Analysis Of Metabolomic Profiles Research Articles

Integrated analysis of metabolomic and transcriptomic profiles elucidates the core role of glycerophospholipid metabolism in hypertension related to metabolic syndrome

BackgroundMetabolic syndrome (MetS) represents a comprehensive framework that encompasses conditions such as diabetes, hypertension (HBP), obesity, and dyslipidemia. MetS without hypertension significantly contributes to the development of refractory hypertension. However, the underlying molecular regulatory mechanisms of hypertension associated with MetS remain incompletely elucidated. The objective of this study was to identify differences in plasma metabolome and leukocyte transcriptome profiles between patients with MetS comorbid HBP compared to those with MetS with hypertension and HBP alone. MethodsIn this study, whole blood samples were collected from 104 participants, including patients with HBP, MetS without hypertension (MS), and MetS with hypertension (MS-HBP). Ultra-high-performance liquid chromatography was employed to perform metabolomic analysis of plasma samples. Comparative analysis was conducted to identify distinct metabolites among the three groups, while MetaboAnalyst 5.0 was utilized for enrichment and pathway analysis. Clinical correlation analysis and receiver operating characteristic analyses were applied to select biomarker metabolites for MS-HBP. Transcriptomic profiling of white blood cells was performed to identify dysregulated genes and KEGG/GO pathways. Integrative analysis of metabolomics and transcriptomics was used to construct molecular interaction networks. Finally, blood pressure was monitored every 2 weeks during the treatment period for experimental validation. ResultsThe metabolomic results indicated that lipid metabolic pathways, particularly glycerophospholipid metabolic pathways, played a crucial role in MS-HBP. The area under the curve of tryptophan-isoleucine for diagnosis in the MS-HBP group was 0.82. Tryptophyl-isoleucine demonstrated a negative correlation with both HbA1c and diastolic blood pressure. Transcriptomic analysis revealed the involvement of MS-HBP in numerous immune and inflammatory pathways. Furthermore, the integrated analysis of metabolomic and transcriptomic data emphasized the importance of glycerophospholipid metabolism in MS-HBP. PPC exhibited a comparable effect on lowering blood pressure in SHR rats. ConclusionThe findings of this study demonstrated that glycerophospholipid metabolism plays a pivotal role in the pathophysiological processes of MS-HBP, providing novel insights into early clinical diagnosis and the optimization of therapeutic strategies.

Untargeted Metabolomic Profiling of Extracellular Vesicles Isolated from Human Seminal Plasma.

Seminal extracellular vesicles (SemEVs) are repositories of biomolecules, including metabolites involved in the regulation of sperm function. The correlation between the metabolite profile of SemEVs and semen parameters, along with their role in regulating sperm function, is an unexplored area. This preliminary study evaluated the metabolomic content of SemEVs. Semen samples were obtained from 18 healthy men, and SemEVs were extracted from seminal plasma using the size exclusion chromatography qEV Gen 2-35 nm column coupled with an automatic fraction collector. The physical characterization of SemEVs was carried out with the ZetaView PMX-430-Z QUATT laser system. EV protein markers were detected using Western blot. In addition, these SemEVs were used for metabolomic profiling and functional bioinformatic analysis. The mean concentration of isolated SemEVs was 1.7 ± 1.1 × 1011/mL of seminal plasma, whereas SemEVs size and zeta potential were 129.5 ± 5.5 nm and -40.03 ± 3.99 mV, respectively. Western blot analysis confirmed the presence of EV specific markers such as CD81, ALIX, and TSG101. A total of 107 metabolites were identified using this untargeted metabolomic approach in SemEVs. Bioinformatics analysis further revealed that metabolites associated with tyrosine metabolism were highly enriched in these SemEVs. Ingenuity Pathway Analysis (IPA) also indicated that these metabolites present in SemEVs were involved in the regulation of the free radical scavenging pathway. Furthermore, our metabolomic results suggest that these SemEV-associated metabolites may play a pivotal role in the maintenance of seminal plasma redox homeostasis.

