Changes in gut microbiota linked to a prevention of cardiac remodeling induced by hypertension in spontaneously hypertensive rats fed a pawpaw fruit diet.

Objective: Dietary intake of fruit is associated with lower incidence of hypertension and cardiovascular risk. Papaya is a kind of delicious fruit and reported has dietary therapeutic effects, such as digestive stimulation and hypotensive efficacy. However, the mechanism of pawpaw involved have not been elucidated. Here, we illustrate that the effect of pawpaw on the gut microbiota and the prevention of cardiac remodeling. Methods: Gut microbiome, cardiac structure/function, and blood pressure were examined in SHR and WKY groups. The intestinal barrier was tested with histopathologic; immunostaining and Western blot were used to measure the tight junction protein level; Gpr41 was tested by RT-PCR, and inflammatory factors were detected with ELISA. Results: We observed a significant decrease in microbial richness, diversity, and evenness is the spontaneously hypertensive rat (SHR), in addition to an increased Firmicutes/Bacteroidetes (F/B) ratio. These changes were accompanied by decreased in acetate and butyrate-producing bacteria. Compared with SHR, treatment with pawpaw at the dosage of 10 g/kg for 12 weeks significantly reduced the blood pressure, cardiac fibrosis and cardiac hypertrophy, while the ratio of F/B decreased. We also found that the concentration of short-chain fatty acids (SCFAs) was increased in SHR fed with pawpaw compared with that in control group, while the gut barrier was restored and level of proinflammatory cytokines in the serum were decreased. Conclusions: Pawpaw, rich of high fiber, led to changes in the gut microbiota that played a protective role in the development of cardiac remodeling. The potential mechanism of pawpaw may explained by the generation of one of the main metabolites of the gut microbiota, the short-chain fatty acid acetate, increasing tight junction protein level occluding to enhance the gut barrier for less releasing the inflammation cytokines, and upregulating G-protein-coupled receptor 41 (GPR41) to reduce blood pressure.

Construction and Analysis of lncRNA-Associated ceRNA Network in Atherosclerotic Plaque Formation.

Atherosclerosis (AS) is a vascular disease with plaque formation. Unstable plaques can be expected to result in cardiovascular disease, such as myocardial infarction and stroke. Studies have verified that long noncoding RNAs (lncRNAs) play a critical role in atherosclerotic plaque formation (APF), including MALAT1, GAS5, and H19. A ceRNA network is a combination of these two interacting processes, which regulate the occurrence and progression of many diseases. However, lncRNA-associated ceRNA network in terms of APF is limited. This study sought to discover novel potential biomarkers and ceRNA network for APF. We designed a triple network based on the lncRNA-miRNA and mRNA-miRNA pairs obtained from lncRNASNP and starBase. Differentially expressed genes (DEGs) and lncRNAs in human vascular tissues derived from the Gene Expression Omnibus database (GSE43292, GSE97210) were systematically selected and analyzed. A ceRNA network was constructed by hypergeometric test, including 8 lncRNAs, 243 miRNAs, and 8 mRNAs. APF-related ceRNA structure was discovered for the first time by combining network analysis and statistical validation. Topological analysis determined the key lncRNAs with the highest centroid. GO and KEGG enrichment analysis indicated that the ceRNA network was primarily enriched in "regulation of platelet-derived growth factor receptor signaling pathway," "negative regulation of leukocyte chemotaxis," and "axonal fasciculation." A functional lncRNA, HAND2-AS1, was identified in the ceRNA network, and the main miRNA (miRNA-570-3p) regulated by HAND2-AS1 was further screened. This present study elucidated the important function of lncRNA in the origination and progression of APF and indicated the potential use of these hub nodes as diagnostic biomarkers and therapeutic targets.

Modulation of transforming growth factor-beta signaling pathway mediates the effects of Kangxian Formula on cardiac remodeling.

