muscle factors irisin on lipid metabolism in breast cancer: A possible mechanism anti-tumor mechanism of physical activity

Breast cancer is the most prevalent cancer in the female population and is a significant cause of global cancer deaths in this group. Obesity increases a woman’s risk of developing breast cancer and has a negative impact on prognosis. Metabolic alterations are an important part of the process of cancer migration; invasion and proliferation, with lipids being a major metabolic substrate for rapid cancer progression, capable of influencing the metabolic crosstalk between tumor cells and other cells in the tumor microenvironment. Physical activity-induced irisin affects the progression of obesity-associated breast cancer and is a new indicator for breast cancer diagnosis. Existing evidence suggests a potential inhibitory effect of physical activity-induced irisin on the progression of breast cancer. A strong association exists between obesity and breast cancer progression and outcomes. This paper discusses how physical activity-induced irisin may achieve cancer suppression by affecting lipid metabolic processes between breast cancer cells and cancer-associated adipocytes, and elucidates the molecular pathways involved in the effects of irisin on cancer lipid reprogramming, thereby helping to prevent the metastatic progression of breast cancer, and ultimately improving the survival rate of this patient group.

Heart Failure: A Deficiency of Energy—A Path Yet to Discover and Walk

Heart failure is a complex syndrome and our understanding and therapeutic approach relies mostly on its phenotypic presentation. Notably, the heart is characterized as the most energy-consuming organ, being both a producer and consumer, in order to satisfy multiple cardiac functions: ion exchange, electromechanical coordination, excitation–contraction coupling, etc. By obtaining further knowledge of the cardiac energy field, we can probably better characterize the basic pathophysiological events occurring in heart disease patients and understand the metabolic substance changes, the relationship between the alteration of energy production/consumption, and hence energetic deficiency not only in the heart as a whole but in every single cardiac territory, which will hopefully provide us with the opportunity to uncover the beginning of the heart failure process. In this respect, using (a) newer imaging techniques, (b) biomedicine, (c) nanotechnology, and (d) artificial intelligence, we can gain a deeper understanding of this complex syndrome. This, in turn, can lead to earlier and more effective therapeutic approaches, ultimately improving human health. To date, the scientific community has not given sufficient attention to the energetic starvation model. In our view, this review aims to encourage scientists and the medical community to conduct studies for a better understanding and treatment of this syndrome.

Synthesis methods of Mg-based scaffolds and their applications in tissue engineering: A review.

Repair and regeneration of damaged tissues due to disease and accidents have become a severe challenge to tissue engineers and researchers. In recent years, biocompatible metal materials such as stainless steels, cobalt alloys, titanium alloys, tantalum alloys, nitinol, and Mg alloys have been studied for tissue engineering applications; as suitable candidates in orthopedic and dentistry implants. These materials and their alloys are used for load-bearing and physiological roles in biological applications. Due to the suitable conditions provided by a porous material, many studies have been performed on the porous implants, including Mg-based scaffolds. Mg alloy scaffolds are attractive due to some outstanding features and susceptibilities, such as providing a cell matrix for cell proliferation, migration, and regeneration, providing metabolic substances for bone tissue growth, biocompatibility, good biodegradability, elastic modulus comparable to the natural bone, etc. Accordingly, in the present study, a general classification of all the production methods of Mg-based scaffolds is provided. Strengths and weaknesses, the effect of the production approach on the final properties of scaffolds, including mechanical and biological capabilities, and the impact of alloying elements and process parameters have been reviewed, and discussed. Finally, the manufacturing methods have been compared and the upcoming challenges have been stated.

Aldehyde-based Activation of C2α-lactylthiamin Diphosphate Decarboxylation on Bacterial 1-deoxy-d-xylulose 5-phosphate Synthase.