PSIII-27 Blood biochemistry, histology, and metabolomic profiling of contaminated with mycotoxin: A repeated dose oral toxicity study in rats

Abstract Mycotoxins causes diseases and physiological responses in humans and livestock. This study was performed to estimate the effects of binary mixtures mycotoxin {e.g., deoxynivalenol (DON) and fumonisin (FB)] on blood biochemistry, histology, and metabolic profiles in rats fed with different toxin concentrations. Experimental animals were administered by oral gavage with 0.9% saline, DON (1, 5, and 10 mg/kg BW), FB (1, 5, and 10 mg/kg) at 8 wk of age. Histological changes, metabolomic profiling, and blood biochemical analysis were performed Masson’s trichrome stain kit, liquid chromatography mass spectrometry, and VetTest chemistry analyzer, respectively. The final BW of the rats contaminated with mixtures mycotoxin significantly decreased compared with the control group. Biochemistry results and fibrosis were also significantly differentially regulated according to mycotoxin concentrations. Additionally, we observed collagen fibers in the liver and kidney showed blue staining after toxin contamination. For metabolomic profiling, data were analyzed using MetaboAnalyst 4.0. Results were analyzed by multivariate analysis to elucidate the potential compounds. The toxin-treated groups observed discriminating metabolites in the liver and kidney tissue but no differences in ileum. The profiling revealed potential metabolites such as glycine, serine and threonine metabolism. Phosphatidylethanolamine and tryptophan were identified with high sensitivity as candidate biomarkers via variable importance in the projection plot in piglets fed with mycotoxin (FDR < 0.05; P < 0.05). The differently treated groups showed discriminating metabolites in different concentrations. In conclusion, these findings suggest that mycotoxin exposure disturbs histological changes and metabolites. Dietary toxins in rats may better understand the physiological effects consistent with metabolism, which are commonly reported in animals.

1H-NMR-based metabolomic profiling and proteomic analysis of soybean (Glycine max L.) in response to dicarboxylic acids (photon) application as a stress priming agent

Soybean (Glycinemax L.) serves not only as food for humans, animals, and industrial purposes, but is also a plant that can be used to comprehend molecular mechanisms occurring in stress response to various development techniques. To reveal the effect of applying dicarboxylic acids as stress priming agents on a metabolic level in soybean leaf extracts, the chemical profile of methanolic extracts were collected at different time points (1 h, 2 h, 12 h, 24 h, 1 week, 2 weeks and 3 weeks) after spraying were analyzed using 1H-NMR based metabolomics by way of PCA and OPLS-DA. The OPLS-DA revealed several metabolites, including organic acids (fumarate, citrate and malate) and amino acids (asparagine, alanine and GABA), which accumulated in higher amounts, with fumarate accumulating the highest in Glycinemax L. leaf extracts compared to untreated leaves. Denaturing 1DE gels were prepared for MS-based protein analysis and the presence of fatty acids (linolenic, oleic and α-linolenic acid) were confirmed by gas chromatography coupled with mass spectrometry (GC-MS), which served as jasmonic acid precursors. The MS-based profiling of proteins on the denaturing 1DE gels revealed several proteins that were differentiated between the treated and untreated leaf extracts. These proteins included ferritins, CaM, ferredoxin-thioredoxin reductase and chalcone-flavanone isomerase 1A. Following the treatment, fumarate was significantly elevated at 12 h to 3 weeks, compared to other compounds. It is, therefore, proposed that elevated quantities of fumarate could be related to the KEAP1-NRF2 metabolic pathway. This study represents the initial investigation of the effect of dicarboxylic acid application as a stress priming agent on Glycinemax L. using 1H-NMR metabolomic analysis, GC-MS and proteomic analysis.

Vernonia amygdalina Leaf Extract Induces Apoptosis in HeLa Cells: A Metabolomics and Proteomics Study.

Medicinal plants produce various bioactive molecules with potential anti-cancer properties with favorable safety profiles. We aimed to investigate the comprehensive composition of Vernonia amygdalina leaf extract and its cytotoxic effects via apoptosis in HeLa cells. The metabolomics approach using LC-MS/MS was conducted to gather the metabolite profile of the extract. Proteomics was performed to understand the comprehensive mechanistic pathways of action. The apoptosis was visualized by cellular staining and the apoptotic proteins were evaluated. V. amygdalina leaf extract exhibited dose-dependent cytotoxic effects on both HeLa and Vero cells after 24 h of exposure in the MTT assay with the IC50 values of 0.767 ± 0.0334 and 4.043 ± 0.469 µg mL-1, respectively, which demonstrated a higher concentration required for Vero cell cytotoxicity. The metabolomic profile of 112 known metabolites specified that the majority of them were alkaloids, phenolic compounds, and steroids. Among these metabolites, deacetylvindoline and licochalcone B were suggested to implicate cytotoxicity. The cytotoxic pathways involved the response to stress and cell death which was similar to doxorubicin. The upstream regulatory proteins, phosphatase and tensin homolog deleted on chromosome ten (PTEN) and X-box binding protein 1 (XBP1), were significantly altered, supporting the regulation of apoptosis and cell death. The levels of apoptotic proteins, c-Jun N-terminal kinases (JNK), p53, and caspase-9 were significantly increased. The novel insights gained from the metabolomic profiling and proteomic pathway analysis of V. amygdalina leaf extract have identified crucial components related to apoptosis induction, highlighting its potential to develop future chemotherapy.

