Precise Metabolomics Defines Systemic Metabolic Dysregulation Distinct to Acute Myocardial Infarction Associated With Diabetes.

BACKGROUND: Acute myocardial infarction (AMI) is a leading cause of death and disability. Diabetes is an important risk factor and a common comorbidity in AMI patients. The higher mortality risk of diabetes-AMI relative to nondiabetes-AMI indicates a need for specific treatment to improve clinical outcome. However, the global metabolic dysregulation of AMI complicated with diabetes is still unclear. We aim to systematically interrogate changes in the metabolic microenvironment immediate to AMI episodes in the absence or presence of diabetes. METHODS: In this work, quantitative metabolomics was used to investigate plasma metabolic differences between diabetes-AMI (n=59) and nondiabetes-AMI (n=59) patients. A diverse array of perturbed metabolic pathways involving carbohydrate metabolism, lipid metabolism, glycolysis, tricarboxylic acid cycle, and amino acid metabolism emerged. RESULTS: In all, our omics-oriented approach defined a metabolic signature of afflicted mitochondrial function aggravated by concurrent diabetes in AMI patients. In particular, our analyses uncovered N-lactoyl-phenylalanine and lysophosphatidylcholines as key functional metabolites that skewed the metabolic picture of diabetes-AMI relative to nondiabetes-AMI. N-lactoyl-phenylalanine was strongly associated with metabolic indicators reflective of mitochondrial overload and negatively correlated with HbA1c (glycosylated hemoglobin, type A1C) specifically in hyperglycemic AMI, suggestive of its central role in glucose utilization and mitochondrial energy production instrumental to the clinical outcome of diabetes-AMI. Reductions in lysophosphatidylcholines, which were negatively correlated with blood glucose and inflammatory markers, might further compromise glucose expenditure and aggravate inflammation leading to poorer prognosis in diabetes-AMI. CONCLUSIONS: As circulating metabolite levels are amenable to therapeutic intervention, such shifts in metabolic signatures provide new clues and potential therapeutic targets specific to the treatment of diabetes-AMI.

Subtyping of major SARS-CoV-2 variants reveals different transmission dynamics

SARS-CoV-2 continues to evolve, causing waves of the pandemic. Up to March 2022, eight million genome sequences have accumulated, which are classified into five major variants of concern. With the growing number of sequenced genomes, analysis of the big dataset has become increasingly challenging. Here we developed systematic approaches for comprehensive subtyping and pattern recognition for transmission dynamics. By analyzing the first two million viral genomes as of July 2021, we found that different subtypes of the same variant exhibited distinct temporal trajectories. For example, some Delta subtypes did not spread rapidly, while others did. We identified sets of characteristic single nucleotide variations (SNVs) that appeared to enhance transmission or decrease efficacy of antibodies for some subtypes of the Delta and Alpha variants. We also identified a set of SNVs that appeared to suppress transmission or increase viral sensitivity to antibodies. These findings are later confirmed in an analysis of six million genomes as of December 2021. For the Omicron variant, the dominant type in the world, we identified the subtypes with enhanced and suppressed transmission in an analysis of seven million genomes as of January 2022 and further confirmed the findings in a later analysis of eight million genomes as of March 2022. While the "enhancer" SNVs exhibited an enriched presence on the spike protein, the "suppressor" SNVs are mainly elsewhere. Disruption of the SNV correlation largely destroyed the enhancer-suppressor phenomena. These results suggest the importance of fine subtyping of variants, and point to potential complex interactions among SNVs.

Dynamic Changes in Plasma Urotensin II and Its Correlation With Plaque Stability.

