Myrtenal exhibits cardioprotective effects by attenuating the pathological progression associated with myocardial infarction.

BACKGROUND: Myocardial infarction poses major risks to human health because of their incredibly high rates of morbidity and mortality. Infarctions are more likely to develop as a result of dysregulation of cell death. Myrtenal can be considered for their bioactive beneficial activity in the context of cardiovascular pathologies and, particularly, in the protection toward oxidative stress followed by ischemic injury. OBJECTIVE: This study aimed to put limelight on the antioxidant, anti-apoptotic, and antibacterial properties of Myrtenal. METHODS: An in vitro model of oxidative stress-induced injury was entrenched in H9c2 cells using hydrogen peroxide, and the effects of Myrtenal were investigated. The MTT, cellular enzyme level, staining, and flow cytometry analysis were used to examine protective, antioxidant, and anti-apoptotic effects. The gene expressions were detected by qPCR. Antibacterial effect and biofilm formation were also done. RESULT: The findings revealed that Myrtenal alone had negligible cytotoxic effects and that Myrtenal protects H9c2 against H2 O2 -induced cell death at micromolar concentrations. Myrtenal pre-treatment inhibited the generation of reactive oxygen species (ROS) as well as remarkably decreased the fluorescence intensity of ROS. Additionally, Myrtenal considerably increased the synthesis of antioxidant enzymes while dramatically decreasing the production of MDA and LDH. qPCR demonstrated the downregulation of Cas-9, TNF-α, NF-κB, P53, BAX, iNOS, and IL-6 expression while an upregulation of Bcl-2 expression in Myrtenal pre-treated groups. Myrtenal also holds the magnificent property of inhibiting bacterial growth. CONCLUSION: Myrtenal ameliorates H2 O2 -induced cardiomyocyte injury and protects cardiomyocyte by inhibiting oxidative stress, inflammation, and apoptosis and may be a promise drug for the treatment of heart diseases.

Defining atherosclerotic plaque biology by mass spectrometry-based omics approaches.

Atherosclerosis is the principal cause of vascular diseases and one of the leading causes of worldwide death. Even though several insights into its natural course, risk factors and interventions have been identified, it is still an ongoing global pandemic. Since the structure and biochemical composition of the plaques show high heterogeneity, a comprehensive understanding of the intraplaque composition, its microenvironment, and the mechanisms of the progression and instability across different vascular beds at their progression stages is crucial for better risk stratification and treatment modalities. Even though several cell-based studies, animal studies, and extensive multicentric population studies have been conducted concerning cardiovascular diseases for assessing the risk factors and plaque biology, the studies on human clinical samples are very limited. New novel approaches utilize samples from percutaneous coronary interventions, which could possibly gain more access to clinical samples at different stages of the diseases without complex invasive resections. As an emerging technological platform in disease discovery research, mass spectrometry-based omics technologies offer capabilities for a comprehensive understanding of the mechanisms linked to several vascular diseases. Here, we discuss the cellular and molecular processes of atherosclerosis, different mass spectrometry-based omics approaches, and the studies mostly done on clinical samples of atheroma plaque using mass spectrometry-based proteomics, metabolomics and lipidomics approaches.

Proteomics Analysis Reveals Diverse Molecular Characteristics between Endocardial and Aortic-Valvular Endothelium.

The variations in the protein profile of aortic-valvular (AVE) and endocardial endothelial (EE) cells are currently unknown. The current study's objective is to identify differentially expressed proteins and associated pathways in both the endothelial cells. We used endothelial cells isolated from the porcine (Sus scrofa) aortic valve and endocardium for the profiling of proteins. Label-free proteomics was performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Our proteomics analysis revealed that 29 proteins were highly expressed, and 25 proteins were less expressed in the valve than the endocardial endothelium. The cell surface markers, such as CD63, ICAM1, PECAM1, PROCR, and TFRC, were highly expressed in EE. In contrast, CD44 was highly expressed in AVE. The pathway analysis showed that metabolic process-related proteins and extracellular matrix-related proteins were enriched in valves. Differential enrichment of signaling pathways was observed in the endocardium. The hemostasis function-related proteins were increased in both endothelial cells. The proteins and pathways enriched in aortic-valvular and endocardial endothelial cells revealed the distinct phenotype of these two closely related cells.

Hyperhomocysteinemia-related serum metabolome alterations not normalized by short-term folic acid treatment.