Metabolic alterations in vitamin D deficient systemic lupus erythematosus patients

Vitamin D deficiency is increasingly common in systemic lupus erythematosus (SLE) patients and is associated with the disease activity and proteinuria. Recently, alterations in metabolism have been recognized as key regulators of SLE pathogenesis. Our objective was to identify differential metabolites in the serum metabolome of SLE with vitamin D deficiency. In this study, serum samples from 31 SLE patients were collected. Levels of 25(OH)D3 were assayed by ELISA. Patients were divided into two groups according to their vitamin D level (20 ng/ml). Untargeted metabolomics were used to study the metabolite profiles in serum by high-performance liquid chromatography-tandem mass spectrometry. Subsequently, we performed metabolomics profiling analysis to identify 52 significantly altered metabolites in vitamin D deficient SLE patients. The area under the curve (AUC) from ROC analyses was calculated to assess the diagnostic potential of each candidate metabolite biomarker. Lipids accounted for 66.67% of the differential metabolites in the serum, highlighted the disruption of lipid metabolism. The 52 differential metabolites were mapped to 27 metabolic pathways, with fat digestion and absorption, as well as lipid metabolism, emerging as the most significant pathways. The AUC of (S)-Oleuropeic acid and 2-Hydroxylinolenic acid during ROC analysis were 0.867 and 0.833, respectively, indicating their promising diagnostic potential. In conclusion, our results revealed vitamin D deficiency alters SLE metabolome, impacting lipid metabolism, and thrown insights into the pathogenesis and diagnosis of SLE.

Metabolomic profiling analysis reveals the benefits of ginseng berry intake on mitochondrial function and glucose metabolism in the liver of obese mice.

Ginseng berry (GB) has previously been demonstrated to improve systemic insulin resistance and regulate hepatic glucose metabolism and steatosis in mice with diet-induced obesity (DIO). In this study, the role of GB in metabolism was assessed using metabolomics analysis on the total liver metabolites of DIO mice. Metabolomic profiling was performed using capillary electrophoresis time-of-flight mass spectrometry (CE-TOF/MS) of liver tissue from mice on a 12-wk normal chow diet (NC), high-fat diet (HFD), and HFD supplemented with 0.1% GB (HFD + GB). The detected metabolites, its pathways, and functions were analyzed through partial least square discriminant analysis (PLS-DA), the small molecular pathway database (SMPDB), and MetaboAnalyst 5.0. The liver metabolite profiles of NC, HFD, and GB-fed mice (HFD + GB) were highly compartmentalized. Metabolites involved in major liver functions, such as mitochondrial function, gluconeogenesis/glycolysis, fatty acid metabolism, and primary bile acid biosynthesis, showed differences after GB intake. The metabolites that showed significant correlations with fasting blood glucose (FBG), insulin, and homeostatic model assessment for insulin resistance (HOMA-IR) were highly associated with mitochondrial membrane function, energy homeostasis, and glucose metabolism. Ginseng berry intake increased the levels of metabolites involved in mitochondrial membrane function, decreased the levels of metabolites related to glucose metabolism, and was highly correlated with metabolic phenotypes. This study demonstrated that long-term intake of GB changed the metabolite of hepatosteatotic livers in DIO mice, normalizing global liver metabolites involved in mitochondrial function and glucose metabolism and indicating the potential mechanism of GB in ameliorating hyperglycemia in DIO mice.

Biofortification, metabolomic profiling and quantitative analysis of vitamin B12 enrichment in guava juice via lactic acid fermentation using Levilactobacillus brevis strain KU15152.

