M6A modification and T cells in adipose tissue inflammation.

Adipose tissue in the obese state can lead to low-grade chronic inflammation while inducing or exacerbating obesity-related metabolic diseases and impairing overall health.T cells, which are essential immune cells similar to macrophages, are widely distributed in adipose tissue and perform their immunomodulatory function; they also cross-talk with other cells in the vascular stromal fraction. Based on a large number of studies, it has been found that N6 methyl adenine (m6A) is one of the most representative of epigenetic modifications, which affects the crosstalk between T cells, as well as other immune cells, in several ways and plays an important role in the development of adipose tissue inflammation and related metabolic diseases. In this review, we first provide an overview of the widespread presence of T cells in adipose tissue and summarize the key role of T cells in adipose tissue inflammation. Next, we explored the effects of m6A modifications on T cells in adipose tissue from the perspective of adipose tissue inflammation. Finally, we discuss the impact of m6a-regulated crosstalk between T cells and immune cells on the prospects for improving adipose tissue inflammation research, providing additional new ideas for the treatment of obesity.

Sirtuins and autophagy in lipid metabolism.

Sirtuins are a family of NAD+ -dependent deacetylases that regulate some important biological processes, including lipid metabolism and autophagy, through their deacetylase function. Autophagy is a new discovery in the field of lipid metabolism, which may provide a new idea for the regulation of lipid metabolism. There are many tandem parts in the regulation process of lipid metabolism and autophagy of sirtuins protein family. This paper summarized these tandem parts and proposed the possibility of sirtuins regulating lipid autophagy, as well as the interaction and synergy between sirtuins protein family. Currently, some natural drugs have been reported to affect metabolism by regulating sirtuins, some of which regulate autophagy by targeting sirtuins.

Enhancing intestinal barrier efficiency: A novel metabolic diseases therapy.

Physiologically, the intestinal barrier plays a crucial role in homeostasis and nutrient absorption and prevents pathogenic entry, harmful metabolites, and endotoxin absorption. Recent advances have highlighted the association between severely damaged intestinal barriers and diabetes, obesity, fatty liver, and cardiovascular diseases. Evidence indicates that an abated intestinal barrier leads to endotoxemia associated with systemic inflammation, insulin resistance, diabetes, and lipid accumulation, accelerating obesity and fatty liver diseases. Nonetheless, the specific mechanism of intestinal barrier damage and the effective improvement of the intestinal barrier remain to be explored. Here, we discuss the crosstalk between changes in the intestinal barrier and metabolic disease. This paper also highlights how to improve the gut barrier from the perspective of natural medicine, gut microbiota remodeling, lifestyle interventions, and bariatric surgery. Finally, potential challenges and prospects for the regulation of the gut barrier-metabolic disease axis are discussed, which may provide theoretical guidance for the treatment of metabolic diseases.

The Potential of Melatonin to Treat Atherosclerosis by Targeting Mitochondria.

As a circadian rhythm hormone, melatonin is widely present in the body and has rich physiological functions. Compared to its prominent circadian role, melatonin has been extensively studied in many fields as an ancient antioxidant. In addition to being considered a potent antioxidant, melatonin has also been found to play an important role in mitochondrial homeostasis. Mitochondrial oxidative stress plays a crucial role in the occurrence and development of atherosclerosis. Therefore, the possible therapeutic value of melatonin as an antioxidant targeting mitochondria in atherosclerosis is worth exploring. The most widespread clinical applications of melatonin are in circadian rhythms and sleep, but the cardiovascular system may be the most promising area.

LSD1 for the Targeted Regulation of Adipose Tissue.

White and thermal (brown and beige) adipose tissue energy storage and oxidative regulation pathways play a central role in maintaining the energy balance throughout the body, and the dysregulation of these pathways is closely related to glucose and lipid metabolism disorders and adipose tissue dysfunction, including obesity, chronic inflammation, insulin resistance, mitochondrial dysfunction, and fibrosis. Recent epigenetic studies have identified the novel regulatory element LSD1, which controls the above parameters, and have provided new mechanistic possibilities for re-encoding the fate and function of adipocytes. In this review, we outline the current advances in adipocyte metabolism in physiology and disease and discuss possible strategies for LSD1 to alter the phenotype of adipose tissue and thus influence energy utilization to improve metabolic health.

Ghrelin attenuates myocardial fibrosis after acute myocardial infarction via inhibiting endothelial-to mesenchymal transition in rat model.