ETHNOPHARMACOLOGICAL RELEVANCE: Kangxian formula (KXF) is a traditional Chinese medicine which shows effective outcomes in treating cardiac remodeling induced by hypertension. However, the exact effects and the mechanisms involved remain obscure. AIM OF THE STUDY: In this study, we aimed to identify the therapeutic role of KXF in vivo and in vitro, and investigate the mechanism of KXF on hypertension induced cardiac remodeling. MATERIALS AND METHODS: After quality control of KXF using fingerprint, blood pressure, cardiac structure/function indexes, and degree of myocardial collagen were measured in vivo. Moreover, the proliferation, migration, and fibroblast-to-myofibroblast transformation (FMT) of cardiac fibroblasts (CFBs) were determined. Using gene chip, the related mechanisms of KXF treatment on cardiac remodeling were identified and further validated by western blot and polymerase chain reaction. RESULTS: A stable quality control standard of KXF was established in this study. KXF administration ameliorated systolic/diastolic blood pressure, cardiac damages, and cardiac fibrosis in vivo. The proliferation, migration, and FMT of CFBs were also inhibited by the treatment of KXF medicated serum. Furthermore, KXF reduced the protein level of transforming growth factor-beta (TGF-ß) receptors Ⅰ, Ⅱ, Tak1, p38, Smad2/3, and Smad4 and the expression of mRNA, which are the hub proteins in the TGF-ß signaling pathway. CONCLUSION: Our findings suggest that KXF attenuates cardiac remodeling by improving cardiac damages, attenuating cardiac fibrosis, and inhibiting the activity of CFBs. In addition, KXF ameliorates cardiac remodeling partially through modulating the TGF-ß signaling pathway. These data provide insights and mechanisms into the wide application of KXF in clinical practice.

Danshenol A Alleviates Hypertension-Induced Cardiac Remodeling by Ameliorating Mitochondrial Dysfunction and Suppressing Reactive Oxygen Species Production.

Current therapeutic approaches have a limited effect on cardiac remodeling, which is characteristic of cardiac fibrosis and myocardial hypertrophy. In this study, we examined whether Danshenol A (DA), an active ingredient extracted from the traditional Chinese medicine Radix Salviae, can attenuate cardiac remodeling and clarified the underlying mechanisms. Using the spontaneously hypertensive rat (SHR) as a cardiac remodeling model, DA ameliorated blood pressure, cardiac injury, and myocardial collagen volume and improved cardiac function. Bioinformatics analysis revealed that DA might attenuate cardiac remodeling through modulating mitochondrial dysfunction and reactive oxygen species. DA repaired the structure/function of the mitochondria, alleviated oxidative stress in the myocardium, and restored apoptosis of cardiomyocytes induced by angiotensin II. Besides, DA inhibited mitochondrial redox signaling pathways in both the myocardium and cardiomyocytes. Thus, our study suggested that DA attenuates cardiac remodeling induced by hypertension through modulating mitochondrial dysfunction and reactive oxygen species.

Construction and analysis of a lncRNA­miRNA­mRNA network based on competitive endogenous RNA reveals functional lncRNAs in diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) is a major cause of mortality in patients with diabetes, particularly those with type 2 diabetes. Long non­coding RNAs (lncRNAs), including terminal differentiation­induced lncRNA (TINCR), myocardial infarction­associated transcript (MIAT) and H19, serve a key role in the regulation of DCM. MicroRNAs (miRNAs/miRs) can inhibit the expression of mRNA at the post­transcriptional level, whereas lncRNAs can mask the inhibitory effects of miRNAs on mRNA. Together, miRNAs and lncRNAs form a competitive endogenous non­coding RNA (ceRNA) network that regulates the occurrence and development of various diseases. However, the regulatory role of lncRNAs in DCM is unclear. In this study, a background network containing mRNAs, miRNAs and lncRNAs was constructed using starBase and a regulatory network of DCM was screened using Cytoscape. A functional lncRNA, X­inactive specific transcript (XIST), was identified in the disease network and the main miRNAs (miR­424­5p and miR­497­5p) that are regulated by XIST were further screened to obtain the ceRNA regulatory network of DCM. In conclusion, the results of this study revealed that lncRNAs may serve an important role in DCM and provided novel insights into the pathogenesis of DCM.

[Silencing RRM1 gene reverses paclitaxel resistance in human breast cancer cell line MCF- 7/R by inducing cell apoptosis].

