Modulation Of Metabolism Research Articles

Glutathione transferase omega 1-1 (GSTO1-1) can effect the inter-cell transfer of cisplatin resistance through the exosomal route.

Glutathione transferase omega-1-1 (GSTO1-1) is a member of the glutathione transferase superfamily (GSTs) involved in the modulation of cell survival, proliferation and metabolism. Increased levels of GSTO1-1 have been associated with cancer progression and chemoresistance in different types of cancer cells, possibly supported by the post-traslational regulation of some major prosurvival pathways regulated by the enzyme. Our data demonstrate for the first time that GSTO1-1 can be released by cancer cells through the exosomal route and transferred to GSTO1-1 knock-out cells, this resulting in an increased resistance against cisplatin toxicity in recipient cells. The use of the exosomal route to transfer the regulatory competences of GSTO1-1 could be a further element supporting its role in neoplastic progression.

Sodium-Glucose Cotransporter-2 Inhibition Normalizes Metabolic Derangements in the Ischemic Myocardium

IntroductionSodium-glucose cotransporter-2 inhibitors (SGLT2i) have shown efficacy in the context of heart failure but have not been well-studied in ischemic heart disease. We employed a large animal model of chronic coronary artery disease and metabolic syndrome (MS) to investigate the hemodynamic and metabolic consequences of SGLT2i administration. MethodsThirty-eight Yorkshire swine were divided into two groups, with half (n = 21) receiving a high fat diet to induce MS, and the other half fed a standard diet (n = 17). All animals underwent thoracotomy for ameroid constrictor placement over the left circumflex coronary artery. Treatment with SGLT2i was then initiated, generating four groups: regular diet placebo (CON, n = 9), regular diet canagliflozin (n = 8), high-fat control (n = 11), and high-fat canagliflozin (n = 10). After 5 wks, all animals underwent terminal myocardial harvest with pressure-volume loop acquisition, perfusion studies, and tissue resection for molecular analysis. ResultsSGLT2i improved multiple measures of myocardial performance, including a nearly 1.5-fold increase in both cardiac output and ejection fraction; these changes were associated with augmented capillary density and a twofold increase perfusion to the ischemic myocardium. These augmentations were blunted; however, in the presence of MS, and associated with modulated myocardial expression of multiple major metabolic enzymes. ConclusionsSGLT2i significantly improved cardiac function in our large animal model of coronary artery disease, with metabolic modulation of the myocardial tissue serving as a candidate account of these changes. The blunting seen with MS underscores the dependence of clinical translatability on faithful representation of the biochemical environment of human disease.

Impaired myocardial energetics and lower cardiac reserve in response to exercise stress in adults born preterm

Abstract Background/Introduction Preterm birth (<37 weeks’ gestation) affects 10% of live births globally and associates with an increased risk of heart failure, early cardiovascular-related mortality, and altered cardiac morphology. At rest, left ventricular (LV) ejection fraction (EF) is similar between adults born preterm and term, but right ventricular (RV) EF is lower in preterm-born adults. Exercise stress uncovers LVEF impairment in preterm-born adults but RVEF response to exercise stress has not been studied. The underlying cause of the impaired LVEF reserve and lower RVEF at rest in preterm-born adults remains uncertain and whether altered myocardial energetics contribute to this cardiac dysfunction is currently unknown. Purpose To measure resting myocardial energetics and ventricular function at rest and during exercise stress to determine whether reduced cardiac reserve in preterm-born adults may be explained by impaired myocardial energetics. Methods We conducted a cross-sectional, observational, case-control study of preterm (n=64; mean gestational age =31 weeks) and term-born (n=36) adults aged 34±5 years to compare myocardial energetics and ventricular function. Following maximal cardiopulmonary exercise testing (CPET), participants underwent 31-phosphorus magnetic resonance (MR) spectroscopy (31-P MRS) and cardiovascular MR imaging (CMR) on a 3-Tesla Siemens MR scanner. 31-P MRS was used to measure myocardial phosphocreatine to adenosine triphosphate ratio (PCr/ATP) as a measure of myocardial energetics. We obtained CMR-derived LVEF and RVEF at rest and during 40% peak wattage exercise (determined from CPET) using a MR compatible cardio-step module and steady-state free precession real-time cine imaging. Outcomes were analysed using unpaired Student’s t-tests and presented as mean±standard deviation. Results Age, body mass index, and sex did not differ between groups (p>0.05). PCr/ATP was 1.8±0.4 in preterm-born adults and 2.0±0.4 in term-born adults (p=0.01, Figure 1). Preterm-born adults had a similar LVEF versus term-born adults at rest (60.3±7.6 versus 62.1±4.5; p=0.19) though resting RVEF was lower in preterm-born adults (53.4±6.7 versus 55.9±4.5; p=0.05). LVEF increased by 6.5±5.5% in preterm-born adults and 10.9±6.0% in term-born adults from rest to 40% peak exercise (p<0.001), while RVEF increased by 9.2±6.3% in preterm-born adults versus 12.0±6.3% in term-born adults (p=0.06) (Figure 2). PCr/ATP associated with resting RVEF in preterm-born adults (R²=0.27, p=0.002), but was not associated with resting LVEF or the delta change in LVEF and RVEF with exercise stress. Conclusions Resting myocardial energetics is impaired in adults born preterm relative to term-born adults, with both the LV and RV demonstrating reduced functional reserve when challenged with low to moderate exercise stress. Metabolic modulators may help prevent progression to heart failure in preterm-born adults.Figure 1Figure 2

