Family members of peroxisome proliferator-activated receptors (PPARs), such as PPARγ, have been shown to be effective in regulating T helper 17 (Th17) cell differentiation. However, whether PPARα, another important family member of PPARs, contributes to Th17 cell differentiation remains controversial. In the present study, we show that PPARα may be a negative regulator of Th17 cell differentiation. In CD4+ T cells from PPARα knockout mice, PPARα deficiency enhances IL-17 and IL-6 levels and promotes Th17 cell differentiation. In contrast, in CD4+ T cells from wild type mice, PPARα activation suppresses Th17 cell differentiation. Furthermore, IL-6 neutralizing antibody dose-dependently reduces the activity of STAT3 and down-regulates the protein expression of RORγt in CD4+ T cells from PPARα knockout mice but has no effect on that of wild type mice. On the other hand, in isolated CD4+ T cells from experimental autoimmune myocarditis (EAM) rats, PPARα agonist Fenofibrate decreased the expression of IL-17 and RORγt, increased the expression of Foxp3, while PPARα antagonist MK886 reversed these effects. Importantly, in vivo activation of PPARα ameliorates EAM by suppressing Th17 cell differentiation through reducing the expression of RORγt and phosphorylated STAT3 that are upregulated in EAM hearts. These results imply that PPARα suppresses Th17 cell differentiation through IL-6/STAT3/RORγt signaling pathway and suggest that PPARα may become a molecular target for treating autoimmune myocarditis.

Purpose: Based on resource-based theory and intellectual capital theory, this paper aims to investigate the impact of digital investment on enterprise value and the mediating role of intellectual capital. Additionally, it explores the heterogeneous impacts of digital investment on enterprise value and intellectual capital.Design/methodology/approach: The study utilizes a sample of listed companies in Chinese A-shares from 2013 to 2020. The entropy-weighted method is applied to measure digital investment from two dimensions: scale and increment. Finally, the research hypotheses are tested through multiple regression analysis.Findings: The empirical results demonstrate that digital investment significantly and positively impacts enterprise value. From the channel mechanism test, digital investment can enhance enterprise value by influencing intellectual capital through human, structural and relational capital. Of these, the mediating effect of human capital is the most significant. Moreover, the impacts of digital investment on enterprise value and intellectual capital are related to the industry sectors. In the agricultural sector, digital investment has adverse effects. In the industrial and service sectors, digital investment promotes intellectual capital and enterprise value. However, in the service sector, the impact on relational capital is not significant, and the mediating effect of relational capital does not hold.Research limitations/implications: This research has a limited potential for generalization due to the lack of standard measurement models for the exploration of digital investment.Practical implications: The research findings are valuable for assessing the economic effects of digital investment comprehensively and providing essential information for policy formulation and strategy implementation.Originality/value: This study represents the first attempt to evaluate the relationship between digital investment and enterprise value using the entropy-weighted method. In addition, this study investigates the mediating role of intellectual capital.

Endothelial dysfunction is involved in the pathophysiological processes of contrast media (CM)–induced acute kidney injury (CI-AKI) after vascular angiography or intervention. Previous study found that apolipoprotein A-I (apoA-I) mimetic peptide, D-4F, alleviates endothelial impairments via upregulating heme oxygenase-1 (HO-1) expression and scavenging excessively generated reactive oxygen species (ROS). However, whether D-4F could ameliorate oxidative injuries in endothelial cells through suppressing ROS production remains unclear. In this study, a representative nonionic iodinated CM, iodixanol, was chosen for the in vitro and in vivo studies. Endothelial cell viability was assayed using micrographs, lactate dehydrogenase (LDH) activity, and cell counting kit-8 (CCK-8). Apoptosis was detected using flow cytometry analysis and caspase-3 activation. Endothelial inflammation was tested using monocyte adhesion assay and adhesion molecule expression. ROS production was detected by measuring the formation of lipid peroxidation malondialdehyde (MDA) through the thiobarbituric acid reactive substance (TBARS) assay. Peroxynitrite (ONOO⁻) formation was tested using the 3-nitrotyrosine ELISA kit. Iodixanol impaired cell viability, promoted vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) expression, and induced cell apoptosis in human umbilical vein endothelial cells (HUVECs). However, D-4F mitigated these injuries. Furthermore, iodixanol induced the phosphorylation of protein kinase C (PKC) beta II, p47, Rac1, and endothelial nitric oxide synthase (eNOS) at Thr495, which elicited ROS release and ONOO⁻ generation. D-4F inhibited NADPH oxidase (NOX) activation, ROS production, and ONOO⁻ formation via the AMP-activated protein kinase (AMPK)/PKC pathway. Additionally, after an intravascular injection of iodixanol in Sprague Dawley rats, iodixanol induced a remarkable inflammatory response in arterial endothelial cells, although significant apoptosis and morphological changes were not observed. D-4F alleviated the vessel inflammation resulting from iodixanol in vivo. Collectively, besides scavenging ROS, D-4F could also suppress ROS production and ONOO⁻ formation through the AMPK/PKC pathway, which ameliorated oxidative injuries in endothelial cells. Hence, D-4F might serve as a potential agent in preventing CI-AKI.

Obesity is a global issue that warrants the identification of more effective therapeutic targets and a better understanding of the pivotal molecular pathogenesis. Annexin A1 (ANXA1) is known to inhibit phospholipase A2, exhibiting anti-inflammatory activity. However, the specific effects of ANXA1 in obesity and the underlying mechanisms of action remain unclear. Our study reveals that ANXA1 levels are elevated in the adipose tissue of individuals with obesity. Whole-body or adipocyte-specific ANXA1 deletion aggravates obesity and metabolic disorders. ANXA1 levels are higher in stromal vascular fractions (SVFs) than in mature adipocytes. Further investigation into the role of ANXA1 in SVFs reveals that ANXA1 overexpression induces lower numbers of mature adipocytes, while ANXA1-knockout SVFs exhibit the opposite effect. This suggests that ANXA1 plays an important role in adipogenesis. Mechanistically, ANXA1 competes with MYC binding protein 2 (MYCBP2) for interaction with PDZ and LIM domain 7 (PDLIM7). This exposes the MYCBP2-binding site, allowing it to bind more readily to the SMAD family member 4 (SMAD4) and promoting its ubiquitination and degradation. SMAD4 degradation downregulates peroxisome proliferator-activated receptor gamma (PPARγ) transcription and reduces adipogenesis. Treatment with Ac2-26, an active peptide derived from ANXA1, inhibits both adipogenesis and obesity through the mechanism. In conclusion, the molecular mechanism of ANXA1 inhibiting adipogenesis was first uncovered in our study, which is a potential target for obesity prevention and treatment.