1-Deoxy-d-xylulose 5-phosphate synthase (DXPS) catalyzes the thiamin diphosphate (ThDP)-dependent formation of DXP from pyruvate (donor substrate) and d-glyceraldehyde 3-phosphate (d-GAP, acceptor substrate) in bacterial central metabolism. DXPS uses a ligand-gated mechanism in which binding of a small molecule "trigger" activates the first enzyme-bound intermediate, C2α-lactylThDP (LThDP), to form the reactive carbanion via LThDP decarboxylation. d-GAP is the natural acceptor substrate for DXPS and also serves a role as a trigger to induce LThDP decarboxylation in the gated step. Additionally, we have shown that O2 and d-glyceraldehyde (d-GA) can induce LThDP decarboxylation. We hypothesize this ligand-gated mechanism poises DXPS to sense and respond to cellular cues in metabolic remodeling during bacterial adaptation. Here we sought to characterize features of small molecule inducers of LThDP decarboxylation. Using a combination of CD, NMR and biochemical methods, we demonstrate that the α-hydroxy aldehyde moiety of d-GAP is sufficient to induce LThDP decarboxylation en route to DXP formation. A variety of aliphatic aldehydes also induce LThDP decarboxylation. The study highlights the capacity of DXPS to respond to different molecular cues, lending support to potential multifunctionality of DXPS and its metabolic regulation by this mechanism.

Multifrequency-STD NMR unveils the first Michaelis complex of an intramolecular trans-sialidase from Ruminococcus gnavus

RgNanH is an intramolecular trans-sialidase expressed by the human gut symbiont Ruminococcus gnavus, to utilise intestinal sialylated mucin glycan epitopes. Its catalytic domain, belonging to glycoside hydrolase GH33 family, cleaves off terminal sialic acid residues from mucins, releasing 2,7-anhydro-Neu5Ac which is then used as metabolic substrate by R. gnavus to proliferate in the mucosal environment. RgNanH is one of the three intramolecular trans-sialidases (IT-sialidases) characterised to date, and the first from a gut commensal organism. Here, saturation transfer difference NMR (STD NMR) in combination with computational techniques (molecular docking and CORCEMA-ST) were used to elucidate the specificity, kinetics and relative affinity of RgNanH for sialoglycans and 2,7-anhydro-Neu5Ac. We propose the first 3D model for the Michaelis complex of an IT-sialidase. This confirms the sialic acid to be the main recognition element for the interaction in the enzymatic cleft and highlights the crucial role of Trp698 to make CH-π stacking with the galactose residue of the substrate 3′-sialyllactose. The same contact is shown not to be possible for 6′-sialyllactose, due to geometrical constrains of the α-2,6 linkage. Indeed 6′-sialyllactose is not a substrate, even though it is shown to bind to RgNanH by STD NMR. These findings corroborate the role of Trp698 for the α-2,3 specificity of trans-sialidases. In this structural study, the use of Differential Epitope Mapping STD NMR (DEEP-STD NMR) approach allowed the validation of the proposed 3D models in solution. These structural approaches are shown to be instrumental in shedding light on the molecular mechanisms underpinning enzymatic reactions in the absence of enzyme-substrate X-ray structures.

Impacts of groundwater depth and tree age on the non-structural carbohydrates of Haloxylon ammodendron

Nonstructural carbohydrates (NSCs) are important substrates for plant growth and metabolism, and their concentration reflects the plant's ability to adapt to environmental changes. Although the response of NSCs to changes in water availability has been extensively studied, it is still not fully understood whether this response is modulated by tree ages and organs. This study investigates Haloxylon ammodendron (C.A. Mey.) Bunge ex Fenzl, the dominant species in the Gurbantunggut Desert in the Uyghur Autonomous Region of China. Utilizing the natural topographic conditions characterized by a gradual increase in groundwater depth from the desert edge to the interior, we collected samples of different age classes of H. ammodendron along a groundwater depth gradient of 3, 7, 10, and 14 meters. We measured the total concentrations of non-structural carbohydrates (NSCs) and their components soluble sugar (SS) and starch (ST) in the assimilative twigs and stems. The results showed that the assimilative twigs of H. ammodendron exhibited higher NSC concentrations at the site with the deepest groundwater, while the other three sites showed similar NSC concentrations. Furthermore, as groundwater depth increased, the concentrations of SS in the assimilative twigs increased, whereas ST concentrations decreased. Similarly, the concentrations of SS in the stems also increased at sites with deeper groundwater. The NSC concentrations in the assimilative twigs were significantly affected by groundwater depth, while variations in stem NSC were primarily driven by plant age. In younger trees, higher soluble sugars concentrations in the stem may enhance water transport efficiency, whereas older trees tend to store more NSC to alleviate drought stress. Overall, elevated nonstructural carbohydrate concentrations contributed to greater drought resilience in H. ammodendron. These results suggest that different age classes of H. ammodendron exhibit distinct physiological responses to decreasing groundwater depth. The varying requirements for soluble sugars and starch in H. ammodendron help to partially mitigate the adverse effects of reduced groundwater accessibility. These findings provide important insights into the physiological adaptations of H. ammodendron in arid environments and offer a scientific basis for future ecological restoration and management strategies.