Targeting an altered sphingolipid profile with consecutive lipotoxicity as therapeutic approach to calcific aortic valve disease

Abstract Background Aortic stenosis due to calcific aortic valve disease (CAVD) is the most common valvular heart disease. In symptomatic patients, without repair the prognosis is poor. Treatment to date is based on surgery or catheter-based interventions. Pharmacological therapy options to prevent the progression of valve calcification are not available. In vascular smooth muscle cells, cellular accumulation of sphingolipids is associated with a proinflammatory response in the sense of lipotoxicity. Chronic inflammatory processes are indeed also essential for aortic valve calcification. Purpose With the subsequent goal of developing innovative treatment approaches for CAVD, we therefore aim to elucidate the unclear role of sphingolipids in the development of CAVD. Methods Human aortic valve and plasma samples of CAVD patients and controls (n=26) were analysed by liquid chromatography–mass spectrometry for lipidomics and proteomics. Human aortic valve interstitial cells (hVICs) were stimulated with ceramides. Calcification was detected by alizarin red staining. mRNA expression of bone-related proteins was determined by qPCR. NF-kB pathway was assessed by proteome profiler. Myriocin and GW4869 were applied to inhibit ceramide biosynthesis. PDTC and MCC950 were used to inhibit NF-kB Pathway and NLRP3 activation. ApoE-/- mice received a gain-of-function PCSK9 adeno-associated virus vector and fed high cholesterol diet for 14 weeks. Myriocin was applied orally over the treatment period to inhibit ceramide de novo synthesis in vivo. Murine echocardiography was used to measure transvalvular velocity and left ventricular function. Calcification degree of murine aortic valve was determined by histological staining. Results A significantly altered sphingolipid profile was observed in aortic valve tissue of CAVD patients (Fig. 1). Ceramide species e.g. Cer (17:1;2O/16:0) were increased. Verifying the biological relevance of these findings in vitro, C2-Cer (d18:1/2:0) enhanced hVIC calcification (Fig. 2). Accordingly, ALP activity and mRNA expression of osteogenic genes RUNX2, ALPL and MSX2 were increased. Furthermore, C2-Cer (d18:1/2:0) enhanced NF-kB p65 phosphorylation and NLRP3 activation, while treatment with both PDTC and MCC950 protected against C2-Cer (d18:1/2:0) induced calcification. Supporting the role of sphingolipid biosynthesis in hVIC calcification, Myriocin and GW4869 both reduced ox-LDL-induced VIC calcification which was reversed by C2-Cer(d18:1/2:0). Finally, Myriocin reduced the degree of calcification and transvalvular jet velocity of aortic valve in the PCSK9-AAV ApoE-/- mice model. Conclusion CAVD is accompanied by an accumulation of ceramides causing lipotoxicity in human aortic valve tissue. Pharmacological modulation of sphingolipid metabolism is an effective approach to prevent the development and progression of aortic valve calcification in vivo and should be considered as a future therapeutic strategy in CAVD patients.Volcano Plot of CAVD tissue lipidomicsC2 Ceramide enhances hVIC calcification