Chemical fortification and dose supplementation of vitamin B12 are widely implemented to combat deficiency symptoms. However, in situ, fortification of vitamin B12 in food matrixes can be a promising alternative to chemical fortification. The present study aimed to produce vitamin B12-rich, probiotic guava juice fermented with Levilactobacillus brevis strain KU15152. Pasteurized fresh guava juice was inoculated with 7.2 log CFU mL-1 L. brevis strain KU15152 and incubated for 72 h at 37 °C anaerobically. The antioxidants, total phenolic compounds, vitamin B12 production, sugars, organic acids, pH and viable count were analyzed at 24, 48 and 72 h of incubation. The fermented juice was stored at 4 °C, and the changes in its functional properties were analyzed at 7-day intervals up to 28 days of storage. During fermentation, the bacteria cell count was increased from 7.01 ± 0.06 to 9.76 ± 0.42 log CFU mL-1 after 72 h of fermentation and was decreased to 6.94 ± 0.34 CFU mL-1 during storage at 4 °C after 28 days. The pH, total soluble solids, crude fiber, citric acid and total sugars decreased, while titratable acidity, total protein, antioxidants, phenolic compounds and lactic acid contents increased during fermentation. The fermented guava juice exhibited higher 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid (ABTS)) radical scavenging activities (85.97% and 75.97%, respectively) at 48 h of fermentation. The concentration of active vitamin B12 in the sample reached 109.5 μg L-1 at 72 h of fermentation. However, this concentration gradually decreased to 70.2 μg L-1 during the storage period. During storage for 28 days at 4 °C, both the fermented and control guava juices exhibited a decline in antioxidant and phenolic compound concentrations. Furthermore, the addition of 20% honey and guava flavor enhanced the organoleptic properties and acceptability of fermented guava juice. The value-added fermented guava juice could be a novel functional food product to combat vitamin B12 deficiency. © 2024 The Author(s). Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Berberine alleviates high-energy and low-protein diet-induced fatty liver hemorrhagic syndrome in laying hens: insights from microbiome and metabolomics

Berberine (BBR), a well-known quaternary ammonium alkaloid, is recognized for its ability to prevent and alleviate metabolic disorders because of its anti-oxidative and anti-inflammatory properties. However, the underlying mechanisms of BBR to mitigate fatty liver hemorrhagic syndrome (FLHS) through the modulation of gut microbiota and their metabolism remained unclear. The results revealed that BBR ameliorates lipid metabolism disorder in high-energy and low-protein (HELP) diet-induced FLHS laying hens, as evidenced by improved liver function and lipid deposition of the liver, reduced blood lipids, and the expression of liver lipid synthesis-related factors. Moreover, BBR alleviated HELP diet-induced barrier dysfunction, increased microbial population, and dysregulated lipid metabolism in the ileum. BBR reshaped the HELP-perturbed gut microbiota, particularly declining the abundance of Desulfovibrio_piger and elevating the abundance of Bacteroides_salanitronis_DSM_18170. Meanwhile, metabolomic profiling analysis revealed that BBR reshaped microbial metabolism and function, particularly by reducing the levels of hydrocinnamic acid, dehydroanonaine, and leucinic acid. Furthermore, fecal microbiota transplantation (FMT) experiments revealed that BBR-enriched gut microbiota alleviated hepatic lipid deposition and intestinal inflammation compared with those chicks that received a gut microbiota by HELP. Collectively, our study provided evidence that BBR effectively alleviated FLHS induced by HELP by reshaping the microbial and metabolic homeostasis within the liver-gut axis.

Comprehensive characterization of bioactive peptides in rice bran protein hydrolysates: A multi‐platform approach for metabolomic profiling, identification, and molecular docking analysis

AbstractBackground and ObjectivesTo optimize the utilization of rice by‐products, the rice bran protein hydrolysate (RBPH) was subjected to a process of separation and purification using ultrafiltration and reversed‐phase high‐performance liquid chromatography (RP‐HPLC). Subsequently, the identification of peptide sequences was carried out using mass spectrometer hybrid quadrupole‐time‐of‐flight and nontargeted metabolomic profiling done using UHPLC‐QTOF‐IMS profiling to identify antioxidant and antihypertensive amino acids.FindingsThree novel bioactive peptides, namely, STCCK, FMKSK, and KICILVFTLTTC, were identified within RBPH through enzymatic digestion using alcalase, pepsin, and trypsin. These peptides showed significant antioxidant activity and angiotensin‐converting enzyme (ACE) inhibitory activity. Molecular docking analyses elucidated various interaction mechanisms between these peptides and the ACE receptor protein, including hydrogen bonding and hydrophobic interactions. This suggested that the peptides effectively suppress ACE by forming hydrogen bonds with the active pockets of human ACE with a high affinity.ConclusionIn summary, peptides derived from rice bran protein exhibited distinguished antihypertensive and antioxidant properties, underscoring their potential for valuable utilization in addressing utilization of rice by‐products.Significance and NoveltyThe study advances scientific knowledge and offers practical solutions for health improvement and sustainable agriculture.

