As a neurodegenerative disease, Alzheimer’s disease (AD) seriously affects the health of older people. Changes in synapses occur first over the course of the disease, perhaps even before the formation of Aβ plaques. Histone deacetylase (HDAC) mediates the damage of Aβ oligomers to dendritic spines. Therefore, we examined the relationship between HDAC activity and synaptic defects using an HDAC inhibitor (HDACI), BG45, in the human neuroblastoma SH-SY5Y cell line with stable overexpression of Swedish mutant APP (APPsw) and in APP/PS1 transgenic mice during this study. The cells were treated with 15 μM BG45 and the APP/PS1 mice were treated with 30 mg/kg BG45. We detected the levels of synapse-related proteins, HDACs, tau phosphorylation, and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors using Western blotting and immunohistochemistry. We also measured the expression of cytoskeletal proteins in the cell model. The mRNA levels of the glutamate ion receptor alginate subunit 2 (GRIK2), sodium voltage-gated channel beta subunit (SCN3B), synaptophysin (SYP), Grm2 (the gene encoding glutamate receptor subunit 2 (GluR2)), Grid2IP, glutamate receptor interacting protein 1 (GRIP1), and GRIP2 were detected to explore the effects of the HDACI on regulating the expression of synaptic proteins and AMPA receptors. According to our studies, the expressions of HDAC1, HDAC2, and HDAC3 were increased, which were accompanied by the downregulation of the synapse-related proteins SYP, postsynaptic dendritic protein (PSD-95), and spinophilin as early as 24 h after transfection with the APPsw gene. BG45 upregulated the expression of synapse-related proteins and repaired cytoskeletal damage. In vivo, BG45 alleviated the apoptosis-mediated loss of hippocampal neurons, upregulated synapse-related proteins, reduced Aβ deposition and phosphorylation of tau, and increased the levels of the synapse-related genes GRIK2, SCN3B, SYP, Grm2, and Grid2IP. BG45 increased the expression of the AMPA receptor subunits GluA1, GluA2, and GluA3 on APPsw-transfected cells and increased GRIP1 and GRIP2 expression and AMPA receptor phosphorylation in vivo. Based on these results, HDACs are involved in the early process of synaptic defects in AD models, and BG45 may rescue synaptic damage and the loss of hippocampal neurons by specifically inhibiting HDAC1, HDAC2, and HDAC3, thereby modulating AMPA receptor transduction, increasing synapse-related gene expression, and finally enhancing the function of excitatory synapses. BG45 may be considered a potential drug for the treatment of early AD in further studies.

BACKGROUND: Hypoxia-induced pulmonary hypertension (HPH) is a T helper 17 cell response-driven disease, and PD-1 (programmed cell death 1)/PD-L1 (programmed cell death-ligand 1) inhibitor–associated pulmonary hypertension has been reported recently. This study is designed to explore whether the PD-1/PD-L1 pathway participates in HPH via regulating endothelial dysfunction and T helper 17 cell response. METHODS: Lung tissue samples were obtained from eligible patients. Western blotting, immunohistochemistry, and immunofluorescence techniques were used to assess protein expression, while immunoprecipitation was utilized to detect ubiquitination. HPH models were established in C57BL/6 WT (wild-type) and PD-1 ^−/− mice, followed by treatment with PD-L1 recombinant protein. Adeno-associated virus vector delivery was used to upregulate PD-L1 in the endothelial cells. Endothelial cell function was assessed through assays for cell angiogenesis and adhesion. RESULTS: Expression of the PD-1/PD-L1 pathway was downregulated in patients with HPH and mouse models, with a notable decrease in PD-L1 expression in endothelial cells compared with the normoxia group. In comparison to WT mice, PD-1 ^−/− mice exhibited a more severe HPH phenotype following exposure to hypoxia, However, administration of PD-L1 recombinant protein and overexpression of PD-L1 in lung endothelial cells mitigated HPH. In vitro, blockade of PD-L1 with a neutralizing antibody promoted endothelial cell angiogenesis, adhesion, and pyroptosis. Mechanistically, hypoxia downregulated PD-L1 protein expression through ubiquitination. Additionally, both in vivo and in vitro, PD-L1 inhibited T helper 17 cell response through the PI3K (phosphoinositide 3-kinase)/AKT (protein kinase B)/mTOR (mammalian target of rapamycin) pathway in HPH. CONCLUSIONS: PD-1/PD-L1 plays a role in ameliorating HPH development by inhibiting T helper 17 cell response through the PI3K/AKT/mTOR pathway and improving endothelial dysfunction, suggesting a novel therapeutic indication for PD-1/PD-L1–based immunomodulatory therapies in the treatment of HPH.

Pulmonary hypertension (PH) is a severe disease characterized by pulmonary vascular remodeling in which various immune cells play a critical role in vascular remodeling, although the details are still vague. Furthermore, current clinical treatments primarily focus on pulmonary vasodilation, but do not fundamentally address vascular remodeling itself. Here, first significant changes in neutrophils during the development of PH are demonstrated and show that neutrophil depletion can effectively attenuate disease progression. Moreover, the data show that neutrophil‐derived S100A9 is the key mediator to promote vascular remodeling, while both knockout and inhibition of S100A9 can prevent PH. In a co‐culture system of neutrophils and endothelial cells (ECs), hypoxic stimulation leads to increased S100A9 secretion by neutrophils, which activates the RAGE/PI3K/AKT pathway and causes dysfunction of ECs. These findings suggest that neutrophil‐derived S100A9 mediated neutrophil‐EC crosstalk plays an important role in pulmonary vascular remodeling, providing a promising strategy for treatment of PH.

Background: How perivascular adipose tissue (PVAT) controls vascular remodeling and perivascular inflammation during pulmonary hypertension progresses remains unknown. Methods: Western blotting, ELISA, immunohistochemistry, and immunofluorescence were used to measure proteins expression. Sugen 5416 combined with hypoxia (SuHx) mouse models were established in C57BL/6 mice, and treated with CL‐316243. Adeno‐associated virus vector delivery was used to specifically delete nesfatin‐1 in adipocytes of lung in mice. Transthoracic echocardiography was performed to evaluate the function of right ventricle. Assays for cell angiogenesis and adhesion were used to analyze endothelial cell function. A noncontact transwell coculture model was used to evaluate the interaction between different types of cells. Results: PVAT dysfunction participates in SuHx‐induced pulmonary vascular remodeling, PVAT exhibits features of white adipose tissue and the adipocytokine nesfatin‐1 is the key mediator. Browning of white adipose tissue via CL‐316243 treatment attenuates pulmonary hypertension phenotype in a SuHx–pulmonary hypertension mouse model. Specific deletion of nesfatin‐1 in adipocytes of lung attenuates SuHx‐induced pulmonary vascular remodeling. Nesfatin‐1 secretion is induced by IL‐17/Th17 via PI3K/AKT/mTOR pathway. In vitro, nesfatin‐1 promotes angiogenesis, adhesion, and apoptosis of endothelial cells. Coculture with 3T3‐L1 adipocytes promotes endothelial dysfunction mediated by nesfatin‐1. Mechanistic research shows that nesfatin‐1 mediates endothelial dysfunction by downregulating BMPR1A expression via MEF2B at the transcriptional and posttranslational levels. Conclusions: PVAT dysfunction participates in pulmonary vascular remodeling through nesfatin‐1–mediated endothelial dysfunction, suggesting that PVAT and nesfatin‐1 may constitute novel therapeutic targets for pulmonary hypertension.