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Abstract Background Necroptosis of macrophages is a necessary element in reinforcing intrapulmonary inflammation during acute lung injury (ALI). However, the molecular mechanism that sparks macrophage necroptosis is still unclear. Triggering receptor expressed on myeloid cells-1 (TREM-1) is a pattern recognition receptor expressed broadly on monocytes/macrophages. The influence of TREM-1 on the destiny of macrophages in ALI requires further investigation. Methods TREM-1 decoy receptor LR12 was used to evaluate whether the TREM-1 activation induced necroptosis of macrophages in lipopolysaccharide (LPS)-induced ALI in mice. Then we used an agonist anti-TREM-1 Ab (Mab1187) to activate TREM-1 in vitro. Macrophages were treated with GSK872 (a RIPK3 inhibitor), Mdivi-1 (a DRP1 inhibitor), or Rapamycin (an mTOR inhibitor) to investigate whether TREM-1 could induce necroptosis in macrophages, and the mechanism of this process. Results We first observed that the blockade of TREM-1 attenuated alveolar macrophage (AlvMs) necroptosis in mice with LPS-induced ALI. In vitro, TREM-1 activation induced necroptosis of macrophages. mTOR has been previously linked to macrophage polarization and migration. We discovered that mTOR had a previously unrecognized function in modulating TREM-1-mediated mitochondrial fission, mitophagy, and necroptosis. Moreover, TREM-1 activation promoted DRP1Ser616 phosphorylation through mTOR signaling, which in turn caused surplus mitochondrial fission-mediated necroptosis of macrophages, consequently exacerbating ALI. Conclusion In this study, we reported that TREM-1 acted as a necroptotic stimulus of AlvMs, fueling inflammation and aggravating ALI. We also provided compelling evidence suggesting that mTOR-dependent mitochondrial fission is the underpinning of TREM-1-triggered necroptosis and inflammation. Therefore, regulation of necroptosis by targeting TREM-1 may provide a new therapeutic target for ALI in the future.

Alveolar epithelial cell (AEC) senescence is a key driver of a variety of chronic lung diseases. It remains a challenge how to alleviate AEC senescence and mitigate disease progression. Our study identified a critical role of epoxyeicosatrienoic acids (EETs), downstream metabolites of arachidonic acid (ARA) by cytochrome p450 (CYP), in alleviating AEC senescence. In vitro, we found that 14,15-EET content was significantly decreased in senescent AECs. Exogenous EETs supplementation, overexpression of CYP2J2, or inhibition of EETs degrading enzyme soluble epoxide hydrolase (sEH) to increase EETs alleviated AECs' senescence. Mechanistically, 14,15-EET promoted the expression of Trim25 to ubiquitinate and degrade Keap1 and promoted Nrf2 to enter the nucleus to exert an anti-oxidant effect, thereby inhibiting endoplasmic reticulum stress (ERS) and alleviating AEC senescence. Furthermore, in D-galactose (D-gal)-induced premature aging mouse model, inhibiting the degradation of EETs by Trifluoromethoxyphenyl propionylpiperidin urea (TPPU, an inhibitor of sEH) significantly inhibited the protein expression of p16, p21, and γH2AX. Meanwhile, TPPU reduced the degree of age-related pulmonary fibrosis in mice. Our study has confirmed that EETs are novel anti-senescence substances for AECs, providing new targets for the treatment of chronic lung diseases.

Alveolar epithelial cell (AEC) senescence is implicated in the pathogenesis of pulmonary fibrosis (PF). However, the exact mechanism underlying AEC senescence during PF remains poorly understood. Here, we reported an unrecognized mechanism for AEC senescence during PF. We found that, in bleomycin (BLM)-induced PF mice, the expressions of isocitrate dehydrogenase 3α (Idh3α) and citrate carrier (CIC) were significantly down-regulated in the lungs, which could result in mitochondria citrate (citratemt) accumulation in our previous study. Notably, the down-regulation of Idh3α and CIC was related to senescence. The mice with AECs-specific Idh3α and CIC deficiency by adenoviral vector exhibited spontaneous PF and senescence in the lungs. In vitro, co-inhibition of Idh3α and CIC with shRNA or inhibitors triggered the senescence of AECs, indicating that accumulated citratemt triggers AEC senescence. Mechanistically, citratemt accumulation impaired the mitochondrial biogenesis of AECs. In addition, the senescence-associated secretory phenotype from senescent AECs induced by citratemt accumulation activated the proliferation and transdifferentiation of NIH3T3 fibroblasts into myofibroblasts. In conclusion, we show that citratemt accumulation would be a novel target for protection against PF that involves senescence.

