The let-7 family is the second microRNA found in C. elegans. Recent researches have found it is highly expressed in the cardiovascular system. Studies have revealed the aberrant expression of let-7 members in cardiovascular diseases, such as heart hypertrophy, cardiac fibrosis, dilated cardiomyopathy (DCM), myocardial infarction (MI), arrhythmia, angiogenesis, atherosclerosis, and hypertension. Let-7 also participates in cardiovascular differentiation of embryonic stem cells. TLR4, LOX-1, Bcl-xl and AGO1 are by now the identified target genes of let-7. The circulating let-7b is suspected to be the biomarker of acute MI and let-7i, the biomarker of DCM. Further studies are necessary for identifying the gene targets and signaling pathways of let-7 in cardiovascular diseases. Let-7 might be a potential therapeutic target for cardiovascular diseases. This review focuses on the research progresses regarding the roles of let-7 in cardiovascular development and diseases.

Angiogenesis in atherosclerotic plaque promotes plaque growth, causes plaque hemorrhage and violates plaque stability. LINC00657 is a long noncoding RNA highly conserved and abundantly expressed in vascular endothelial cells. The present study was designed to investigate the effects and mechanisms of LINC00675 on the low concentration of oxidized low-density lipoprotein (oxLDL) induced angiogenesis. Cell proliferation assay, transwell assay, wound healing assay, and tube formation assay were conducted to detect the effects of low concentration of oxLDL on angiogenesis; The results discovered that oxLDL promoted the cell proliferation, migration, and tube formation. OxLDL also up-regulated LINC00657 expression. Inhibition of LINC00657 by siRNA significantly suppressed the oxLDL-induced endothelial cell proliferation, migration, and tube formation. Bioinformatic assay indicated six binding sites in LINC00657 sequence to miR-590-3p. The up-regulation of LINC00657 was related to the down-regulation of miR-590-3p in oxLDL-treated endothelial cells; while down-regulation of LINC00657 resulted in up-regulation of miR-590-3p. The anti-angiogenesis effects of si-LINC00657 were partly abrogated by miR-590-3p inhibitor. Further dual-luciferase assay found miR-590-3p inhibited the expression of HIF-1a by binding to the position of 689-696 in HIF-1a 39-UTR directly. MiR-590-3p also inhibited the oxLDL-induced up-regulation of HIF-1a, VEGF, MMP-2, and MMP-9. These results suggested that in oxLDL treated endothelial cells, LINC00657 acted as a miR-590-3p sponge to attenuate the suppression of miR-590-3p on HIF-1a, and to promote angiogenesis through VEGF, MMP-2, and MMP-9. The present study provided a new insight into the roles of LINC00657 and miR-590-3p on preventing oxLDL-induced angiogenesis and may provide a novel strategy for atherosclerosis treatment.

Aim: In China, warfarin is usually prescribed with Chuanxiong Rhizoma for treating thromboembolism diseases. However, the reason for their combination is still being determined. The present study explored the pharmacokinetics interactions of warfarin, Chuanxiong Rhizoma, and gut microbiota in the rat model of middle cerebral artery occlusion (MCAO).Methods: A total of 48 rats were randomly divided into six groups: MCAO rats orally administered warfarin (W group), pseudo germ-free MCAO rats orally administered warfarin (W-f group), MCAO rats co-administered Chuanxiong Rhizoma and warfarin (C + W group), pseudo germ-free MCAO rats co-administered Chuanxiong Rhizoma and warfarin (C + W-f group), MCAO rats co-administered warfarin and senkyunolide I (S + W group); pseudo germ-free MCAO rats co-administered warfarin and senkyunolide I (S + W-f group). After treatment, all animals’ blood and stool samples were collected at different time points. The stool samples were used for 16S rRNA sequencing analysis. Ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) method was established to quantify warfarin, internal standards, and the main bioactive components of Chuanxiong in blood samples. The main pharmacokinetics parameters of warfarin were calculated by DAS 2.1.1 software.Results: The relative abundance of Allobaculum and Dubosiella in the pseudo germ-free groups (W-f, C + W-f, S + W-f) was lower than that in the other three groups (W, C + W, S + W). The relative abundance of Lactobacillus in the W-f group was higher than that of the W group, while the relative abundance of Akkermansia decreased. The relative abundance of Ruminococcaceae_UCG-014 and Ruminococcaceae_NK4A214_group in the S + W-f group was lower than in the S + W group. Compared to the W group, the AUC_0-t and C_max of warfarin in the W-f group increased significantly to 51.26% and 34.58%, respectively. The AUC_0-t and C_max in the C + W group promoted 71.20% and 65.75% more than the W group. Compared to the W group, the AUC_0-t and C_max increased to 64.98% and 64.39% in the S + W group.Conclusion: Chuanxiong Rhizoma and senkyunolide I (the most abundant metabolites of Chuanxiong Rhizoma aqueous extract) might affect the pharmacokinetics features of warfarin in MCAO rats through, at least partly, gut microbiota.