Ghrelin, a peptide hormone produced in the gastrointestinal tract, has recently been found to be associated with the onset of myocardial fibrosis (MF). The exact mechanism, however, remains elusive. This study sought to identify the function and mechanism of ghrelin on MF after acute myocardial infarction (AMI). AMI was established in Spraque-Dawley rats by ligation of the left anterior descending (LAD). Ghrelin or saline was intraperitoneally injected two times per day for 8 weeks after ligation. The weight of heart (mg) and the weight ratio of heart to body (mg/g) as well as the fibrotic area were increased, while serum level of ghrelin was decreased after AMI. Ghrelin significantly ameliorated MF and decreased deposition of collagens in perivascular fibrosis area. In addition, ghrelin inhibited Endothelial-to-mesenchymal transition (EndMT), a crucial process for MF, in perivascular fibrosis area and TGF-ß1-induced human coronary artery endothelial cells (HCAECs). Mechanistically, ghrelin persistently decreased the phosphorylation of Smad2/3 and enhanced the expression of Smad7 and p-AMPK in vivo and in vitro. After the abolition of Smad7, GHSR-1a and AMPK pathway, the effect of ghrelin on EndMT was significantly inhibited. In conclusion, these results presented a novel finding that ghrelin attenuated MF after AMI via regulation EndMT in a GHSR-1a/AMPK/Smad7- dependent manner.

Apolipoprotein A1 Inhibits the TGF-ß1-Induced Endothelial-to-Mesenchymal Transition of Human Coronary Artery Endothelial Cells.

OBJECTIVE: Transforming growth factor ß1 (TGF-ß1) is the major cytokine for stimulating endothelial cells (ECs) to transdifferentiate to mesenchymal cells (MCs) in the process known as endothelial-to-mesenchymal transition (EndMT). Recently, TGF-ß1-induced EndMT has been implicated in the pathogenesis of atherosclerosis (AS). It has been identified that apolipoprotein A1 (ApoA-I) obstructs TGF-ß1-induced endothelial dysfunction, providing a protective effect for ECs and also anti-AS activity. However, the exact role of ApoA-I in TGF-ß1-induced EndMT is not clear. In this study, we aimed to investigate whether ApoA-I can modulate TGF-ß1-induced EndMT in human coronary artery ECs (HCAECs). METHODS AND RESULTS: The HCAECs were treated with TGF-ß1 with or without ApoA-I. Morphological changes in HCAECs and the expression of EndMT-related markers were evaluated. HCAECs treated with TGF-ß1 were found to transform to MC morphology, with inconspicuous expression of EC markers such as vascular endothelial cadherin and CD31, and conspicuous expression of fibroblast-specific protein 1 (FSP-1) and α-smooth muscle actin. The treatment of HCAECs with ApoA-I inhibited the TGF-ß1-induced EndMT, and elevated expression of EC markers was observed but reduced expression of MC markers. Moreover, ApoA-I impeded the expression level of Slug and Snail, crucial transcriptional factors of EndMT, and it inhibited the TGF-ß1-induced phosphorylation of Smad2 and Smad3 which affected the EC morphology. In addition, the knockdown of ABCA1 by RNA interference eliminated the inhibition effect of ApoA-I on TGF-ß1-induced EndMT. CONCLUSIONS: Our findings revealed a novel mechanism for the ApoA-I protective effect on endothelium function via the inhibition of TGF-ß1-induced EndMT. This might provide new insights for developing strategies for modulating AS and vascular remodeling.

miR-7 inhibits the invasion and metastasis of gastric cancer cells by suppressing epidermal growth factor receptor expression.