CYP2C19 Loss-of-Function is an Associated Risk Factor for Premature Coronary Artery Disease: A Case-Control Study.

Cytochrome P450 2C19 (CYP2C19) is a major enzyme involved in the biotransformation and metabolism of various substances. Loss-of-function of the CYP2C19 gene represents downregulation of CYP2C19 enzyme indication limited or no enzymatic function, which may be, in turn, associated with some disease susceptibility. The relationship between CYP2C19 polymorphisms and susceptibility to premature coronary artery disease (PCAD) is not fully understood. This study aimed to assess this relationship. This study included 635 PCAD patients, and 548 age-matched non-CAD individuals as controls, from November 2019 to August 2023. The CYP2C19 rs4244285 (681G > A, *2) and rs4986893 (636G > A, *3) were genotyped, and the distribution of CYP2C19 polymorphisms between patients and controls and the relationship between CYP2C19 polymorphisms and PCAD risk were analyzed. A total of 442 (37.4%), 543 (45.9%), and 198 (16.7%) individuals had CYP2C19 extensive metabolizer (EM) (*1/*1), intermediate metabolizer (IM) (*1/*2 and *1/*3), and poor metabolizer (PM) (*2/*2, *2/*3, and *3/*3) phenotypes, respectively. CYP2C19 *2/*2 genotype frequency was higher, *1/*1 genotype was lower in PCAD patients than controls. Individuals with CYP2C19 PM phenotype had higher triglyceride (TG) levels than those with CYP2C19 EM or IM phenotypes. Logistic regression analysis showed that body mass index (BMI) ≥24.0 kg/m2 (≥24.0 kg/m2 vs 18.5-23.9 kg/m2, odds ratio (OR): 1.326, 95% confidence interval (CI): 1.041-1.688, p = 0.022), smoking (OR: 1.974, 95% CI: 1.283-3.306, p = 0.002), hypertension (OR: 1.327, 95% CI: 1.044-1.687, p = 0.021), diabetes mellitus (OR: 1.390, 95% CI: 1.054-1.834, p = 0.020), CYP2C19 PM phenotype (PM phenotype vs EM phenotype, OR: 1.701, 95% CI: 1.200-2.411, p = 0.003), and CYP2C19 IM+PM phenotypes (IM+PM vs EM phenotype, OR: 1.369, 95% CI: 1.077-1.740, p = 0.010) were associated with PCAD. CYP2C19 PM or IM+PM phenotypes, overweight, smoking, hypertension, and diabetes mellitus were associated with PCAD.

Heart Rate and Its Variability Are Associated With Resting Metabolic Rate and Substrate Oxidation in Young Women but Not in Men.

This study aims to examine the relationship between resting vagal-related heart rate variability (HRV) parameters and heart rate (HR) with resting metabolic rate (RMR) and respiratory exchange ratio (RER) in young adults. A total of 74 young adults (22 ± 2 years old, 51 women) were included in this cross-sectional study. HRV was assessed using a HR monitor, whereas RMR and RER were determined by indirect calorimetry. Linear regression analyses showed a positive association between HR and RER in women (standardized β = 0.384, p = 0.008), while negative associations were observed between vagal-related HRV parameters and RER in women (β ranged from -0.262 to -0.254, all p ≤ 0.042). No significant association was found between the abovementioned physiological parameters in men. Here, we show that HR is positively associated with RER in young women but not in men, while vagal-related HRV parameters are inversely related to RMR, therefore suggesting a potential sexual dimorphism between cardiac rhythm and its relationship with markers of cardiometabolic health status. ClinicalTrials.gov identifier: NCT02365129.

Natural Honey Proteins Prevent Diet-Induced Obesity and Metabolic Disorders in Rats.