INTRODUCTION: Hyperhomocysteinemia (HHCys) is an independent risk factor for various diseases such as cardiovascular diseases, Alzheimer's, and cancers. Folate deficiency is one of the significant reasons for HHCys. However, it is not known whether folate deficiency with HHCys is associated with any serum metabolites. OBJECTIVES: Our objective was to identify the metabolic alterations in people having folate deficiency with HHCys and check whether a short-term folic acid therapy could reverse those metabolic changes. METHODS: The study enrolled 34 participants aged between 18 and 40 years having folate deficiency (< 4.6 ng/mL) with HHCys (> 15 µmol/L) and 21 normal healthy individuals. A short-term intervention of oral folic acid (5 mg/day) was done in the HHCys group for 30 days. Untargeted metabolomics analysis of serum was performed in all study subjects before and after the folic acid treatment. Different univariate methods and the multivariable-adjusted linear regression models were employed to determine an association between homocysteine level and metabolite profile. RESULTS: Metabolomics analysis data showed that many metabolites involved in the biochemical pathways of lipid metabolisms such as polyunsaturated fatty acids, glycerolipids, and phospholipids were downregulated in the HHCys group. Short-term oral folic acid therapy significantly reduced their serum homocysteine level. However, the metabolic pathway alterations observed in folate-deficient HHCys-condition were unaltered even after the folic acid treatment. CONCLUSIONS: Our study revealed that people who have a folic acid deficiency with HHCys have an altered metabolite profile related to lipid metabolism, which cannot be reversed by short-term folic acid therapy.

The venom proteome of three common scyphozoan jellyfishes (Chrysaora caliparea, Cyanea nozakii and Lychnorhiza malayensis) (Cnidaria: Scyphozoa) from the coastal waters of India.

The jellyfish venom stored in nematocysts contains highly toxic compounds comprising of polypeptides, enzymes and other proteins, which form their chemical defence armoury against predators. We have characterized the proteome of crude venom extract from three bloom-forming scyphozoan jellyfish along the south-west coast of India, Chrysaora caliparea, Cyanea nozakii and Lychnorhiza malayensis using a Quadrupole-Time of Flight (Q/TOF) mass spectrometry analysis. The most abundant toxin identified from Chrysaora caliparea and Lychnorhiza malayensis is similar to the pore-forming toxins and metalloproteinases. A protective antioxidant enzyme called peroxiredoxin was found abundantly in Cyanea nozakii. Metalloproteinase identified from the C. caliparea shows similarity with the venom of pit viper (Bothrops pauloensis), while that of L. malayensis was similar to the venom of snakes such as the Bothrops insularis and Bothrops asper. Kininogen-1 is a secreted protein, identified for the first time from the jellyfish L. malayensis. The proteome analysis of Cyanea nozakii, Chrysaora caliparea and Lychnorhiza malayensis contained 20, 12, 8 unique proteins, respectively. Our study characterized the proteome map of crude venom extract from L. malayensis and C. caliparea for the first time, and the venom profile is compared with published information elsewhere. Proteomic data from this study has been made available in the public domain.

The protein tyrosine phosphatase PTP-PEST mediates hypoxia-induced endothelial autophagy and angiogenesis via AMPK activation.

Global and endothelial loss of PTP-PEST (also known as PTPN12) is associated with impaired cardiovascular development and embryonic lethality. Although hypoxia is implicated in vascular remodelling and angiogenesis, its effect on PTP-PEST remains unexplored. Here we report that hypoxia (1% oxygen) increases protein levels and catalytic activity of PTP-PEST in primary endothelial cells. Immunoprecipitation followed by mass spectrometry revealed that α subunits of AMPK (α1 and α2, encoded by PRKAA1 and PRKAA2, respectively) interact with PTP-PEST under normoxia but not in hypoxia. Co-immunoprecipitation experiments confirmed this observation and determined that AMPK α subunits interact with the catalytic domain of PTP-PEST. Knockdown of PTP-PEST abrogated hypoxia-mediated tyrosine dephosphorylation and activation of AMPK (Thr172 phosphorylation). Absence of PTP-PEST also blocked hypoxia-induced autophagy (LC3 degradation and puncta formation), which was rescued by the AMPK activator metformin (500 µM). Because endothelial autophagy is a prerequisite for angiogenesis, knockdown of PTP-PEST also attenuated endothelial cell migration and capillary tube formation, with autophagy inducer rapamycin (200 nM) rescuing angiogenesis. In conclusion, this work identifies for the first time that PTP-PEST is a regulator of hypoxia-induced AMPK activation and endothelial autophagy to promote angiogenesis.

Plasma leptin level mirrors metabolome alterations in young adults.