Neoergosterol-rich mushroom extract, resourced from wild edible mushroom Termitomyces heimii Natarajan, induces robust apoptosis against lung cancer

The non-specificity of conventional cancer drugs imposes a significant obstacle in cancer treatment, so the development of a safe anti-cancer alternative by methodologically revisiting several traditional medicinal systems may be a possible way to get rid of this problem. Therefore, the present study evaluates the anti-cancer potentiality of one of the Asiatic and African regions’ widely popular edible and ethnobotanically significant termite mushroom, Termitomyces heimii Natarajan (T. heimii), against various cancers. The anti-proliferative and chemo-preventive potentiality of two different extracts of T. heimii was evaluated against a panel of eight cancer cell lines and normal cells through an MTT assay. In vitro screening highlights that the methanolic extract of T. heimii had the highest anti-proliferative potential against A549 cells and had a negligible effect on normal cells. The extract specifically induced robust apoptosis in A549 cells through augmentation of intracellular ROS, disrupting mitochondrial membrane polarity, thus ultimately resulting in caspase-dependent apoptosis in lung cancer cells. Post-treatment, down-regulation of anti-apoptotic BCL-2 coordinated up-regulation of BAX expression, and an elevated expression of p53 signified the p53-dependent apoptosis. Moreover, the mushroom extract restricted cellular migration in the palladin-dependent pathway by downregulating the expression of PALLADIN. LC-MS-based metabolomic profiling was conducted to identify the potential anti-cancer mycocompounds in the methanol extract. The metabolomic profiling analysis, followed by an in silico molecular docking study, identified a unique mycosterol, neoergosterol, as a possible anti-cancer compound in the mushroom extract. The present study concludes a novel mycocompound neoergosterol resourcing from Termitomyces heimii Natarajan, demonstrating selective robust apoptosis against non-small cell lung cancer cells and also provides a chemoprotective shield against normal cells, which holds great promise for future drug development to treat lung cancer.

Metabolomics Profiling of Stages of Coronary Artery Disease Progression.

Coronary artery disease (CAD) and atherosclerosis pose significant global health challenges, with intricate molecular changes influencing disease progression. Hypercholesterolemia (HC), hypertension (HT), and diabetes are key contributors to CAD development. Metabolomics, with its comprehensive analysis of metabolites, offers a unique perspective on cardiovascular diseases. This study leveraged metabolomics profiling to investigate the progression of CAD, focusing on the interplay of hypercholesterolemia, hypertension, and diabetes. We performed a metabolomic analysis on 221 participants from four different groups: (I) healthy individuals, (II) individuals with hypercholesterolemia (HC), (III) individuals with both HC and hypertension (HT) or diabetes, and (IV) patients with self-reported coronary artery disease (CAD). Utilizing data from the Qatar Biobank, we combined clinical information, metabolomic profiling, and statistical analyses to identify key metabolites associated with CAD risk. Our data identified distinct metabolite profiles across the study groups, indicating changes in carbohydrate and lipid metabolism linked to CAD risk. Specifically, levels of mannitol/sorbitol, mannose, glucose, and ribitol increased, while pregnenediol sulfate, oleoylcarnitine, and quinolinate decreased with higher CAD risk. These findings suggest a significant role of sugar, steroid, and fatty acid metabolism in CAD progression and point to the need for further research on the correlation between quinolinate levels and CAD risk, potentially guiding targeted treatments for atherosclerosis. This study provides novel insights into the metabolomic changes associated with CAD progression, emphasizing the potential of metabolites as predictive biomarkers.