ABSTRACT: Urotensin II (UII) is involved in the formation of atherosclerosis, but its role in the stability of atherosclerotic plaques is unknown. The purpose of this study was to observe the dynamic changes in plasma UII and analyze its relationship to the stability of atherosclerotic plaques. One hundred thirty-five consecutive patients with acute coronary syndrome (ACS) were enrolled. The plasma UII levels were measured immediately after admission and during three-month follow-up. A vulnerable plaque model was established using local transfection of a recombinant P53 adenovirus into plaques in rabbits fed with a high-cholesterol diet and subjected to balloon arterial injury. The levels of plasma UII were measured weekly. The changes in plasma UII during the formation of atherosclerotic plaques and before and after plaque transfection were observed. The morphology of the plaques and the expression, distribution, and quantitative expression of UII in the plaques also were observed. Our results showed that the levels of plasma UII in patients with ACS at admission were lower than levels observed at the three-month follow-up. UII dynamic changes and its correlation with plaque stabilities were further verified in rabbits with atherosclerotic vulnerable plaques. The UII levels in rabbits were significantly decreased immediately after the P53 gene transfection, which led to plaque instability and rupture. These results suggested that UII expression was down-regulated in ACS, which may be related to its ability to modulate mechanisms involved in plaque stability and instability.

Tripartite motif 10 regulates cardiac hypertrophy by targeting the PTEN/AKT pathway.

The pathogenesis of cardiac hypertrophy is tightly associated with activation of intracellular hypertrophic signalling pathways, which leads to the synthesis of various proteins. Tripartite motif 10 (TRIM10) is an E3 ligase with important functions in protein quality control. However, its role in cardiac hypertrophy was unclear. In this study, neonatal rat cardiomyocytes (NRCMs) and TRIM10-knockout mice were subjected to phenylephrine (PE) stimulation or transverse aortic constriction (TAC) to induce cardiac hypertrophy in vitro and in vivo, respectively. Trim10 expression was significantly increased in hypertrophied murine hearts and PE-stimulated NRCMs. Knockdown of TRIM10 in NRCMs alleviated PE-induced changes in the size of cardiomyocytes and hypertrophy gene expression, whereas TRIM10 overexpression aggravated these changes. These results were further verified in TRIM10-knockout mice. Mechanistically, we found that TRIM10 knockout or knockdown decreased AKT phosphorylation. Furthermore, we found that TRIM10 knockout or knockdown increased ubiquitination of phosphatase and tensin homolog (PTEN), which negatively regulated AKT activation. The results of this study reveal the involvement of TRIM10 in pathological cardiac hypertrophy, which may occur by prompting of PTEN ubiquitination and subsequent activation of AKT signalling. Therefore, TRIM10 may be a promising target for treatment of cardiac hypertrophy.

Genomic, geographic and temporal distributions of SARS-CoV-2 mutations

The COVID-19 pandemic is the most significant public health issue in recent history. Its causal agent, SARS-CoV-2, has evolved rapidly since its first emergence in December 2019. Mutations in the viral genome have critical impacts on the adaptation of viral strains to the local environment, and may alter the characteristics of viral transmission, disease manifestation, and the efficacy of treatment and vaccination. Using the complete sequences of 1,932 SARS-CoV-2 genomes, we examined the genomic, geographic and temporal distributions of aged, new, and frequent mutations of SARS-CoV-2, and identified six phylogenetic clusters of the strains, which also exhibit a geographic preference in different continents. Mutations in the form of single nucleotide variations (SNVs) provide a direct interpretation for the six phylogenetic clusters. Linkage disequilibrium, haplotype structure, evolutionary process, global distribution of mutations unveiled a sketch of the mutational history. Additionally, we found a positive correlation between the average mutation count and case fatality, and this correlation had strengthened with time, suggesting an important role of SNVs on disease outcomes. This study suggests that SNVs may become an important consideration in virus detection, clinical treatment, drug design, and vaccine development to avoid target shifting, and that continued isolation and sequencing is a crucial component in the fight against this pandemic. Significance StatementMutation is the driving force of evolution for viruses like SARS-CoV-2, the causal agent of COVID-19. In this study, we discovered that the genome of SARS-CoV-2 is changing rapidly from the originally isolated form. These mutations have been spreading around the world and caused more than 2.5 million of infected cases and 170 thousands of deaths. We found that fourteen frequent mutations identified in this study can characterize the six main clusters of SARS-CoV-2 strains. In addition, we found the mutation burden is positively correlated with the fatality of COVID-19 patients. Understanding mutations in the SARS-CoV-2 genome will provide useful insight for the design of treatment and vaccination.