INTRODUCTION: Leptin is known to regulate pathways of energy metabolism, reproduction, and control appetite. Whether plasma leptin levels reflect changes in metabolites of these pathways is unknown. OBJECTIVES: We aimed to find whether there is an association between leptin levels and levels of metabolites of energy and hormone metabolism. METHODS: We performed an untargeted metabolomics analysis of plasma from 110 healthy adults (men: women = 1:1; aged 18-40 years), using liquid chromatography-tandem mass spectrometry. Blood samples were collected from all the study subjects in the fasting state. Clinical features and markers of obesity and Type 2 diabetes mellitus (T2DM) were assessed in all. The association between levels of metabolites and clinical and biochemical parameters was identified using the multivariable-adjusted linear regression model and PLS-DA analysis. RESULTS: The leptin level was found to have a significant association with a substantial number of metabolites in women and men. Leptin level was positively associated with glycocholic acid and arachidic acid, metabolites related to energy metabolisms, pregnanediol-3-glucuronide, a metabolite of progesterone metabolism, and quercetin 3'-sulfate, a diet-derived metabolite. Leptin level was negatively associated with ponasteroside A and barringtogenol C levels. Leptin level was positively correlated with adiponectin and negatively with total calorie intake and levels of triglyceride and very-low-density lipoprotein. Leptin levels were associated with lipid and sex hormone metabolism in women, while metabolites involved in amino acid metabolism were correlated to leptin in men. CONCLUSION: Our study indicates that leptin level reflects metabolome alterations and hence could be a useful marker to detect early changes in energy and hormone metabolisms.

L-Ascorbic Acid and α-Tocopherol Synergistically Triggers Apoptosis Inducing Antileukemic Effects of Arsenic Trioxide via Oxidative Stress in Human Acute Promyelocytic Leukemia Cells.

Chemosensitization is an effective strategy to overcome the drawbacks of arsenic trioxide (As2O3) treatment, which may be possible through the use of dietary supplements in combination. The present investigation evaluates the synergistic mechanism of action of vitamins, such as L-ascorbic acid (L-AA) and α-tocopherol (α-TOC) in As2O3 chemotherapy using human leukemia (HL-60) cells. In vitro assays on the cytotoxicity of As2O3 and vitamins and cellular apoptotic evidences were done; a proteomic investigation with mass spectrometry was also performed. The combination of L-AA and α-TOC potentiates As2O3 cytotoxicity in HL-60 cells, substantiated by depletion in antioxidant status, mitochondrial transmembrane potential, and inhibition of nuclear factor erythroid 2-related factor 2 and B-cell lymphoma 2 transcription factors. Mass spectrometry results showed decreased expression of proteins regulating cell cycle and translation in cells treated with As2O3, L-AA, and α-TOC when compared with As2O3-treated sample. In addition, this combination treatment identified numerous proteins associated with apoptosis and cell stress. HL-60 cells became more prone to As2O3 on exposure to L-AA and α-TOC, indicating that this combination may be a promising approach to increase the outcome of As2O3 chemotherapy.

Postprandial Metabolism is Impaired in Overweight Normoglycemic Young Adults without Family History of Diabetes.

While the risk factors for Type 2 diabetes (T2DM) are known, early predictive markers of transition from normal to a prediabetes state are unidentified. We studied the basal metabolism and metabolic response to a mixed-meal challenge in 110 healthy subjects in the age group of 18 to 40 years (Male:Female = 1:1); grouped into first degree relatives of patients with T2DM (n = 30), those with a body mass index >23 kg/m2 but <30 kg/m2 (n = 30), those with prediabetes (n = 20) and normal controls (n = 30). We performed an untargeted metabolomics analysis of plasma and related that with clinical and biochemical parameters, markers of inflammation, and insulin sensitivity. Similar to prediabetes subjects, overweight subjects had insulin resistance and significantly elevated levels of C-peptide, adiponectin and glucagon and lower level of ghrelin. Metabolites such as MG(22:2(13Z, 16Z)/0:0/0:0) and LysoPC (15:0) were reduced in overweight and prediabetes subjects. Insulin sensitivity was significantly lower in men. Fasting levels of uric acid, xanthine, and glycochenodeoxycholic-3-glucuronide were elevated in men. However, both lysophospholipids and antioxidant defense metabolites were higher in women. Impaired postprandial metabolism and insulin sensitivity in overweight normoglycemic young adults indicates a risk of developing hyperglycemia. Our results also indicate a higher risk of diabetes in young men.

Metabolomic Signature of Human Aortic Valve Stenosis.

This study outlines the first step toward creating the metabolite atlas of human calcified aortic valves by identifying the expression of metabolites and metabolic pathways involved at various stages of calcific aortic valve stenosis progression. Untargeted analysis identified 72 metabolites and lipids that were significantly altered (p < 0.01) across different stages of disease progression. Of these metabolites and lipids, the levels of lysophosphatidic acid were shown to correlate with faster hemodynamic progression and could select patients at risk for faster progression rate.

Metastability and uniqueness of vortex states at depinning.

We present results from numerical simulations of the transport of vortices in the zero-field-cooled (ZFC) and the field-cooled (FC) state of a type-II superconductor. In the absence of an applied current I, we find that the FC state has a lower defect density than the ZFC state, and is stable against thermal cycling. On the other hand, by cycling I, surprisingly, we find that the ZFC state is the stable state. The FC state is metastable as manifested by increasing I to the depinning current I(c), in which case the FC state evolves into the ZFC state. We also find that all configurations acquire a unique defect density at the depinning transition independent of the history of the initial states.