Previous studies have shown that oral whole honey reduces weight gain in rats on a normal diet (ND) or high-fat diet (HFD) and suppresses inflammation by modulating immunological cytokines in human neutrophils and macrophages. We hypothesize that the honey proteins (HP) are responsible for the reduced weight gain in rats on ND and HFD and that HP would alleviate obesity parameters. To test this, proteins were isolated from acacia honey through the salting-out method. Wistar rats (N = 24) were randomized to get ND or HFD for 4 weeks, then further randomized to four groups and treated with HP or saline for another 4 weeks. Energy intake (EI), body weight gain, EI per gram body weight gain, serum glucose, and lipids were measured. Expression of adipose tissue genes fatty acid binding protein (FABP), lipase C (LIPC), and apolipoprotein A-1 (APOA1) was evaluated through the quantitative polymerase chain reaction. HFD increased the body weight versus ND in weeks 1-4. HP for the next 4 weeks reduced weight gain in ND-HP and HFD-HP groups versus saline controls (P < .01). EI was not significantly different among groups. However, EI per gram body weight gain among groups was markedly different (P < .01), demonstrating reduced weight gain efficiency by HP (P < .01). HP reduced glucose in ND but not in HFD groups. Triglycerides were lower in both HP groups. The expressions of FABP, LIPC, and APOA1 genes were significantly increased (P < .05) in HP-treated HFD rats. Collectively, weight gain efficiency was remarkably reduced without altering EI in rats following the HP treatment, suggesting HP increased metabolic rate or substrate partitioning. Studies of HP are suggested in humans.

A novel 3D cardiac microtissue model for investigation of cardiovascular complications in rheumatoid arthritis

BackgroundRheumatoid arthritis (RA) is a chronic inflammatory disease that affects not only the joints but also has significant cardiovascular (CV) manifestations. The mechanistic interplay between RA and cardiovascular complications is not yet well understood due to the lack of relevant in vitro models. In this study, we established RA cardiac microtisses (cMTs) from iPSC-derived cardiomyocytes (CMs), endothelial cells (ECs) and cardiac fibroblasts (CFs) to investigate whether this fully human 3D multicellular system could serve as a platform to elucidate the connection between RA and CV disorders.MethodsPBMC and FLS from healthy and RA donors were reprogrammed to hiPSCs with Sendai vectors. hiPSCs pluripotency was assessed by IF, FACS, spontaneous embryoid bodies formation and teratoma assay. hiPSCs were differentiated to cardiac derivatives such as CMs, ECs and CFs, followed by cell markers characterizations (IF, FACS, qRT-PCR) and functional assessments. 3D cMTs were generated by aggregation of 70% CMs, 15% ECs and 15% CFs. After 21 days in culture, structural and metabolic properties of 3D cMTs were examined by IF, qRT-PCR and Seahorse bioanalyzer.ResultshiPSCs demonstrated typical colony-like morphology, normal karyotype, presence of pluripotency markers, and ability to differentiate into cells originating from all three germ layers. hiPSC-CMs showed spontaneous beating and expression of cardiac markers (cTnT, MYL7, NKX2.5, MYH7). hiPSC-ECs formed sprouting spheres and tubes and expressed CD31 and CD144. hiPSC-CFs presented spindle-shaped morphology and expression of vimentin, collagen 1 and DDR2. Self-aggregation of CMs/ECs/CFs allowed development of contracting 3D cMTs, demonstrating spherical organization of the cells, which partially resembled the cardiac muscle, both in structure and function. IF analysis confirmed the expression of cTnT, CD31, CD144 and DDR2 in generated 3D cMTs. RA cMTs exhibited significantly greater formation of capillary-like structures, mimicking enhanced vascularization—key RA feature—compared to control cMTs. Seahorse examination of cMTs revealed changes in mitochondrial and glycolytic rates in the presence of metabolic substrates and inhibitors.ConclusionsThe cMTs model may represent an advanced human stem cell-based platform for modeling CV complications in RA. The highly developed capillary-like structures observed within RA cMTs highlight a critical feature of inflammation-induced CV dysfunction in chronic inflammatory diseases.

Revealing the adaptation mechanism of different color morphs of sea cucumber Apostichopus japonicus to light intensities from the perspective of metabolomics