Adipose tissue/ heart lipid transport determines cardiac diastolic function

Abstract Introduction Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction and often occurring in obese individuals. Previous research has demonstrated that the modification of lipid metabolism can prevent the onset of diastolic dysfunction. In our project we have investigated how lipid transport influences the onset of diastolic dysfunction utilizing heart- and adipose tissue-specific knockdowns of the fatty acid (FA) transport protein 1 (FatP1) in Drosophila melanogaster. Methods We generated Drosophila with heart-specific (+/+; Hand4.2-GAL4/UAS-FatP1; tdtK/+) (cFatP1-KD) and adipose tissue-specific (+/+; ppl-GAL4/UAS-FatP1; tdtK/+) (atFat-P1-KD) FatP1 knockdowns using the UAS/GAL4 system. The flies' cardiomyocytes endogenously express tdTomato, facilitating fluorescence-based live imaging of the heart by high-resolution video fluorescence microscopy, as previously described. Cardiac morphology and cardiac lipid accumulation was monitored by confocal microscopy. Additionally, mitochondrial function was evaluated using the glycolytic Seahorse assay of whole hearts. Results Blocking FA-uptake into adipose tissue in atFatP1-KD flies resulted in a highly significant reduction in relaxation velocity (p=0.0009, WT vs. atFatP1-KD), indicative of diastolic dysfunction in flies, while contraction velocity and fractional shortening (systolic function) remained unchanged. Diastolic dysfunction was associated with a significant increase of cardiac lipid droplet (LD) quantity and size in flies lacking FatP1 in adipose tissue (p=0.0275 and p<0.0001, respectively, WT vs. atFatP1-KD). Cardiac mitochondrial function was significantly impaired in atFatP1-KD flies compared to WT flies. Reducing cardiac FA uptake in heart-specific FatP1 KD flies led to a decrease in end-diastolic diameter and a significant reduction in relaxation and contraction velocity (p<0.0001 and p=0.0001, respectively, WT vs. cFatP1-KD), suggesting impairment in both diastolic and systolic function. Interestingly, the number of cardiac LDs increased in cFATP1-KD, however their size decreased significantly resulting in an overall unchanged lipid content compared to WT flies (p=0.0475 and p=0.0367, respectively, WT vs. atFatP1-KD). Mitochondrial function showed no significant alterations. Conclusion This study demonstrates that reducing FA-uptake in adipose or cardiac tissue results in cardiac dysfunction in Drosophila melanogaster. Reduction of adipose tissue FA-uptake results exclusively in diastolic dysfunction likely mediated by cardiac lipid overload and subsequent mitochondrial dysfunction. In contrast, blockade of Fatp1-mediated cardiac FA-uptake induces diastolic/ systolic dysfunction which was unrelated to alterations in cardiac lipid content and mitochondrial dysfunction suggesting alternative mechanisms. These study identifies FatP1-mediated FA-uptake in adipose tissue as a potential therapeutic target for the treatment of diastolic dysfunction.

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

Candida tropicalis-derived vitamin B3 exerts protective effects against intestinal inflammation by promoting IL-17A/IL-22-dependent epithelial barrier function

ABSTRACT Candida tropicalis-a prevalent gut commensal fungus in healthy individuals – contributes to intestinal health and disease. However, how commensal C. tropicalis influences intestinal homeostasis and barrier function is poorly understood. Here, we demonstrated that the reference strain of C. tropicalis (MYA-3404) ameliorated intestinal inflammation in murine models of chemically induced colitis and bacterial infection. Intestinal colonization of C. tropicalis robustly upregulated the expression of IL-17A and IL-22 to increase barrier function and promote proliferation of intestinal epithelial cells in the mouse colon. Metabolomics analysis of fecal samples from mice colonized with C. tropicalis revealed alterations in vitamin B3 metabolism, promoting conversion of nicotinamide to nicotinic acid. Although nicotinamide worsened colitis, treatment with nicotinic acid alleviated disease symptoms and enhanced epithelial proliferation and Th17 cell differentiation. Oral gavage of C. tropicalis mitigated nicotinamide-induced intestinal dysfunction in experimental colitis. Blockade of nicotinic acid production with nicotinamidase inhibitors lowered the protective effects against colitis in mice treated with C. tropicalis. Notably, a clinical C. tropicalis strain isolated from patients with candidemia lacked the protective effects against murine colitis observed with the reference strain. Together, our results highlight a novel role for C. tropicalis in resolving intestinal inflammation through the modulation of vitamin B3 metabolism.