OBJECTIVE: To investigate the effects of ribonucleotide reductase catalytic subunit M1 (RRM1) gene silencing on drug resistance of human breast cancer cell line MCF-7/R. METHODS: We established a paclitaxel-resistant breast cancer MCF-7 cell line (MCF-7/R) by exposing the cells to high-concentration paclitaxel in a short time. Small interfering RNAs (siRNAs) targeting RRM1 were designed to silence RRM1 expression in human breast cancer MCF-7/R cells. MTT assay was used to detect the IC50 values and the sensitivity to paclitaxel in the cells with or without siRNA transfection. The changes in the proliferative activity of MCF7 and MCF-7/R cells following RRM1 gene silencing were evaluated using EdU assay. Flow cytometry was used to analyze the cell apoptosis and cell cycle changes. We assessed the effect of RRM1 gene silencing and paclitaxel on the tumor growth in a nude mouse model bearing subcutaneous xenografts with or without siRNA transfection. RESULTS: We detected significantly higher expressions of RRM1 at both the mRNA and protein levels in the drug-resistant MCF- 7/R cells than in the parental MCF-7 cells (P < 0.01). Transfection with the specific siRNAs significantly reduced the expression of RRM1 in MCF-7/R cells (P < 0.05), which showed a significantly lower IC50 value of paclitaxel than the cells transfected with the negative control siRNA (P < 0.05). RRM1 silencing significantly inhibited the proliferation (P < 0.01) and enhanced the apoptosis-inducing effect of paclitaxel in MCF-7/R cells (P < 0.001); RRM1 silencing also resulted in obviously reduced Akt phosphorylation, suppressed Bcl-2 expression and promoted the expression of p53 protein in MCF-7/R cells. In the tumor-bearing nude mice, the volume of subcutaneously transplanted tumors was significantly smaller in MCF-7/R/siRNA+ PTX group than in the other groups (P < 0.001). CONCLUSIONS: RRM1 gene silencing can reverse paclitaxel resistance in human breast cancer cell line MCF-7/R by promoting cell apoptosis.

Ferulic acid ameliorates nonalcoholic fatty liver disease and modulates the gut microbiota composition in high-fat diet fed ApoE-/- mice.

The objective of this study was to investigate the effects of ferulic acid (FA) on nonalcoholic fatty liver disease (NAFLD) and gut microbiota, and its regulation mechanism in ApoE-/- mice fed on a high-fat diet (HFD). Liver morphology, blood lipids, gut microbiota and their metabolite indole-3-acetic acid (I3A) were determined in ApoE-/- mice. We also examined the hepatic expression of aryl hydrocarbon receptor (AHR), which inhibits the expression of fatty acid synthase (FASN) and sterol regulatory element-binding protein 1c (SREBP-1c), and ultimately reduces the deposition of triglycerides (TG) and total cholesterol (TC) in the liver. The results of the animal experiment showed that oral administration of FA markedly alleviated the formation of NAFLD and decreased the levels of serum TC, TG and low-density lipoprotein cholesterol (LDL-C). Furthermore, FA supplementation altered the composition of gut microbiota, in particular, modulating the ratio of Firmicutes to Bacteroidetes, and decreased the generation of I3A. Additionally, FA could increase the expression of hepatic AHR and inhibit the expression of FASN and SREBP-1c in the liver. Finally, we found that FA did not have hepatorenal toxicity. The findings above illustrate that FA has the potential to ameliorate NAFLD, some of which are closely related to the modulation of specific gut microbiota and the regulation of genes involved in TG and TC metabolism.

Understand the acquired resistance of RTK inhibitors by computational receptor tyrosine kinases network.

Receptor Tyrosine Kinase inhibitors are the most popular anti-cancer drug types. But the resistance is the major challenge. Our study on the network with 1334 proteins and their 2623 interactions which retrieved from 52 RTKs indicated that most RTKs proteins were the key controllers of the protein-protein network. Direct or indirect interactions with RTKs (shortest path of 2) were often associated with resistance to RTKs inhibitors in the literature. The results based on the KEGG pathway analysis demonstrated the Rap1 signal pathway would also contribute to the resistance of RTKs inhibitor as well as the known Ras pathway and PI3K/Akt pathway. The pathways can crosstalk within and between complex signals transduction networks, then activate the upstream or downstream pathway, and/or activate the other oncogenes, which lead to the acquired resistance. Our results gave a systematically global view to understand the drug resistance and provided a clue to how to combine the different targets or pathways for synergy of targeted RTKs inhibitors.