Global warming has multi-dimensional and complex impacts on the Earth's system, among which changes in light intensities cannot be overlooked. Sea cucumbers are a marine biological resource with significant economic and ecological value. Their presence and activity help maintain the balance and stability of marine ecosystems. The variation in light intensities have important ecological effects on sea cucumbers. Light intensities can alter the synthesis and degradation of metabolic substances within the bodies of Apostichopus japonicus by changing their body color. Their changes affect the production of microorganisms in the environment, thereby achieving the goal of bioremediation. This study investigated metabolic variations in green, purple, and white sea cucumber Apostichopus japonicus under different light conditions (0 lx and 910 lx) with a 12-h light and 12-h dark photoperiod. The findings indicated that the sea cucumbers displayed more diverse metabolic alterations under 910 lx illumination compared to 0 lx. Specifically, these color morphs primarily responded to changes in light intensities through “tryptophan metabolism” and “biosynthesis of steroid hormones”. Additionally, high light intensities environment exacerbated the consumption of fatty acids by sea cucumbers. Different color morphs of sea cucumbers have differences in key metabolites in response to changes in light intensities. Green and white sea cucumbers primarily adapt to environment through phospholipids, while purple sea cucumbers mainly utilize fatty acids. These results enhance our comprehension of how sea cucumbers adapt ecologically to varying light intensities, and they offer valuable insights for systematically uncovering the regulatory processes that marine animals employ in response to environmental changes.

Higher myocardial mitochondrial ketone body oxidation capacity in human heart failure

Abstract Introduction/Purpose Recent studies suggest that the ketone bodies (KB) beta-hydroxybutyrate (HBA) and acetoacetate (ACA) are relevant substrates for myocardial energy metabolism in heart failure (HF). However, the amount of KB-dependent mitochondrial respiration in HF has not yet been quantified. High-resolution respirometry (HRR) is the gold-standard method for quantifying substrate-dependent mitochondrial oxidative capacity. Therefore, we aimed to evaluate the association between myocardial KB-dependent oxidative capacity and human HF using HRR. Methods The primary endpoint of this single-center prospective cohort study was KB-dependent and overall mitochondrial oxidative capacity in permeabilized myocardium. We used two different protocols for our measurements. In the first HRR protocol, conventional respirometry substrates including fatty acids, complex I- and complex II substrates were used to quantify the maximum coupled oxidative phosphorylation capacity (OXPHOS). Leak respiration was quantified using oligomycin to calculate the respiratory control ratio (RCR, state 3/state 4o), and leak control ratio (LCR, state 4o/state u). In the second protocol which was recently established by our working group, HBA and ACA were used as respirometry substrates to quantify KB-dependent respiration down to the enzyme level. The relative contribution of the KBs was obtained by comparing HBA- and ACA-derived respiration to OXPHOS. We applied both protocols to myocardial samples from individuals with advanced HF (HF group, catheter-acquired endomyocardial biopsies from non-ischemic HF patients or samples of explanted hearts collected during orthotopic heart transplantation surgery in end-stage heart failure patients) as well as previously heart transplanted individuals without current heart failure (Control group). Results Controls and HF had similar demographic characteristics, with comparable age distribution (mean±SD, 56.3±10.3 vs. 54.2±10.7 years, p=0.36), sex (68.75% vs. 66.67% male, p=0.87), or body mass index (25.0±5.8 vs. 29.0±10.6 kg/m2, p=0.08) and differed significantly in cardiac index (3.06±0.67 vs. 1.93±0.44) and ejection fraction (55.8±10.2 vs. 26.6±9.1) (both p&amp;lt;0.0001). The HF group exhibited lower OXPHOS and respiration for all substrate combinations tested (Fig. 1A). In contrast, KB-dependent respiration did not differ between HF and controls (Fig. 1B). The relative HBA-dependent respiration (Fig. 1C) and the relative and absolute ACA-dependent respiration (Fig. 1C and D) were higher in the HF group compared to controls. Mitochondrial uncoupling (LCR) (0.47±0.29 vs. 0.44±0.09 [AU], p=0.79) and coupling efficiency (RCR) (2.75±1.38 vs. 2.11±0.39 [AU], p=0.15) were not different between the groups. Conclusion These findings suggest that mitochondria in the failing heart can utilize KBs for OXPHOS to a greater extent and further hint towards KB metabolism as a potential therapeutic target for HF.

SGLT2 inhibitor empagliflozin prevents anthracycline-induced cardiotoxicity in a large-animal model