[Midterm follow-up outcomes of ticagrelor on acute ST segment elevation myocardial infarction undergoing emergency percutaneous coronary intervention].

OBJECTIVE: To evaluate the safety and efficacy of antiplatelet therapy of ticagrelor on patients suffering from acute ST segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. METHODS: In the study, 96 patients suffering from acute ST segment elevation myocardial infarction onset within 12 h undergoing primary percutaneous coronary intervention from May to October in 2013 were randomly divided into ticagrelor group (n=48) and clopidogrel group (n=48) by using the method of random number table. Ticagrelor and clopidogrel antiplatelet treatment were used before and after operation. Their baseline data, coronary artery disease characteristics, platelet count, adenosine diphosphate(ADP)-induced platelet inhibition rate by thrombelastograph after 5 days of treatment, the major adverse cardiovascular events of the follow up for 6 months and bleeding complications were observed and compared in the two groups. RESULTS: The differences between the two groups of patients with their baseline data, the features of coronary artery lesions, platelet count before and after 5 days of treatment had no statistical significance (P>0.05). ADP induced platelet inhibition rate [(80.2±10.7)%] after 5 days of treatment in ticagrelor group was significantly higher than that in clopidogrel group [(75.3±12.1)%, P<0.05]. The two groups of patients were followed up for 6 months, 8 cases of major adverse cardiovascular events occurred in clopidogrel group, 2 cases of major adverse cardiovascular events occurred in ticagrelor group, and there was significant difference between the two groups (P<0.05). The two groups (7 cases of 48 patients in ticagrelor group vs. 3 cases of 48 patients in clopidogrel group) had no statistically significant difference in bleeding complications (P>0.05). CONCLUSION: Antiplatelet therapy of ticagrelor on patients suffering from acute ST segment elevation myocardial infarction undergoing emergency PCI has good efficacy and safety.

[Cardioprotective effect and mechanism of intensive lipid modulation on patients with coronary artery disease undergoing noncardiac surgery].

OBJECTIVE: To explore the protective effect and possible mechanism of intensive lipid modulation on the perioperative period of patients with stable coronary artery disease undergoing noncardiac surgery. METHODS: In the study, 60 patients with stable coronary artery disease undergoing elective noncardiac surgery were randomly divided into intensive lipid modulation group (n = 30) and conventional group (n = 30). In intensive lipid modulation group, the patients were given atorvastatin 40 mg every night before surgery, 80 mg 12 h before surgery, and 40 mg 2 h before surgery, and 40 mg every night after noncardiac surgery. In conventional group, the patients were given atorvastatin 20 mg every night before surgery and also after the surgery. The occurrence of perioperative major adverse cardiac events (including sudden cardiac death, acute myocardial infarction, unplanned revascularization) were compared in the two groups. Preoperative and 48 h postoperative changes of lipid levels and inflammatory markers were also compared in the two groups. RESULTS: In conventional group, one patient suffered myocardial infarction with acute anterior ST-segment elevation and was given emergency left anterior descending artery interventional reperfusion therapy, and 7 patients suffered asymptomatic myocardial infarction. In intensive lipid modulation group, one patient suffered asymptomatic myocardial infarction, and the incidence rate of perioperative acute myocardial infarction reduced significantly compared with conventional group (P < 0.05). There was no significant difference in preoperative and postoperative changes of lipid levels in the two groups (P > 0.05), and compared with conventional group, there was significantly lower levels of inflammatory markers in intensive lipid modulation group (P < 0.05). CONCLUSION: The intensive lipid modulation group significantly reduced the incidence of perioperative major adverse cardiac events especially asymptomatic myocardial infarction, and the inhibition of the inflammatory response may be one of the protective mechanisms, which still needs to be further confirmed by large multicenter randomized controlled clinical trials.