Recombinant leptins affect lipid metabolism in hepatocytes of Cynoglossus semilaevis

Leptin is a peptide hormone primarily produced by adipose tissue, which plays a crucial role in regulating energy balance by controlling appetite and energy expenditure. To better understand the intricate physiological functions of leptin in hepatocytes in tongue sole (Cynoglossus semilaevis), this study presents an integrated transcriptomic and metabolomic analysis of tongue sole hepatocytes following stimulation with lepA and lepB. Comparative analysis identified 2971 and 2900 upregulated differentially expressed genes (DEGs) and 1895 and 1821 downregulated DEGs in response to lepA and lepB stimulation, respectively. Notably, 5706 genes were commonly regulated by both stimulations, suggesting overlapping functional roles of these two leptin proteins. GO and KEGG enrichment analysis indicated significant enrichment in immune response (JAK-STAT signaling pathway, NF-κB signaling pathway, etc.) and lipid metabolism pathways, such as fatty acid synthesis, with similar findings for lepB. Metabolomic analysis demonstrated clear separation between treatment and control groups, with 34 medium- to long-chain fatty acids and numerous differentially expressed metabolites (DEMs) identified. KEGG analysis of the metabolome paralleled the transcriptomic findings, with shared pathways in lipid metabolism and immune function. Finally, joint analysis highlighted co-enrichment in linoleic acid metabolism and leishmaniasis pathways. Detailed mechanistic insights revealed the activation of JAK-STAT and NF-κB signaling pathways, modulation of arachidonic acid metabolism, and the influence on the MAPK signaling pathway. Additionally, lepA uniquely co-enriched in the fatty acid synthesis pathway, with specific gene regulation affecting the synthesis of various fatty acids. The study concluded that lepA and lepB exerted significant regulatory effects on lipid metabolism and immune responses in tongue sole hepatocytes through complex molecular networks. To our current knowledge, this represents the first direct evidence of leptin's role in immune function within teleost fish and offers valuable insights into the molecular mechanisms of lipid metabolism underlying the actions of lepA and lepB.

Intravenous administration of gold nanoparticles in rats exhibit alterations in sphingomyelins, bile acids, sphingolipids, and cholesterol esters levels

AbstractNanoparticles (NP) have gained significant attention in biomedical research due to their unique properties and potential applications in drug delivery, imaging, and diagnostics. Gold (AuNPs) and silver (AgNPs) NPs are among the important nanoplatforms that received extensive attention recently for various biomedical applications. Understanding the complex interaction of these NP in biological systems is essential to unveil their pharmacological, Pharmacokinetic and toxicological attributes. Metabolomics has proven invaluable in providing detailed insights into NP’s biodistribution, metabolic effects, and potential toxicity. This study aims to investigate the underlying metabolic pathways affected by in vivo exposure to NP using a robust metabolomics approach. In this work, spherical polyethylene glycol (PEG) modified AuNPs (13 nm, diameter) or AgNPs (20 nm, diameter) were synthesized and dosed into rats via intravenous route to study the associated metabolic changes. Rats (n = 14) were divided into three groups: control (n = 2), AuNPs (n = 6) and AgNPs (n = 6), to mimic potential biomedical exposure scenarios. Duplicate serum samples were collected 24 h post-dosing, and comprehensive metabolite profiling was performed using liquid chromatography-mass spectrometry (LC-MS/MS) and flow injection analysis-mass spectrometry (FIA-MS/MS). Metabolite extraction followed the MxP Quant 500 Kit protocol, with chromatographic separation using the Xevo TQS system. Metabolite identification and quantification were conducted with isotopically labelled internal standards and multiple reaction monitoring (MRM), utilizing optimized conditions under mass spectrometry (MS) as provided by Biocrates. Annotation of metabolites was determined by retention times and specific MRMs for each compound. Results indicate that AuNPs treatment significantly impacted several metabolic pathways. Notably, there was an increase in sphingomyelin (SM 34:2) levels (estimate 0.23, p ≤ 0.001), which are critical for cell membrane structure and signalling. Additionally, a decrease in glycochenodeoxycholic acid levels was also triggered by treatment with AuNPs, suggesting modulation of bile acid metabolism with potential effects on lipid homeostasis. Furthermore, treatment with AuNPs caused significant alterations in cholesterol ester levels, essential for lipid storage and transport, indicating disruptions in these mechanisms. These metabolic changes suggest that gold nanoparticles can disrupt fatty acid metabolism, pyrimidine/purine metabolism, and amino acid synthesis. These findings contribute to the growing understanding of nanoparticle toxicity profile and underscore the need for further research to ensure the safe application of nanoparticles in biomedical and other fields.