Objective. Atherosclerosis is a chronic inflammatory disease which is responsible for many clinical manifestations. The present study was to investigate the anti-inflammatory functions and mechanisms of TNK1 in atherosclerosis. Methods. The ApoE(-/-) mice and human carotid endarterectomy (CEA) atherosclerotic plaques were used to investigate the differential expression of TNK1. The ApoE(-/-) mice were fed with high-fat diet (HFD) or normal-fat diet (NFD) for 8 weeks; the aorta was separated and stained with oil red O to evaluate the formation of atherosclerosis. TNK1 in mice aorta was measured by qPCR. The human CEA were obtained and identified as ruptured and stable plaques. The level of TNK1 was measured by qPCR and Western-blot staining. Further studies were conducted in THP-1 cells to explore the anti-inflammatory effects of TNK1. We induced the formation of macrophages by incubating THP-1 cells with PMA (phorbol 12-myristate 13-acetate). Afterwards, oxidized low-density lipoprotein (oxLDL) was used to stimulate the inflammation, and the secretion of inflammatory factors was measured by ELISA and qPCR. The levels of TNK1, total STAT1 and Tyk2, and the phosphorylation of STAT1 and Tyk2 were measured by western blot to uncover the mechanisms of TNK1. Results. The oil red O staining indicated obvious deposition of lipid on the aorta of ApoE(-/-) mice after 8-week HFD treatment. The TNK1 level was much higher in both the HFD-fed ApoE(-/-) mice aorta arch and the ruptured human CEA plaques. We found that TNK1 was highly expressed in THP-1 cells, compared to other atherosclerotic related cells (HUVEC, HBMEC, and HA-VSMC), indicating TNK1 might be involved in the inflammation. Suppressing the expression of TNK1 by shTNK1 inhibited the oxLDL-induced secretion of inflammatory factors, such as IL-12, IL-6, and TNF-α. ShTNK1 also inhibited the uptake of lipid and decreased the cellular cholesterol content in THP-1 cells. Furthermore, the shTNK1 suppressed the oxLDL-induced phosphorylation of Tyk2 and STAT1. Conclusion. TNK1 participated in the inflammation in atherosclerosis. shTNK1 suppressed the oxLDL-induced inflammation and lipid deposition in THP-1 cells. The mechanism might be related to the Tyk2/STAT signal pathway.

Epilepsy remains a prevalent chronic neurological disease that is featured by aberrant, recurrent and hypersynchronous discharge of neurons and poses a great challenge to healthcare systems. Although several therapeutic interventions are successfully utilized for treating epilepsy, they can merely provide symptom relief but cannot exert disease-modifying effect. Therefore, it is of urgent need to explore other potential mechanism to develop a novel approach to delay the epileptic progression. Since approximately 30 years ago, histone deacetylases (HDACs), the versatile epigenetic regulators responsible for gene transcription via binding histones or non-histone substrates, have grabbed considerable attention in drug discovery. There are also substantial evidences supporting that aberrant expressions and/activities of HDAC isoforms are reported in epilepsy and HDAC inhibitors (HDACi) have been successfully utilized for therapeutic purposes in this condition. However, the specific mechanisms underlying the role of HDACs in epileptic progression have not been fully understood. Herein, we reviewed the basic information of HDACs, summarized the recent findings associated with the roles of diverse HDAC subunits in epilepsy and discussed the potential regulatory mechanisms by which HDACs affected the development of epilepsy. Additionally, we also provided a brief discussion on the potential of HDACs as promising therapeutic targets for epilepsy treatment, serving as a valuable reference for basic study and clinical translation in epilepsy field.

Background: Previous observational studies have investigated the association between endocrine and metabolic factors and idiopathic pulmonary fibrosis (IPF), yet have produced inconsistent results. Therefore, it is imperative to employ the Mendelian randomization (MR) analysis method to conduct a more comprehensive investigation into the impact of endocrine and metabolic factors on IPF.Methods: The instrumental variables (IVs) for 53 endocrine and metabolic factors were sourced from publicly accessible genome-wide association study (GWAS) databases, with GWAS summary statistics pertaining to IPF employed as the dependent variables. Causal inference analysis encompassed the utilization of three methods: inverse-variance weighted (IVW), weighted median (WM), and MR-Egger. Sensitivity analysis incorporated the implementation of MR-PRESSO and leave-one-out techniques to identify potential pleiotropy and outliers. The presence of horizontal pleiotropy and heterogeneity was evaluated through the MR-Egger intercept and Cochran’s Q statistic, respectively.Results: The IVW method results reveal correlations between 11 traits and IPF. After correcting for multiple comparisons, seven traits remain statistically significant. These factors include: “Weight” (OR= 1.44; 95% CI: 1.16, 1.78; P=8.71×10^-4), “Body mass index (BMI)” (OR= 1.35; 95% CI: 1.13, 1.62; P=1×10^-3), “Whole body fat mass” (OR= 1.40; 95% CI: 1.14, 1.74; P=1.72×10^-3), “Waist circumference (WC)” (OR= 1.54; 95% CI: 1.16, 2.05; P=3.08×10^-3), “Trunk fat mass (TFM)” (OR=1.35; 95% CI: 1.10,1.65; P=3.45×10^-3), “Body fat percentage (BFP)” (OR= 1.55; 95% CI: 1.15,2.08; P=3.86×10^-3), “Apoliprotein B (ApoB)” (OR= 0.78; 95% CI: 0.65,0.93; P=5.47×10^-3). Additionally, the sensitivity analysis results confirmed the reliability of the MR results.Conclusion: The present study identified causal relationships between seven traits and IPF. Specifically, ApoB exhibited a negative impact on IPF, while the remaining six factors demonstrated a positive impact. These findings offer novel insights into the underlying etiopathological mechanisms associated with IPF.