COVID-19 exhibits extensive patient-to-patient heterogeneity. To link immune response variation to disease severity and outcome over time, we longitudinally assessed circulating proteins as well as 188 surface protein markers, transcriptome, and T-cell receptor sequence simultaneously in single peripheral immune cells from COVID-19 patients. Conditional-independence network analysis revealed primary correlates of disease severity, including gene expression signatures of apoptosis in plasmacytoid dendritic cells and attenuated inflammation but increased fatty acid metabolism in CD56 dim CD16 hi NK cells linked positively to circulating IL-15. CD8 + T cell activation was apparent without signs of exhaustion. While cellular inflammation was depressed in severe patients early after hospitalization, it became elevated by days 17-23 post symptom onset, suggestive of a late wave of inflammatory responses. Furthermore, circulating protein trajectories at this time were divergent between and predictive of recovery-fatal outcomes. Our findings stress the importance of timing in the analysis, clinical monitoring, and therapeutic intervention of COVID-19.
Peroxisome proliferator-activated receptor g g (PPARg g), a member of the nuclear receptor of ligand-activated transcription factors, regulates the expression of key genes involved in lipid and glucose metabolism or adipocyte differentiation. Ligands for this receptor have emerged as potent insulin sensitizers used in the treatment of Type2 diabetes. Ginseng saponins or ginsenosides are reported to provide anti-diabetic activity as well as to modulate glucose metabolism, although the mechanism remains unclear. In this study, we examined the effect of ginsenosides on activation of PPARg g and adipogenes in 3T3-L1. Using a GAL-4/PPARg g transactivation assay, 20(S)-protopanaxatriol (PPT), one of the ginsenoside metabolites, was found to increase PPARg g-transactivation activity dose-dependently with similar activity as troglitazone, a well-known PPARg g agonist. PPT enhanced adipogenesis by increasing the expression of PPARg g target genes such as aP2, LPL and PEPCK. Furthermore, PPT significantly increased expression of glucose transporter 4 (GLUT4). These results indicate that PPT can be developed as a PPARg g agonist for the improvement of insulin resistance associated with diabetes.
OBJECTIVE-Peroxisome proliferator-activated receptor (PPAR)␣/␥ dual agonists have the potential to be used as therapeutic agents for the treatment of type 2 diabetes. This study evaluated the function of macelignan, a natural compound isolated from Myristica fragrans, as a dual agonist for PPAR␣/␥ and investigated its antidiabetes effects in animal models.RESEARCH DESIGN AND METHODS-GAL4/PPAR chimera transactivation was performed and the expression of PPAR␣/␥ target genes was monitored to examine the ability of macelignan to activate PPAR␣/␥. Additionally, macelignan was administrated to obese diabetic (db/db) mice to investigate antidiabetes effects and elucidate its molecular mechanisms.RESULTS-Macelignan reduced serum glucose, insulin, triglycerides, free fatty acid levels, and triglycerides levels in the skeletal muscle and liver of db/db mice. Furthermore, macelignan significantly improved glucose and insulin tolerance in these mice, and without altering food intake, their body weights were slightly reduced while weights of troglitazone-treated mice increased. Macelignan increased adiponectin expression in adipose tissue and serum, whereas the expression and serum levels of tumor necrosis factor-␣ and interleukin-6 decreased. Macelignan downregulated inflammatory gene expression in the liver and increased AMP-activated protein kinase activation in the skeletal muscle of db/db mice. Strikingly, macelignan reduced endoplasmic reticulum (ER) stress and c-Jun NH 2 -terminal kinase activation in the liver and adipose tissue of db/db mice and subsequently increased insulin signaling. T he worldwide prevalence of type 2 diabetes is steadily rising; therefore, in addition to a more aggressive approach in managing diabetes through diet and exercise, antidiabetes agents that ameliorate insulin resistance and hyperlipidemia are also needed. CONCLUSIONS-MacelignanAs members of the nuclear hormone receptor superfamily, peroxisome proliferator-activated receptors (PPARs) bind to specific DNA response elements as heterodimers with the retinoid-X receptor to control glucose and lipid metabolism, which offers a promising therapeutic approach for treating the metabolic syndrome (1). There are several PPAR isoforms, including PPAR ␣, ␥, and ␦ that share 60 -80% homology in the ligand-and DNA-binding domains (2). Widely expressed in the liver, PPAR␣ functions in the catabolism of fatty acids responsible for decreasing serum triglyceride levels and increasing HDL cholesterol levels in dyslipidemia (3). Therefore, PPAR␣ agonists have the potential to be used to ameliorate insulin resistance and hyperlipidemia. Moreover, PPAR␥ is highly expressed in adipocytes and is involved in adipocyte differentiation, lipid storage, glucose homeostasis, and adipocytokine regulation, which can improve insulin sensitivity and glucose tolerance (4). The primary issue with the utility of classic full PPAR␥ agonists is that they exert a variety of side effects, chiefly weight gain due to edema and increased fat mass (5). However, the side effects ...
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