The Research Progress of Metformin Regulation of Metabolic Reprogramming in Malignant Tumors.

Metabolism reprogramming is a crucial hallmark of malignant tumors. Tumor cells demonstrateenhanced metabolic efficiency, converting nutrient inputs into glucose, amino acids, and lipids essential for theirmalignant proliferation and progression. Metformin, a commonly prescribed medication for type 2 diabetes mellitus,has garnered attention for its potential anticancer effects beyond its established hypoglycemic benefits. This review adopts a comprehensive approach to delineate the mechanisms underlying metabolite abnormalities within the primary metabolic processes of malignant tumors. This review examines the abnormal activation of G protein-coupled receptors (GPCRs) in these metabolic pathways, encompassing aerobic glycolysis with increased lactate production in glucose metabolism, heightened lipid synthesis and cholesterol accumulation in lipid metabolism, and glutamine activation alongside abnormal protein post-translational modifications in amino acid and protein metabolism. Furthermore, the intricate metabolic pathways and molecular mechanisms through which metformin exerts its anticancer effects are synthesized and analyzed, particularly its impacts on AMP-activated protein kinase activation and the mTOR pathway. The analysis reveals a multifaceted understanding of how metformin can modulate tumor metabolism, targeting key nodes in metabolic reprogramming essential for tumor growth and progression. The review compiles evidence that supports metformin's potential as an adjuvant therapy for malignant tumors, highlighting its capacity to interfere with critical metabolic pathways. In conclusion, this review offers a comprehensive overview of the plausible mechanisms mediating metformin's influence on tumor metabolism, fostering a deeper comprehension of its anticancer mechanisms. By expanding the clinical horizons of metformin and providing insight into metabolism-targeted tumor therapies, this review lays the groundwork for future research endeavors aimed at refining and advancing metabolic intervention strategies for cancer treatment.

Dietary supplementation of probiotic Lactobacillus modulates metabolic dysfunction-associated steatotic liver disease and intestinal barrier integrity in obesity-induced mice.

The impact of Lacticaseibacillus paracasei NWAFU334 and Limosilactobacillus fermentum NWAFU0035 on the amelioration of liver function, oxidative stress reduction, and lipid metabolism modulation in mice subjected to an obesity-inducing high-fat diet (HFD) model was investigated. L. paracasei NWAFU334 and L. fermentum NWAFU0035 supplementations over 12weeks have been shown to have numerous beneficial effects in mice with induced obesity. These effects comprise the restoration of liver function and the reduction of oxidative stress within the liver. Furthermore, the supplementation led to a decreased content of fat accumulation in the liver, mitigation of the expression of inflammatory cytokines in the liver and colon, and a decrease in the expression levels of tight-junction proteins, for example, claudin-1, PPARγ, occludin, and ZO-1. Additionally, a notable improvement in the colonic expression proteins, including IL-6, TNF-α, IL-1β, Muc-2, Muc-3, Zo-1, claudin-1, and occludin. These proposed strains considerably decreased proinflammatory cytokines and influenced the regulation of lipid metabolism in the liver. These findings indicate that the potential mechanisms, primarily the impact of L. paracasei NWAFU334 and L. fermentum NWAFU0035 on obesity-induced liver function in mice, involve two regulated pathways: downregulation of lipogenesis and upregulation of gene expression related to fatty acid oxidation and lipolysis. In other words, these probiotic bacterial strains might be beneficial in reducing fat production and increasing fat breakdown in the liver. They may serve as effective therapeutic supplements for alleviating abnormalities induced by an HFD.