Metabolic self-feeding in HBV-associated hepatocarcinoma centered on feedback between circulation lipids and the cellular MAPK/mTOR axis

IntroductionHepatitis B Virus (HBV) is widely recognized as a “metabolic virus” that disrupts hepatic metabolic homeostasis, rendering it one of the foremost risk factors for hepatocellular carcinoma (HCC). Except for antiviral therapy, the fundamental principles underlying HBV− and HBV+ HCC have remained unchanged, limiting HCC treatment options.ObjectivesIn this study, we aim to identify the distinctive metabolic profile of HBV-associated HCC, with the promise of identifying novel metabolic targets that confer survival advantages and ultimately impede cancer progression.MethodsWe employed a comprehensive methodology to evaluate metabolic alterations systematically. Initially, we analyzed transcriptomic and proteomic data obtained from a public database, subsequently validating these findings within our test cohort at both the proteomic and transcriptomic levels. Additionally, we conducted a comprehensive analysis of tissue metabolomics profiles, lipidomics, and the activity of the MAPK and AKT signaling pathway to corroborate the abovementioned changes.ResultsOur multi-omics approach revealed distinct metabolic dysfunctions associated with HBV-associated HCC. Specifically, we observed upregulated steroid hormone biosynthesis, primary bile acid metabolism, and sphingolipid metabolism in HBV-associated HCC patients’ serum. Notably, metabolites involved in primary bile acid and sphingolipids can activate the MAPK/mTOR pathway. Tissue metabolomics and lipidomics analyses further validated the serum metabolic alterations, particularly alterations in lipid composition and accumulation of unsaturated fatty acids.ConclusionOur findings emphasize the pivotal role of HBV in HCC metabolism, elucidating the activation of a unique MAPK/mTOR signaling axis by primary bile acids and sphingolipids. Moreover, the hyperactive MAPK/mTOR signaling axis transduction leads to significant reprogramming in lipid metabolism within HCC cells, further triggering the activation of the MAPK/mTOR pathway in turn, thereby establishing a self-feeding circle driven by primary bile acids and sphingolipids.

Effects of sn-2 Palmitic Triacylglycerols and the Ratio of OPL to OPO in Human Milk Fat Substitute on Metabolic Regulation in Sprague-Dawley Rats.

In this study, the influence of total sn-2 palmitic triacylglycerols (TAGs) and ratio of 1-oleoyl-2-palmitoyl-3-linoleoylglycerol (OPL) to 1,3-dioleoyl-2-palmitoylglycerol (OPO) in human milk fat substitute (HMFS) on the metabolic changes were investigated in Sprague-Dawley rats. Metabolomics and lipidomics profiling analysis indicated that increasing the total sn-2 palmitic TAGs and OPL to OPO ratio in HMFS could significantly influence glycine, serine and threonine metabolism, glycerophospholipid metabolism, glycerolipid metabolism, sphingolipid metabolism, bile acid biosynthesis, and taurine and hypotaurine metabolism pathways in rats after 4 weeks of feeding, which were mainly related to lipid, bile acid and energy metabolism. Meanwhile, the up-regulation of taurine, L-tryptophan, and L-cysteine, and down-regulations of lysoPC (18:0) and hypoxanthine would contribute to the reduction in inflammatory response and oxidative stress, and improvement of immunity function in rats. In addition, analysis of targeted biochemical factors also revealed that HMFS-fed rats had significantly increased levels of anti-inflammatory factor (IL-4), immunoglobulin A (IgA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-px), and decreased levels of pro-inflammatory factors (IL-6 and TNF-α) and malondialdehyde (MDA), compared with those of the control fat-fed rats. Collectively, these observations present new in vivo nutritional evidence for the metabolic regulatory effects of the TAG structure and composition of human milk fat substitutes on the host.

Transcriptomic and metabolomic profiling provide insight into the role of sugars and hormones in leaf senescence of Pinellia ternata.

The interaction network and pathway map uncover the potential crosstalk between sugar and hormone metabolisms as a possible reason for leaf senescence in P. ternata. Pinellia ternata, an environmentally sensitive medicinal plant, undergoes leaf senescence twice a year, affecting its development and yield. Understanding the potential mechanism that delays leaf senescence could theoretically decrease yield losses. In this study, a typical senescent population model was constructed, and an integrated analysis of transcriptomic and metabolomic profiles of P. ternata was conducted using two early leaf senescence populations and two stay-green populations. The result showed that two key gene modules were associated with leaf senescence which were mainly enriched in sugar and hormone signaling pathways, respectively. A network constructed by unigenes and metabolisms related to the obtained two pathways revealed that several compounds such as D-arabitol and 2MeScZR have a higher significance ranking. In addition, a total of 130 hub genes in this network were categorized into 3 classes based on connectivity. Among them, 34 hub genes were further analyzed through a pathway map, the potential crosstalk between sugar and hormone metabolisms might be an underlying reason of leaf senescence in P. ternata. These findings address the knowledge gap regarding leaf senescence in P. ternata, providing candidate germplasms for molecular breeding and laying theoretical basis for the realization of finely regulated cultivation in future.