Abstract Background While the development of cancer therapies has significantly improved the survival of cancer patients, more than 35% of cancer survivors treated with anthracyclines will develop cardiotoxicity. There is currently a lack of preventative therapies against anthracycline-induced cardiotoxicity (AIC). AIC is characterised by a disruption in myocardial metabolism. Sodium-glucose co-transporter (SLGT2) inhibitors represent a potential therapy as they have been shown to modulate myocardial substrate utilisation in other heart-failure contexts. Purpose We developed a highly translational large-animal model to test the ability of SGLT2 inhibitor empagliflozin to prevent AIC at different doses. Methods Female Large-White pigs were randomised (2:1:1) to no treatment (AIC-control group) or empagliflozin at a daily oral dose of 10 mg or 20 mg, beginning at the start of the doxorubicin regimen and continuing to 21 weeks. All pigs received 6 doses of doxorubicin intravenous infusion (25 mg/m2/every 3 weeks) with 2 additional off-dose visits. Pigs were assessed by cardiac magnetic resonance (CMR) and MR spectroscopy (MRS) at baseline and every 3 weeks for 21 weeks. At the end of 21-week follow-up, the LV was collected and processed for analysis by transmission electron microscopy (TEM) and mitochondrial respirometry. Results The primary outcome, final LVEF, was significantly higher in pigs receiving 20 mg empagliflozin than in the AIC-control group (57.5% (IQR=55.5, 60.3) vs 47.0% (40.8, 47.8); p=0.027). Final LVEF in pigs receiving 10 mg empagliflozin was 51% (46.5, 55.5) (p=0.020 vs 20 mg empagliflozin). The 20 mg empagliflozin dose prevented the doxorubicin-induced change in cardiac metabolic substrate utilisation and was associated with preservation of myocardial energetics (ATP/PCr ratio on MRS). TEM revealed disrupted mitochondrial structure and cristae density in AIC-control pigs, while mitochondria respirometry detected deteriorated respiratory function. Both mitochondrial structure and function were preserved in empagliflozin-treated pigs, with the 20 mg dose having the strongest cardioprotective effect. Conclusion The results from our translational large-animal model provide strong evidence that SGLT2 inhibition with empagliflozin prevents AIC by preserving LV systolic function and energetics as well as mitochondrial structural integrity and function. Our results establish the basis for clinical trial testing SGLT2i therapy in patients at high risk of AIC.

Fenofibrate modulates cardiac energy metabolism in moderate-severe aortic stenosis: a mechanistic double-blinded randomised controlled MR trial

Abstract Background Aortic stenosis (AS) is associated with impaired cardiac metabolism and high-energy phosphate production which can further exacerbate the progression to HF. Myocardial lipid accumulation and reduced production of high-energy phosphates have important implications for both systolic and diastolic heart function in AS. Peroxisome proliferator-activated receptor alpha (PPAR-alpha agonist, has the potential to optimise cardiac substrate metabolism, thereby, may be effective in improving cardiac dysfunction and functional capacity in AS. Methods In this prospective, randomized, double-blind, placebo-controlled study, patients with moderate-to-severe asymptomatic AS (n=72) were randomly assigned to Fenofibrate 200 mg daily or matching placebo for 6 months in 4:1 fashion. Of the total 72 participants, 59 received Fenofibrate and 13 received placebo. All subjects underwent cardiac magnetic resonance (CMR) and exercise testing at 0 and 6 months, with follow-up data available in 47 patients. The primary end point was change in myocardial triglyceride content (MTG) determined by proton magnetic resonance spectroscopy (1H-MRS). Secondary outcome measures included change in cardiac energetics (PCr/ATP) determined by phosphorus magnetic resonance spectroscopy (31P-MRS), left ventricular strain determined by myocardial tagging and exercise capacity i.e. peak VO2 assessment via cardiopulmonary exercise testing. Results Cardiac energetics (PCr/ATP) showed statistically significant improvement in the Fenofibrate group (0.14 ± 0.48; CI: - 0.03, 0.30; p=0.05) vs placebo group (0.11 ± 0.75; CI -0.42, 0.65; p=0.64). There was also significant reduction in MTG in the Fenofibrate group (mean change -0.40 ± 0.97; 95% CI -0.74, -0.06; p=0.02). MTG content also reduced in the placebo group (mean change -0.41 ± 0.26, 95% CI -1.10, 0.18, p 0.13), but the reduction was not statistically significant. Though no significant changes were seen in the systolic function parameters, there was a significant improvement in diastolic function in the fenofibrate group only (peak diastolic longitudinal strain rate 9.6, 95% CI: 1.13, 18.1; p = 0.02). Peak VO2 did not show any significant improvement in either group. Conclusions Fenofibrate works as a metabolic modulator upregulating fatty acid metabolism in pressure overload AS hearts. Such modulation is associated with an improvement in cardiac energetics and diastolic function in moderate-severe AS.Main results from baseline to 6 monthsBaseline demographic and CMR parameters

Recent Advances Associated with Cardiometabolic Remodeling in Diabetes-induced Heart Failure.