Variability of plant transcriptomic responses under stress acclimation: a review from high throughput studies

Plant transcriptomes are complex entities shaped spatially and temporally by a multitude of stressors. The aim of this review was to summarize the most relevant transcriptomic responses to selected abiotic (UV radiation, chemical compounds, drought, suboptimal temperature) and biotic (bacteria, fungi, viruses, viroids) stress conditions in a variety of plant species, including model species, crops, and medicinal plants. Selected basic and applicative studies employing RNA-seq from various sequencing platforms and single-cell RNA-seq were involved. The transcriptomic responsiveness of various plant species and the diversity of affected gene families were discussed. Under stress acclimation, plant transcriptomes respond particularly dynamically. Stress response involved both distinct, but also similar gene families, depending on the species, tissue, and the quality and dosage of the stressor. We also noted the over-representation of transcriptomic data for some plant organs. Studies on plant transcriptomes allow for a better understanding of response strategies to environmental conditions. Functional analyses reveal the multitude of stress-affected genes as well as acclimatory mechanisms and suggest metabolome diversity, particularly among medicinal species. Extensive characterization of transcriptomic responses to stress would result in the development of new cultivars that would cope with stress more efficiently. These actions would include modern methodological tools, including advanced genetic engineering, as well as gene editing, especially for the expression of selected stress proteins in planta and for metabolic modifications that allow more efficient synthesis of secondary metabolites.

Bacillus amyloliquefaciens MZ895491: an endophytic bacterium as potential biocontrol agent in integrated pest management of fall armyworm in maize

ABSTRACT The fall armyworm, Spodoptera frugiperda is a major pest of maize crops and necessitates effective control measures. Excessive use of chemical pesticides often results in the development of resistant insect populations and environmental contamination, highlighting the need for environmentally friendly substitutes. This research aimed to estimate the potential of maize (COH6) apoplastic fluid bacterium Bacillus amyloliquefaciens (MZ895491), as a biocontrol agent against second instar S. frugiperda larvae under laboratory and pot culture conditions. The results suggest that the presence of B. amyloliquefaciens in the artificial diet could reduce the growth and development of S. frugiperda larvae. Metabolic profiling of extracellular components of B. amyloliquefaciens revealed the presence of numerous defensive and anti-feeding metabolites. A study conducted in pots demonstrated that foliar application of B. amyloliquefaciens to 5 d old maize resulted in a significant increase in antioxidant activity (83.3%), chlorophyll content (63.3%) and phenolic content (81.3%) in the leaves of 35 d old maize after 24 h of S. frugiperda infestation. Feeding bioassay further indicated significant reduction in the feeding capacity of S. frugiperda larvae on maize inoculated with B. amyloliquefaciens. The study observed that a metabolic modification in maize leaves likely led to reduced growth in larvae during the whole plant bioassay. This suggests that foliar application of B. amyloliquefaciens may effectively serve as one of the biocontrol agents against Spodoptera frugiperda. The application appears to alter the feeding behaviour of the larvae and modify maize leaf metabolism.

Modulation of Redox Metabolism, CD147, and CD47 Expression with the Maturation of Hematopoietic Stem Cells in Bone Marrow

Modulation of Redox Metabolism, CD147, and CD47 Expression with the Maturation of Hematopoietic Stem Cells in Bone Marrow

Effects of three elicitors on primary metabolism six days after treatment in healthy <i>Vitis vinifera</i> leaves and eight days after treatment in healthy and downy mildew-inoculated leaves

Elicitors can be used to reduce the application of conventional pesticides against grapevine diseases; however, they may disrupt plant primary metabolism. The long-term effects (more than 6 days after treatment) of applying plant defence stimulators (PDS) to protect grapevine from Plasmopara viticola were investigated. We studied the effect of three PDS (acibenzolar-S-methyl/ASM, potassium phosphonate/PHOS, methyl jasmonate/MeJA) and one surfactant (Triton) on gene expression and metabolite production in leaves of Vitis vinifera cv. Cabernet-Sauvignon before or after their inoculation with P. viticola. The molecular and biochemical results show the impact of these PDS on grapevine metabolism more than 6 days after treatment, and after inoculation. High-throughput q-RT-PCR revealed that sixty of the primary metabolism genes (ion homeostasis and hormones pathways) were modulated by all treatments, some modulations being specific to a given PDS. Meanwhile, 1H NMR studies revealed variations in metabolite abundances (amines, amino acids, organic acids, polyphenols and sugars), with some being common to all treatments (organic acid increase) and others specific to a single one. By combining two methodological approaches, it was possible to determine the specific effects of each PDS on Vitis. All PDS-induced resistance involved modulation of the primary metabolism. This innovative approach can be extended to vineyard studies in order to help better understand the variability of PDS effects in natura.

Oral co-administration of Lactiplantibacillus plantarum 16 and Lacticaseibacillus rhamnosus P118 improves host defense against influenza A virus infection.