Salecan ameliorates LPS-induced acute lung injury through regulating Keap1-Nrf2/HO-1 pathway in mice

Acute lung injury (ALI) is a severe clinical condition with high mortality, characterized by rapid onset and limited treatment options. The pathogenesis of ALI involves inflammation and oxidative stress. The polysaccharide salecan, a water-soluble β-(1,3)-D-glucan, has been found to possess numerous pharmaceutical effects, including anti-inflammatory properties, inhibition of oxidative stress, and anti-fatigue effects. This study aims to investigate the protective effect and underlying mechanism of salecan against LPS-induced ALI in mice. Using an in vivo LPS-induced ALI mouse model and an in vitro RAW264.7 cell system, we investigated the role of salecan in ALI with various experimental approaches, including histological staining, quantitative real-time PCR, flow cytometry, western blot analysis, and other relevant assays. Pre-treatment with salecan effectively attenuated LPS-induced ALI in vivo, reducing the severity of pulmonary edema, inflammation, and oxidative stress. NMR-based metabolomic profiling analysis revealed that salecan attenuated LPS-induced metabolic imbalances associated with ALI. Furthermore, salecan downregulated Keap1 and upregulated Nrf2 and HO-1 protein levels, indicating its modulation of the Keap1-Nrf2/HO-1 signaling pathway as a potential mechanism underlying its protective effects against ALI. In vitro studies on RAW264.7 cells revealed that salecan exhibited binding affinity towards macrophages, thereby alleviating LPS-induced apoptosis and inflammation, which underpin its therapeutic potential against ALI. Our study suggests that salecan can alleviate LPS-induced ALI by modulating oxidative stress, inflammatory response, and apoptosis through the activation of the Keap1-Nrf2/HO-1 pathway. These findings provide novel insights into the potential therapeutic use of salecan for the treatment of ALI.

Exercise alleviates diabetic kidney disease through PPARδ-CPT1α pathway-dependent fatty acid β-oxidation

<p>Diabetic kidney disease (DKD), a severe diabetic complication affecting approximately one-third of diabetic patients, is the leading cause of end-stage chronic kidney disease. The benefits of regular exercise for patients with DKD have been well documented, particularly in overweight patients with DKD. However, the underlying mechanisms are incompletely understood. The present study demonstrates that exercise improves kidney function in diabetic <i>db/db</i> mice through activating PPARδ-mediated fatty acid β-oxidation (FAO). Twelve-week treadmill running exercise improved kidney function in <i>db/db</i> mice. Metabolomics and transcriptomics profiling analysis collectively revealed that dysregulation of FAO in <i>db/db</i> mice was largely corrected by running exercise. KEGG pathway enrichment revealed that PPAR pathway, a critical signalling cascade in FAO and exercise, is involved in DKD, suggesting PPARδ activation protects renal function through promoting FAO. Which was confirmed by improved renal function and enhanced FAO in <i>db/db</i> mice treated with PPARδ agonist GW501516. Oppositely, PPARδ-specific inhibitor GSK0660 abolished exercise-mediated improvement in renal function and FAO. In combining with gene expression profiling data we identified CPT1α, the rate-limiting enzyme in fatty acid oxidation, was suppressed in the kidney of diabetic mice and reversed by exercise and the PPARδ agonist GW501516. The findings hint at a potential role for the PPARδ-CPT1α pathway in exercise-induced improvements in diabetic renal function and may warrant further exploration of the PPARδ-CPT1α pathway as a therapeutic target in DKD.</p>

Study of Gnetum gnemon metabolites as potential anti-breast and prostate cancer by metabolomic and molecular docking

