DNA methylation plays critical roles in vascular pathology of pulmonary hypertension (PH). The underlying mechanism, however, remains undetermined. Here, we demonstrate that global DNA methylation was elevated in the lungs of PH rat models after monocrotaline administration or hypobaric hypoxia exposure. We showed that DNA methyltransferase 3B (DNMT3B) was up-regulated in both PH patients and rodent models. Furthermore, Dnmt3b^−/− rats exhibited more severe pulmonary vascular remodeling. Consistently, inhibition of DNMT3B promoted proliferation/migration of pulmonary artery smooth muscle cells (PASMCs) in response to platelet-derived growth factor–BB (PDGF-BB). In contrast, overexpressing DNMT3B in PASMCs attenuated PDGF-BB–induced proliferation/migration and ameliorated hypoxia-mediated PH and right ventricular hypertrophy in mice. We also showed that DNMT3B transcriptionally regulated inflammatory pathways. Our results reveal that DNMT3B is a previously undefined mediator in the pathogenesis of PH, which couples epigenetic regulations with vascular remodeling and represents a therapeutic target to tackle PH.

Immune and inflammatory responses have an important function in the pathophysiology of pulmonary hypertension (PH). However, little is known about the immune landscape in peripheral circulation in patients with high-altitude pulmonary hypertension (HAPH). We apply single-cell transcriptomics to characterize the monocytes that are significantly enriched in the peripheral blood mononuclear cells (PBMC) of HAPH patients. We discover an increase in C1 (non-classical) and C2 (intermediate) monocytes in PBMCs and a decrease in hypoxia-inducible transcription factor-1α (HIF-1α) in all monocyte subsets associated with HAPH. In addition, we demonstrate that similar immune adaptations may exist in HAPH and PH. Overall, we characterize an immune cell atlas of the peripheral blood in HAPH patients. Our data provide evidence that specific monocyte subsets and HIF-1α downregulation might be implicated in the pathogenesis of HAPH.

Chemokines and their receptors represent a potential target for immunotherapy in chronic inflammation. They comprise a large family of cytokines with chemotactic activity, and their cognate receptors are expressed on all cells of the body. This network dictates leukocyte recruitment and activation, angiogenesis, cell proliferation and maturation. Dysregulation of chemokine and chemokine receptor expression as well as function participates in many pathologies including cancer, autoimmune diseases and chronic inflammation. In atherosclerosis, a lipid-driven chronic inflammation of middle-sized and large arteries, chemokines and their receptors participates in almost all stages of the disease from initiation of fatty streaks to mature atherosclerotic plaque formation. Atherosclerosis and its complications are the main driver of mortality and morbidity in cardiovascular diseases (CVD). Hence, exploring new fields of therapeutic targeting of atherosclerosis is of key importance. This review gives an overview of the recent advances on the role of key chemokines and chemokine receptors in atherosclerosis, addresses chemokine-based biomarkers at biochemical, imaging and genetic level in human studies, and highlights the clinial trials targeting atherosclerosis.

Pathological mechanisms of pulmonary arterial hypertension (PAH) remain largely unexplored. Effective treatment of PAH remains a challenge. The aim of this study was to discover the underlying mechanism of PAH through functional metabolomics and to help develop new strategies for prevention and treatment of PAH.Metabolomic profiling of plasma in patients with idiopathic PAH was evaluated through high-performance liquid chromatography mass spectrometry, with spermine identified to be the most significant and validated in another independent cohort. The roles of spermine and spermine synthase were examined in pulmonary arterial smooth muscle cells (PASMCs) and rodent models of pulmonary hypertension.Using targeted metabolomics, plasma spermine levels were found to be higher in patients with idiopathic PAH compared to healthy controls. Spermine administration promoted proliferation and migration of PASMCs and exacerbated vascular remodelling in rodent models of pulmonary hypertension. The spermine-mediated deteriorative effect can be attributed to a corresponding upregulation of its synthase in the pathological process. Inhibition of spermine synthasein vitrosuppressed platelet-derived growth factor-BB-mediated proliferation of PASMCs, andin vivoattenuated monocrotaline-mediated pulmonary hypertension in rats.Plasma spermine promotes pulmonary vascular remodelling. Inhibiting spermine synthesis could be a therapeutic strategy for PAH.

Apolipoprotein E4 (ApoE4) is the main genetic risk factor for Alzheimer’s disease (AD), but the exact way in which it causes AD remains unclear. Curcumin is considered to have good therapeutic potential for AD, but its mechanism has not been clarified. This study aims to observe the effect of curcumin on ApoE4 transgenic mice and explore its possible molecular mechanism. Eight-month-old ApoE4 transgenic mice were intraperitoneally injected with curcumin for 3 weeks, and the Morris water maze test was used to evaluate the cognitive ability of the mice. Immunofluorescence staining, immunohistochemistry, western blotting, and enzyme-linked immunosorbent assay (ELISA) were used to examine the brain tissues of the mice. Curcumin reduced the high expression of ApoE4 and the excessive release of inflammatory factors in ApoE4 mice. In particular, the expression of marker proteins of endoplasmic reticulum (ER) stress was significantly increased in ApoE4 mice, while curcumin significantly reduced the increase in the expression of these proteins. Collectively, curcumin alleviates neuroinflammation in the brains of ApoE4 mice by inhibiting ER stress, thus improving the learning and cognitive ability of transgenic mice.

Cornuside is an iridoid glycoside from Cornus officinalis, with the activities of anti-inflammatory, antioxidant, anti-mitochondrial dysfunction, and neuroprotection. In the present research, a triple-transgenic mice model of AD (3 × Tg-AD) was used to explore the beneficial actions and potential mechanism of cornuside on the memory deficits. We found that cornuside prominently alleviated neuronal injuries, reduced amyloid plaque pathology, inhibited Tau phosphorylation, and repaired synaptic damage. Additionally, cornuside lowered the release of interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and nitric oxide (NO), lowered the level of malondialdehyde (MDA), and increased the activity of superoxide dismutase (SOD) and the level of glutathione peroxidase (GSH-Px). Cornuside also significantly reduced the activation of astrocytes and modulated A1/A2 phenotypes by the AKT/Nrf2/NF-κB signaling pathway. We further confirmed that LY294002 and Nrf2 silencing could block the cornuside-mediated phenotypic switch of C6 cells induced by microglia conditioned medium (MCM) in response to lipopolysaccharide (LPS), which indicated that the effects of cornuside in astrocyte activation are dependent on AKT/Nrf2/NF-κB signaling. In conclusion, cornuside may regulate the phenotypic conversion of astrocytes, inhibit neuroinflammation and oxidative stress, improve synaptic plasticity, and alleviate cognitive impairment in mice through the AKT/Nrf2/NF-κB axis. Our present work provides an experimental foundation for further research and development of cornuside as a candidate drug for AD management.