Influenza is an important zoonotic disease that persistently threatens global public health. While it is widely acknowledged that probiotics can modulate the host response to protect the host against infectious disease, the prophylactic efficacy on respiratory viral infection and the detailed mechanism remains elusive. Lactobacillus, the most commonly used probiotic widely applied in food production, has garnered significant attention. In our study utilizing both C57BL/6 and BALB/c mouse models, we explored the protective effect against two strains of influenza virus, A/Mink/China/01/2014(H9N2) and A/California/04/2009(H1N1), through the administration of Lactiplantibacillus plantarum strain 16 (L. plantarum 16) and Lacticaseibacillus rhamnosus strain P118 (L. rhamnosus P118), aiming to identify robust probiotic strains with antiviral properties. Our findings indicate that administering L. plantarum 16 or L. rhamnosus P118 alone does not provide sufficient protection against influenza. However, the co-administration of L. plantarum 16 and L. rhamnosus P118 dramatically reduces viral titers in the respiratory tract and lung, thereby markedly alleviating the clinical symptoms, improving prognosis, and reducing mortality. The mechanisms underlying this effect involve the modulation of host gut microbiota and metabolism through the co-administration of L. plantarum 16 and L. rhamnosus P118, resulting in enrichment of Firmicutes and enhancement of phenylalanine-related metabolism, ultimately leading to an augmentation of the antiviral immune response. Notably, we identified that the circulating metabolic molecule 2-Hydroxycinnamic acid plays a significant role in combating influenza. Our data suggest the potential utility of L. plantarum 16 and L. rhamnosus P118 two-bacterium or 2-Hydroxycinnamic acid in preventing influenza.IMPORTANCEVaccination represents the most optimal strategy to control influenza. Nevertheless, influenza viruses constantly evolve due to antigenic drift and shift, leading to the need for regular updates on influenza vaccines. Additionally, vaccination failure poses significant challenges to influenza prevention. Therefore, it is essential and beneficial to identify novel or universal antiviral measures to protect against influenza. While cumulative data suggest that probiotics offer protection against infectious diseases, the specific mechanisms, such as the effective metabolites or components, remain largely unknown. Our research discovered the capacity of combinational two-bacterium Lactiplantibacillus plantarum 16 and Lacticaseibacillus rhamnosus P118 to fight against influenza infection in a mouse model. The protection may occur through modulating the host's gut microbiota and metabolism, further influencing the host's antiviral immune response. Notably, we have identified a novel metabolic molecule, 2-Hydroxycinnamic acid, capable of enhancing antiviral response and restricting viral replication in vivo.

β-catenin-inhibited Sumoylation modification of LKB1 and fatty acid metabolism is critical in renal fibrosis

Liver kinase B1 (LKB1) is a serine/threonine kinase controlling cell homeostasis. Among post-translational modification, Sumoylation is vital for LKB1 activating adenosine 5’-monophosphate (AMP)-activated protein kinase (AMPK), the key regulator in energy metabolism. Of note, AMPK-regulated fatty acid metabolism is highly involved in maintaining normal renal function. However, the regulative mechanisms of LKB1 Sumoylation remain elusive. In this study, we demonstrated that β-catenin, a notorious signal in renal fibrosis, inhibited the Sumoylation of LKB1, thereby disrupting fatty acid oxidation in renal tubular cells and triggering renal fibrosis. Mechanically, we found that Sumo3 was the key mediator for LKB1 Sumoylation in renal tubular cells, which was transcriptionally inhibited by β-catenin/Transcription factor 4 (TCF4) signaling. Overexpression of Sumo3, not Sumo1 or Sumo2, restored β-catenin-disrupted fatty acid metabolism, and retarded lipid accumulation and fibrogenesis in the kidney. In vivo, conditional knockout of β-catenin in tubular cells effectively preserved fatty acid oxidation and blocked lipid accumulation by maintaining LKB1 Sumoylation and AMPK activation. Furthermore, ectopic expression of Sumo3 strongly inhibited Wnt1-aggravated lipid accumulation and fibrogenesis in unilateral ischemia-reperfusion mice. In patients with chronic kidney disease, we found a loss of Sumo3 expression, and it was highly related to LKB1 repression. This contributes to fatty acid metabolism disruption and lipid accumulation, resulting in renal fibrosis. Overall, our study revealed a new mechanism in fatty acid metabolism dysfunction and provided a new therapeutic target pathway for regulating Sumo modification in renal fibrosis.