BackgroundTai Chi Chuan (TCC) is a physical activity modality that originated in China and is now widely popular around the world. Although there are a series of articles reporting that TCC can improve balance and other functional symptoms in a variety of populations, including the elderly, patients with stroke, and patients with Parkinson's disease, its efficiency has not been scientifically and methodically evaluated in subjects with functional ankle instability (FAI). Moreover, there is no literature directly comparing TCC and conventional balance training (CBT) interventions for FAI. The objective of this study is to investigate the comparative effects of TCC intervention and CBT protocols in improving postural balance and subjective instability feelings in patients with FAI.MethodsThis study will be a single-center, parallel group, randomized controlled trial. Sixty-eight patients with FAI will be included and randomly assigned in a 1:1 ratio to either an intervention group (n =34) or a control group (n = 34). The participants in the intervention group will complete 12 weeks of TCC intervention (40 min/time, 3 times/week for 12 weeks) on the basis of health education treatment. The control group will receive health education and 36 CBT sessions during a 12-week period. Outcome measures include postural stability and self-reported feelings of instability at baseline, after the end of the intervention, and 3-month follow-up. The postural stability assessment of patients with FAI will be detected by performing static and dynamic postural tests, which will be carried out through a specific balance platform (TecnoBody ProKin). Self-reported feelings of instability will be assessed by Cumberland Ankle Instability Tool (CAIT), American Orthopedics Foot and Ankle Society's Ankle–Hindfoot Evaluation Scale (AOFAS-AHES), and the MOS item Short Form Health Survey (SF-36).DiscussionThis trial will demonstrate whether a 12-week TCC intervention positively affects postural stability and self-reported outcomes in patients with FAI. At the same time, the superiority of its clinical efficacy will also be compared with that of CBT. This study may also help to redefine the value of traditional Chinese exercises in the treatment of chronic ankle instability.Clinical trial registrationChinese Clinical Trial Registry: ChiCTR2100041790. Registration date: 22 March 2021. http://www.chictr.org.cn/edit.aspx?pid=119501&htm=4.

ABSTRACT: Since 2012, some advances have been made through the resource investigation, metallogenesis research, and comprehensive utilizing of lithium deposits in China. Firstly, the progress of lithium exploration has been made in Sichuan, Xinjiang, Qinghai and Jiangxi provinces (autonomous region). Li deposits are not only found within the pegmatite rocks but also within the granitic rocks and sedimentary rocks. Secondly, the methods of geological survey, geochemical and geophysical exploration, remote sensing technology and even drilling technology have been improved, which can be delineating orebodies quickly. Thirdly, the mechanisms of Li mineralization were summarized by analyzing the relationship between the Li contents and kinds of geological phenomena. Based on practice, a new understanding of “multi-cycle, deep circulation, integration of internal and external” metallogenic mechanism or “MDIE” metallogenic mechanism for short has been put forwarded further in this paper, and the “five levels + basement” exploration model has been successfully expanded to guide the prospecting work both in the Jiajika and Keeryin pegmatite ore fields in western Sichuan Province. Besides, new progress has been made in the aspect of amblygonite deposits of granite-type and hydrothermal type in the Mufushan-Jiuling ore district, which points out a new direction for prospecting new types of lithium deposits in China.

Atherosclerosis (AS) is a progressive disease of multifactorial origin, which occurs in response to endothelial injury. Increased homocysteine (Hcy) is considered a major cause of endothelial dysfunction, oxidative stress and DNA methylation; however, the mechanisms remain to be fully elucidated. The aim of the present study was to investigate whether Hcy causes injury to endothelial cells (ECs) by the effect of lectin-like oxidized-low density lipoprotein receptor-1 (LOX-1) DNA methylation through toll-like receptor 4(TLR4)/nuclear factor (NF)-κB/DNA methyltransferase (DNMT)1. The ECs were treated with different concentrations of Hcy, and it was found that Hcy promoted the expression of TLR4, leading to EC injury. The effect of oxidative stress was analyzed by measuring superoxide dismutase, malondialdehyde and hydrogen peroxide in the ECs. In addition, the association between NF-κB and DNMT1 was examined by treatment of the ECs with pyrrolidine dithiocarbamate (PDTC). The results suggested that Hcy induced LOX-1 DNA hypomethyaltion to promote the expression levels of LOX-1. Taken together, Hcy injured the ECs through the effect of methylation and trans-sulfuration metabolism of LOX-1 through TLR4/NF-κB/DNMT1. Following injury to the ECs, lipids, particularly ox-LDL, accumulated in the sub-endothelial layer to promote the formation of AS. [ABSTRACT FROM AUTHOR]