A novel retinoic acid analog, 4-amino-2-trifluoromethyl-phenyl retinate, inhibits gastric cancer cell growth.

Retinoic acid (RA) analogs have been used in the treatment of a variety of cancers; however, their application is limited due to serious therapy-related sequelae. In the present study, the effects of a novel RA analog, 4-amino-2-trifluoromethyl-phenyl retinate (ATPR), on the growth of gastric cancer cells were evaluated. Three gastric cancer cell lines, AGS, MKN-74 and SC-M1, were treated with either all­trans retinoic acid (ATRA) or ATPR, and their growth and distribution in different cell cycle phases were assessed using an MTT assay and propidium iodide (PI) staining followed by flow cytometry. The binding affinity of ATPR to the retinoic acid receptors, retinoic acid receptor-α (RAR-α) and retinoid X receptor-α (RXR-α), was determined using ligand-binding assays. Activator protein-1 (AP-1) activity was measured using a luciferase reporter assay. Western blot analysis was used to determine cyclin E, Bcl-2 and Bax protein expression. ATPR preferentially bound RXR-α (0.04 nM) as compared with RAR-α (20.96 nM). Although both ATRA and ATPR inhibited the growth of AGS, MKN-74 and SC-M1 cells in a dose-dependent manner, a significantly greater inhibitory effect was observed with treatment with 5 and 500 µM ATPR for 3 days (P<0.05). In addition, ATPR (50 µM), but not ATRA, significantly increased the population of AGS and MKN-74 cells in the subG1 phase and decreased the Bcl-2/Bax ratio (P<0.05). Furthermore, in MNK-74 and SC-M1 cells treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) and 5 or 10 µM of ATPR significantly suppressed the activity of the AP-1 reporter as compared to treatment with ATRA (P<0.05). Thus, ATPR inhibits cancer cell proliferation to a greater extent compared to ATRA, possibly through the RXR-mediated inhibition of AP-1 activity.

Urotensin II inhibits skeletal muscle glucose transport signaling pathways via the NADPH oxidase pathway.

Our previous studies have demonstrated that the urotensin (UII) and its receptor are up-regulated in the skeletal muscle of mice with type II diabetes mellitus (T2DM), but the significance of UII in skeletal muscle insulin resistance remains unknown. The purpose of this study was to investigate the effect of UII on NADPH oxidase and glucose transport signaling pathways in the skeletal muscle of mice with T2DM and in C2C12 mouse myotube cells. KK/upj-AY/J mice (KK) mice were divided into the following groups: KK group, with saline treatment for 2 weeks; KK+ urantide group, with daily 30 µg/kg body weight injections over the same time period of urantide, a potent urotensin II antagonist peptide; Non-diabetic C57BL/6J mice were used as normal controls. After urantide treatment, mice were subjected to an intraperitoneal glucose tolerance test, in addition to measurements of the levels of ROS, NADPH oxidase and the phosphorylated AKT, PKC and ERK. C2C12 cells were incubated with serum-free DMEM for 24 hours before conducting the experiments, and then administrated with 100 nM UII for 2 hours or 24 hours. Urantide treatment improved glucose tolerance, decreased the translocation of the NADPH subunits p40-phox and p47-phox, and increased levels of the phosphorylated PKC, AKT and ERK. In contrast, UII treatment increased ROS production and p47-phox and p67-phox translocation, and decreased the phosphorylated AKT, ERK1/2 and p38MAPK; Apocynin abrogated this effect. In conclusion, UII increased ROS production by NADPH oxidase, leading to the inhibition of signaling pathways involving glucose transport, such as AKT/PKC/ERK. Our data imply a role for UII at the molecular level in glucose homeostasis, and possibly in skeletal muscle insulin resistance in T2DM.