The present study profiled differentially expressed microRNAs (miRs) in gastric cancer cell lines and then investigated miR-7 expression in gastric cancer tissue specimens and the effects of miR-7 on the growth, invasion and metastasis of gastric cancer cells and the underlying molecular events. A microRNA microarray was used to profile differentially expressed miRNAs in human gastric cancer cell lines relative to a normal stomach mucosal epithelial cell line. The miRNA miR-7 was selected for further investigation, which included real-time reverse-transcription PCR (qRT-PCR) analysis of miR-7 levels in different gastric cancer cell lines and tissues and distant non-tumor tissues from patient resections. Cell counting kit-8 (CCK-8), Transwell migration and invasion, and western blot assays were performed to assess tumor cell viability, invasion and gene expression, respectively, after miR-7 transfection. The miRNA microarray profiling revealed 14 upregulated miRNAs (including miR-21, miR-26b and miR-30b) and 19 downregulated miRNAs (including let-7i, miR-7 and miR-622) between gastric cancer and normal cell lines. The qRT-PCR analysis confirmed that reduced miR-7 expression occurred more frequently in poorly and moderately differentiated gastric cancer MGC-803, MKN-45 and SGC-7901 cell lines than in the well-differentiated gastric cancer NCI-N87 cell line, which was consistent with the results for gastric cancer tissues. Expression of miR-7 was downregulated in 86.9% (20/23) of the gastric cancer tissues compared with that in the distant non-tumor tissues. Restoration of miR-7 expression significantly inhibited tumor cell viability, invasiveness and migration when compared with the control cells. Luciferase assay confirmed the epidermal growth factor receptor (EGFR) as a target gene of mR-7, and expression of miR-7 significantly suppressed EGFR expression at both the mRNA and protein levels. The data from the present study demonstrated that reduced miR-7 expression contributes to gastric cancer development and progression. Further study will investigate miR-7 in the regulation of EGFR expression in vitro and in vivo.

Apolipoprotein A-I inhibits LPS-induced atherosclerosis in ApoE(-/-) mice possibly via activated STAT3-mediated upregulation of tristetraprolin.

AIM: To investigate the effects of the major component of high-density lipoprotein apolipoprotein A-I (apoA-I) on the development of atherosclerosis in LPS-challenged ApoE(-/-) mice and the underlying mechanisms. METHODS: Male ApoE-KO mice were daily injected with LPS (25 µg, sc) or PBS for 4 weeks. The LPS-challenged mice were intravenously injected with rAAV-apoA-I-GFP or rAAV-GFP. After the animals were killed, blood, livers and aortas were collected for biochemical and histological analyses. For ex vivo experiments, the abdominal cavity macrophages were harvested from each treatment group of mice, and cultured with autologous serum, then treated with LPS. RESULTS: Chronic administration of LPS in ApoE(-/-) mice significantly increased the expression of inflammatory cytokines (TNF-α, IL-1ß, IL-6, and MCP-1), increased infiltration of inflammatory cells, and enhanced the development of atherosclerosis. In LPS-challenged mice injected with rAAV-apoA-I-GFP, viral particles and human apoA-I were detected in the livers, total plasma human apoA-I levels were grammatically increased; HDL-cholesterol level was significantly increased, TG and TC were slightly increased. Furthermore, overexpression of apoA-I significantly suppressed the expression of proinflammatory cytokines, reduced the infiltration of inflammatory cells, and decreased the extent of atherosclerotic lesions. Moreover, overexpression of apoA-I significantly increased the expression of the cytokine mRNA-destabilizing protein tristetraprolin (TTP), and phosphorylation of JAK2 and STAT3 in aortas. In ex vivo mouse macrophages, the serum from mice overexpressing apoA-I significantly increased the expression of TTP, accompanied by accelerated decay of mRNAs of the inflammatory cytokines. CONCLUSION: ApoA-I potently suppresses LPS-induced atherosclerosis by inhibiting the inflammatory response possibly via activation of STAT3 and upregulation of TTP.

[Assessment of left ventricular systolic and diastolic function by Doppler tissue imaging in patients with chronic heart failure].

OBJECTIVE: To investigate the application of pulsed-wave Doppler tissue imaging ( PW-DTI) in evaluating left ventricular systolic and diastolic function in patients with chronic heart failure (CHF). METHODS: Mitral annular velocities (MAV) were measured by PW-DTI in 35 patients with CHF and 25 healthy subjects. Traditional indices for evaluating the global left ventricular function by conventional echocardiography were also studied as a comparison. RESULTS: Peak systolic, peak early diastolic, peak late diastolic mitral annular velocities ( Sa, Ea, Aa), and Ea/Aa ratio progressively decreased in CHF patients compared with the healthy subjects (P <0.01 ). Sa of the mitral annulus correlated linearly with the left ventricle ejection fraction (LVEF) (r =0.890, P < 0.01). Compared with the healthy subjects, Ea in all 3 subgroups of diastolic dysfunction in the CHF group significantly decreased (P <0.01). Aa in 2 subgroups (pseudonormal filling and restrictive filling) decreased (P < 0.01 ) and the decreased Ea/Aa was found in the delayed relaxation and pseudonormal filling subgroups compared with the healthy subjects (P<0.001). CONCLUSION: MAV measured by PW-DTI can be used for assessing the left ventricular systolic and diastolic function in CHF patients.