Vascular smooth muscle cell (VSMC) proliferation is a primary pathological event in atherosclerosis (AS), and homocysteine (Hcy) is an independent risk factor for AS. However, the underlying mechanisms are still lagging. Studies have used the combination of methylation of promoters of multiple genes to diagnose tumors, thus the aim of the current study was to investigate the role of methylation status of several genes in VSMCs treated with Hcy. CpG islands were identified in the promoters of platelet‑derived growth factor (PDGF), p53, phosphatase and tensin homologue on chromosome 10 (PTEN) and mitofusin 2 (MFN2). Hypomethylation was observed to occur in the promoter region of PDGF, hypermethylation in p53, PTEN and MFN2, and hypomethylation in two global methylation indicators, aluminium (Alu) and long interspersed nucleotide element‑1 (Line‑1). This was accompanied by an increase in the expression of PDGF, and reductions of p53, PTEN and MFN2, both in mRNA and protein levels. An elevation of S‑adenosylmethionine (SAM) and a reduction of S‑adenosylhomocysteine (SAH) and the SAM/SAH ratio were also identified. In conclusion, Hcy impacted methylation the of AS‑associated genes and global methylation status that mediate the cell proliferation, which may be a character of VSMCs treated with Hcy. The data provided evidence for mechanisms of VSMCs proliferation in AS induced by Hcy and may provide a new perspective for AS induced by Hcy. [ABSTRACT FROM AUTHOR]

The aim of the present study was to identify an effective method for detecting early-phase atherosclerosis (AS), as well as to provide useful DNA methylation profiles to serve as biomarkers for the detection of AS. A total of 300 individuals (150 AS patients and 150 healthy subjects) were recruited for peripheral blood DNA methylation analyses at 12 gene promoter loci using nested methylation-specific polymerase chain reaction in a test set. Based on the test set, the promoter methylation of TIMP metallopeptidase inhibitor 1 (TIMP1), ATP binding cassette subfamily A member 1 (ABCA1), and acetyl-CoA acetyltransferase 1 (ACAT1) were determined to be candidate biomarkers; demonstrating the highest sensitivity (88%) and specificity (90%). The biomarkers that were candidates for early AS detection were validated in an independent validation set (n=100). In the validation set, the combination of T1MP1, ABCA1 and ACAT1 methylation achieved sensitivity, specificity and coincidence rate values of 88, 70 and 79%, respectively. In the current pilot study, the patterns of DNA methylation of AS-associated genes were observed to be significantly altered in the peripheral blood of AS patients. Thus, the AS-specific methylation of the three-gene panel (TIMP1, ABCA1, and ACAT1) may serve as a valuable biomarker for the early detection of AS. [ABSTRACT FROM AUTHOR]

Accumulating evidence has suggested that homocysteine (Hcy) is an independent risk factor for atherosclerosis (AS). Hcy can promote vascular smooth muscle cell (VSMC) proliferation, which is pivotal in the pathogenesis and progression of AS. The aim of the present study was to investigate the epigenetic regulatory mechanism of microRNA (miR).143.mediated VSMCs proliferation induced by Hcy. The results of a 3.(4,5.dimethylthiazol.2.yl).2,5.diphe.nyltetrazolium bromide assay revealed that VSMC proliferation was increased by 1.39.fold following treatment with 100 mM Hcy, compared with the control group. The levels of miR.143 were markedly downregulated in the Hcy group, compared with the control group, as determined using reverse transcription.quantitative polymerase chain reaction analysis. In addition, the level of miR.143 methylation was increased markedly in the VSMCs treated with Hcy, compared with the control, and was reduced following transfection with DNA methyltransferase (DNMT)3a small interfering RNA, determined using methylation.specific.PCR. The activities of DNMT3a luciferase were also altered accordingly in VSMCs transfected with pre-miR-143 and miR-143 inhibitor, respectively. In addition, the expression of miR-143 was observed to be inversely correlated with the mRNA and protein expression of DNMT3 in the VSMCs. Taken together, these findings suggest that DNMT3a is a direct target of miR-143, and that the upregulation of DNMT3 is responsible for the hypermethylation of miR-143 in Hcy-induced VSMC proliferation. [ABSTRACT FROM AUTHOR]