Breast and prostate cancers are significant health concerns worldwide, demanding novel and effective therapeutic approaches. This study explores the potential of Gnetum gnemon seed metabolites as anticancers agent through metabolomic profiling and molecular docking analysis. Six metabolites from G. gnemon seed were identified, which met Lipinski’s rule of five criteria, suggesting their drug-like properties. A panel of 10 molecular target proteins, including PTGS1, PTGS2, ESR1, SIRT1, SIRT3, SIRT5, AKT1, JAK2, BRAF, and NOS3, relevant to breast and prostate cancer pathways, were selected for molecular docking simulations. The binding interactions and free binding energy assessments identified gnetol and gnetin C as the most promising metabolites, showing strong interactions with multiple target proteins. Gnetol exhibited potential in targeting ESR1 and SIRT5, suggesting a mechanism for breast cancer inhibition. On the other hand, gnetin C emerged as a potent allosteric inhibitor of AKT1, potentially impacting breast and prostate cancer pathways. These findings highlight G. gnemon metabolites, particularly gnetol and gnetin C, as potential candidates for further preclinical and clinical studies as anti-breast and prostate cancer agents.

High-Throughput Combined Analysis of Saliva Microbiota and Metabolomic Profile in Chinese Periodontitis Patients: A Pilot Study.

The onset and progression of periodontitis involves complicated interactions between the dysbiotic oral microbiota and disrupted host immune-inflammatory response, which can be mirrored by the changes in salivary metabolites profile. This pilot study sought to examine the saliva microbiome and metabolome in the Chinese population by the combined approach of 16s rRNA sequencing and high-throughput targeted metabolomics to discover potential cues for host-microbe metabolic interactions. Unstimulated whole saliva samples were collected from eighteen Stage III and IV periodontitis patients and thirteen healthy subjects. Full-mouth periodontal parameters were recorded. The taxonomic composition of microbiota was obtained by 16s rRNA sequencing, and the metabolites were identified and measured by ultra-high performance liquid chromatography and mass spectrometry-based metabolomic analysis. The oral microbiota composition displayed marked changes where the abundance of 93 microbial taxa differed significantly between the periodontitis and healthy group. Targeted metabolomics identified 103 differential metabolites between the patients and healthy individuals. Functional enrichment analysis demonstrated the upregulation of protein digestion and absorption, histidine metabolism, and nicotinate and nicotinamide metabolism pathways in the dysbiotic microbiota, while the ferroptosis, tryptophan metabolism, glutathione metabolism, and carbon metabolism pathways were upregulated in the patients. Correlation analysis confirmed positive relationships between the clinical parameters, pathogen abundances, and disease-related metabolite levels. The integral analysis of the saliva microbiome and metabolome yielded an accurate presentation of the dysbiotic oral microbiome and functional alterations in host-microbe metabolism. The microbial and metabolic profiling of the saliva could be a potential tool in the diagnosis, prognosis evaluation, and pathogenesis study of periodontitis.

4-octyl itaconate protects against oxidative stress-induced liver injury by activating the Nrf2/Sirt3 pathway through AKT and ERK1/2 phosphorylation

4-octyl itaconate (4-OI) is a cell-permeable itaconate derivative with anti-inflammatory and antioxidant properties. However, its therapeutic potential for oxidative stress-induced liver injury remains unknown. This study investigated the hepatoprotective effects and mechanisms of 4-OI against oxidative damage in in vitro and in vivo models. 4-OI attenuated H2O2-induced cytotoxicity, oxidative stress, and mitochondrial dysfunction in L02 and HepG2 cells. Untargeted metabolomics profiling and pathway analysis identified the PI3K/AKT/mTOR and MAPK pathways as key regulators of 4-OI's protective effects. Specifically, 4-OI induced phosphorylation of AKT and ERK1/2, leading to activation of the Nrf2 signaling pathway. Nrf2 upregulated expression of the mitochondrial deacetylase Sirt3, which subsequently alleviated H2O2-induced cell injury. In mice, 4-OI reduced acetaminophen (APAP)-induced liver injury as evidenced by attenuated hepatocellular necrosis and decreased serum liver enzymes. It also elevated hepatic expression of Nrf2, Sirt3, p-AKT and p-ERK1/2. Inhibition of AKT, ERK1/2 or Nrf2 blocked the protective effects of 4-OI in vitro, suggesting its antioxidant activity is mediated by activating the Nrf2/Sirt3 pathway via AKT and ERK1/2 phosphorylation. In summary, 4-OI exerted antioxidant and hepatoprotective effects by activating the Nrf2/Sirt3 signaling pathway through AKT and ERK1/2 phosphorylation, which were elucidated using in vitro and in vivo oxidative stress models. This provides novel insights into the mechanisms of 4-OI against oxidative stress-related liver diseases.