Diabetes mellitus (DM) is characterized by chronic hyperglycemia, and despite intensive glycemic control, the risk of heart failure in diabetic patients remains high. Diabetes-induced heart failure (DHF) presents a unique metabolic challenge, driven by significant alterations in cardiac substrate metabolism, including increased reliance on fatty acid oxidation, reduced glucose utilization, and impaired mitochondrial function. These metabolic alterations lead to oxidative stress, lipotoxicity, and energy deficits, contributing to the progression of heart failure. Emerging research has identified novel mechanisms involved in the metabolic remodeling of diabetic hearts, such as autophagy dysregulation, epigenetic modifications, polyamine regulation, and branched-chain amino acid (BCAA) metabolism. These processes exacerbate mitochondrial dysfunction and metabolic inflexibility, further impairing cardiac function. Therapeutic interventions targeting these pathways-such as enhancing glucose oxidation, modulating fatty acid metabolism, and optimizing ketone body utilization-show promise in restoring metabolic homeostasis and improving cardiac outcomes. This review explores the key molecular mechanisms driving metabolic remodeling in diabetic hearts and advanced methodology, highlighting the latest therapeutic strategies to mitigate the progression of DHF. Understanding these emerging pathways offers new opportunities to develop targeted therapies that address the root metabolic causes of heart failure in diabetes.

Peculiarities of brain cell functioning during hyperglicemia and diabetes mellitus

Hyperglycemia is a symptom and damaging factor of diabetes mellitus (DM) that leads to systemic complications in the body, including macro- and microangiopathies of the brain, impaired blood supply, the appearance of foci of neurodegeneration and might be a trigger of neuroinflammation. Nervous tissue is characterized by a high level of energy consumption and is highly sensitive to fluctuations in the level of metabolic substrates. Therefore, it is extremely important to study the effect of high glucose levels on the functional state of the central nervous system. This review attempts to comprehensively assess the effects of hyperglycemia on brain cells. Analysis of experimental data obtained in in vivo and in vitro models of diabetes on the morphofunctional state of neurons, microglia and astrocytes showed that the direct and indirect effects of glucose in high concentrations depends on the cell type. Receptors and intracellular signaling cascades of astrocytes and microglia, that mediate the effects of hyperglycemia and the development of neuroinflammation, can act as therapeutic targets for the correction for the consequences of diabetes. Thus, finding ways to modulate the functional activity of glial cells may be an effective strategy to reduce the severity of the consequences of CNS damage.

FABP5+ macrophages contribute to lipid metabolism dysregulation in type A aortic dissection

Type A aortic dissection (TAAD) is an acute onset disease with a high mortality rate. TAAD is caused by a tear in the aortic intima and subsequent blood infiltration. The most prominent characteristics of TAAD are aortic media degeneration and inflammatory cell infiltration, which disturb the structural integrity and function of nonimmune and immune cells in the aortic wall. However, to date, there is no systematic evaluation of the interactions between nonimmune cells and immune cells and their effects on metabolism in the context of aortic dissection. Here, multiomics, including bulk RNA-seq, single-cell RNA-seq, and lipid metabolomics, was applied to elucidate the comprehensive TAAD lipid metabolism landscape. Normally, monocytes in the stress response state secrete a variety of cytokines. Injured fibroblasts lack the ability to degrade lipids, which is suspected to contribute to a high lipid environment. Macrophages differentiate into fatty acid binding protein 5-positive (FABP5+) macrophages under the stimulation of metabolic substrates. Moreover, the upregulation of Fabp5+ macrophages were retrospectively validated in TAAD model mice and TAAD patients. Finally, Fabp5+ macrophages can generate a wide range of proinflammatory cytokines, which possibly contribute to TAAD pathogenesis.

Environmentally Persistent Free Radicals stimulate CYP2E1-mediated generation of reactive oxygen species at the expense of substrate metabolism.