Bioactive Compounds and Their Chondroprotective Effects for Osteoarthritis Amelioration: A Focus on Nanotherapeutic Strategies, Epigenetic Modifications, and Gut Microbiota

In degenerative joint disease like osteoarthritis (OA), bioactive compounds like resveratrol, epigallocatechin gallate, curcumin, and other polyphenols often target various signalling pathways, including NFκB, TGFβ, and Wnt/β-catenin by executing epigenetic-modifying activities. Epigenetic modulation can target genes of disease pathophysiology via histone modification, promoter DNA methylation, and non-coding RNA expression, some of which are directly involved in OA but have been less explored. OA patients often seek options that can improve the quality of their life in addition to existing treatment with nonsteroidal anti-inflammatory drugs (NSAIDs). Although bioactive and natural compounds exhibit therapeutic potential against OA, several disadvantages loom, like insolubility and poor bioavailability. Nanoformulated bioactive compounds promise a better way to alleviate OA since they also control systemic events, including metabolic, immunological, and inflammatory responses, by modulating host gut microbiota that can regulate OA pathogenesis. Recent data suggest gut dysbiosis in OA. However, limited evidence is available on the role of bioactive compounds as epigenetic and gut modulators in ameliorating OA. Moreover, it is not known whether the effects of polyphenolic bioactive compounds on gut microbial response are mediated by epigenetic modulatory activities in OA. This narrative review highlights the nanotherapeutic strategies utilizing bioactive compounds, reporting their effects on chondrocyte growth, metabolism, and epigenetic modifications in osteoarthritis amelioration.

Automatic metabolism modulator for glycolytic intervention‐induced cascade cancer therapy

AbstractEffective intervention in glycolytic metabolism is a promising way to inhibit tumor malignant invasion. However, the inherent hypoxia environment and unitary regulating model subsequently compromise its therapeutic efficacy. Herein, a facile way to design an automatic metabolism modulator (auto‐MMOD) is developed by loading glucose oxidase (GOx) and DNA‐templated silver nanoclusters (DNA‐AgNCs) into a pH‐responsive zeolitic imidazolate frameworks‐8 (ZIF‐8) nanocarrier, which can activate a cascaded metal ion‐killing effect during GOx‐regulated glycolysis metabolism. When the acidic lysosome microenvironment induces ZIF‐8 decomposition, the released GOx can effectively consume glucose and generate H2O2, thus inhibiting Adenosine Triphosphate synthesis and accelerating tumor starvation. Moreover, the released Ag+ in response to H2O2 can disturb bioenergy metabolism to inhibit tumor proliferation, which further enhances the tumor‐killing effect in hypoxic microenvironments. This study achieves effective tumor suppression in vitro and in vivo by integrating ion therapy into glycolysis intervention, which establish a promising strategy for nano‐theranostics.

Exogenous Nitric Oxide Induces Pathogenicity of Alternaria alternata on Huangguan Pear Fruit by Regulating Reactive Oxygen Species Metabolism and Cell Wall Modification.

Black spot caused by Alternaria alternata is one of the most common postharvest diseases in fruit and vegetables. A comprehensive investigation into its pathogenicity mechanism is imperative in order to propose a targeted and effective control strategy. The effect of nitric oxide (NO) on the pathogenicity of A. alternata and its underlying mechanism was studied. The results showed that treatment with 0.5 mM L-1 of sodium nitroprusside (SNP) (NO donor) increased the lesion diameter of A. alternata in vivo and in vitro, which was 22.8% and 13.2% higher than that of the control, respectively. Exogenous NO treatment also induced endogenous NO accumulation by activating nitric oxide synthase (NOS). In addition, NO triggered an increase in reactive oxygen species (ROS) levels. NO enhanced activities and gene expression levels of NADPH oxidase (NOX), superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX), glutathione peroxidase (GPX), and glutathione reductase (GR). Moreover, NO stimulated cell wall degrading enzymes by activating the corresponding gene expression in vivo and in vitro. These results suggested that exogenous NO promoted the pathogenicity of A. alternata by inducing ROS accumulation and activating antioxidants and cell wall degrading enzymes. The present results could establish a theoretical foundation for the targeted control of the black spot disease in pear fruit.