Environmentally persistent free radicals (EPFRs) are a recently recognized component of particulate matter that cause respiratory and cardiovascular toxicity. The mechanism of EPFR toxicity appears to be related to their ability to generate reactive oxygen species (ROS), causing oxidative damage. EPFRs were shown to affect P450 function, inducing the expression of some forms through the Ah receptor. However, another characteristic of EPFRs lies in their ability to inhibit P450 activities. CYP2E1 is one of the P450s that is inhibited by EPFR (MCP230) exposure. As CYP2E1 is also known to generate ROS, it is important to understand the ability of EPFRs to influence the function of this enzyme and to identify the mechanisms involved. CYP2E1 was shown to be inhibited by EPFRs, and to a lesser extent by non-EPFR particles. As EPFR-mediated inhibition was more robust at subsaturating NADPH-cytochrome P450 reductase (POR) concentrations, disruption of POR·CYP2E1 complex formation and electron transfer were examined. Surprisingly, neither complex formation nor electron transfer between POR and CYP2E1 were inhibited by EPFRs. Examination of ROS production showed that MCP230 generated a greater amount of ROS than the non-EPFR CuO-Si. When a POR/CYP2E1-containing reconstituted system was added to the pollutant-particle systems there was a synergistic stimulation of ROS production. The results indicate that EPFRs cause inhibition of CYP2E1-mediated substrate metabolism, yet do not alter electron transfer and actually stimulate ROS generation. Taken together, the results are consistent with EPFRs affecting CYP2E1 function by inhibiting substrate metabolism and increasing the generation of ROS. Significance Statement Environmentally persistent free radicals affect CYP2E1 function by inhibition of monooxygenase activity. This inhibition is not due to disruption of the POR·CYP2E1 complex or inhibition of electron transfer, but due to uncoupling of NADPH and oxygen consumption from substrate metabolism to the generation of ROS. These results show that EPFRs block the metabolism of foreign compounds, and also synergistically stimulate the formation of reactive oxygen species that lead to oxidative damage within the organism.

Bioactive metabolites: a clue to the link between MASLD and CKD?

Metabolites produced as intermediaries or end-products of microbial metabolism provide crucial signals for health and diseases, such as metabolic dysfunction-associated steatotic liver disease (MASLD). These metabolites include products of the bacterial metabolism of dietary substrates, modification of host molecules [such as bile acids (BAs), trimethylamine-N-oxide, and short-chain fatty acids], or products directly derived from bacteria. Recent studies have provided new insights into the association between MASLD and the risk of developing chronic kidney disease (CKD). Furthermore, alterations in microbiota composition and metabolite profiles, notably altered BAs, have been described in studies investigating the association between MASLD and the risk of CKD. This narrative review discusses alterations of specific classes of metabolites, BAs, fructose, vitamin D, and microbiota composition that may be implicated in the link between MASLD and CKD.

Endophytic bacteria in Camellia reticulata pedicels: isolation, screening and analysis of antagonistic activity against nectar yeasts.

Camellia reticulata, an ancient plant species endemic to Yunnan Province, China, remains underexplored in terms of its endophytic bacterial communities. The plant tissue pedicel serves as the connection between the flower and the stem, not only delivers nutrients but also transmits metabolic substances from endophytic bacteria to the nectar during long-term microbial colonization and probably improves the antagonistic activity of nectar against yeast. Hence, 138 isolates of endophytic bacteria have been isolated in this study from the pedicels of 12- and 60-year-old C. reticulata. Comparative analysis revealed significantly higher density of endophytic bacteria in older trees. Among these isolates, 29 exhibited inhibitory effects against nectar yeasts. Most of the isolates displayed positive results for Gram staining, catalase reaction, gelatin liquefaction, and motility. Additionally, the isolates demonstrated the ability to utilize diverse substrates, such as glucose, nitrate, and starch. Based on 16S rRNA molecular biology analysis, these isolates were identified to be 11 different species of 6 genera, with the majority belonging to Bacillus genus. Notably, C1 isolate, identified as Bacillus spizizenii, exhibited strongest antagonistic effect against three yeasts, i.e., Metschnikowia reukaufii, Cryptococcus laurentii, and Rhodotorula glutinis, with minimum inhibitory concentration values below 250 μg/mL. Major metabolites of B. spizizenii were aminoglycosides, beta-lactams, and quinolones, which possess antimicrobial activities. Furthermore, KEGG enrichment pathways primarily included the synthesis of plant secondary metabolites, phenylpropanoids, amino acids, alkaloids, flavonoids, neomycin, kanamycin, and gentamicin. Therefore, antagonistic activity of B. spizizenii against yeasts could be attributed to these antibiotics. The findings highlight the diverse endophytic bacteria associated with C. reticulata, indicating their potential as a valuable resource of bioactive metabolites. Additionally, this study provides new insights into the role of endophytic bacteria of pedicels in enhancing nectar resistance against yeasts.