Familial hypercholesterolemia (FH) is a common monogenic disease which is associated with high serum levels of low-density lipoprotein cholesterol (LDL-C) and leads to atherosclerosis and cardiovascular disease (CVD). Early diagnosis and effective treatment strategy can significantly improve prognosis. Recently, non-coding RNAs (ncRNAs) have emerged as novel biomarkers for the diagnosis and innovative targets for therapeutics. Non-coding RNAs have essential roles in the regulation of LDL-C homeostasis, suggesting that manipulation and regulating ncRNAs could be a promising theranostic approach to ameliorate clinical complications of FH, particularly cardiovascular disease. In this review, we briefly discussed the mechanisms and pathophysiology of FH and novel therapeutic strategies for the treatment of FH. Moreover, the theranostic effects of different non-coding RNAs for the treatment and diagnosis of FH were highlighted. Finally, the advantages and disadvantages of ncRNA-based therapies vs. conventional therapies were discussed.

/pdf/regulatory-non-coding-rnas-in-familial-hypercholesterolemia-2foz6l0r.pdf

Regulatory Non-Coding RNAs in Familial Hypercholesterolemia, Theranostic Applications

Colorectal cancer (CRC) is the third most threatening malignancy worldwide. Colorectal tumors transfer information with their tumor microenvironment (TME) and communicate together which can be detected through exosome transmission. Exosomes are important regulators made by different types of cells in all body fluids containing RNA, DNA, metabolites, and proteins. Recently, Exosome-derived noncoding RNAs (ncRNAs) applications have gained great consideration based on their potential role in the different pathological processes. Therefore, in this review, we summarized the recent discoveries on exosomal ncRNAs function in CRC initiation and development, and drug resistance to provide a novel insight into exosomal ncRNAs' clinical application and their potential to be biomarkers for CRC patients. 

Exosomal noncoding RNAs in colorectal cancer: An overview of functions, challenges, opportunities, and clinical applications.

The treatment of hypercholesterolemia is mainly based on statins. However, the response to pharmacological therapy shows high inter-individual variability, resulting in variable effects in both lipid lowering and risk reduction. Thus, a better understanding of the lipid-lowering mechanisms and response variability at the molecular level is required. Previously, we demonstrated a deregulation of the microRNA expression profile in HepG2 cells treated for 24 h with atorvastatin, using a microarray platform. In the present study, we evaluated the expression of hsa-miR-17-5p, hsa-miR-20a-5p and hsa-miR-106a-5p in hypercholesterolemic patients before and after atorvastatin treatment and in HepG2 cells treated for 24 h with atorvastatin The miRNA hsa-mir-20a-5p was repressed after atorvastatin treatment in hypercholesteremic subjects and in HepG2 cells in culture. Repression of hsa-mir-20a-5p increased LDLR gene and protein expression in HepG2 cells, while hsa-mir-20a-5p overexpression reduced LDLR gene and protein expression.

/pdf/microrna-20a-5p-downregulation-by-atorvastatin-a-potential-263mwgg8.pdf

MicroRNA-20a-5p Downregulation by Atorvastatin: A Potential Mechanism Involved in Lipid-Lowering Therapy

Proprotein convertase subtilisin/kexin 9 inhibitor downregulates microRNA-130a-3p expression in hepatocytes to alleviates atherosclerosis progression

Abstract Background Proprotein convertase subtilisin/kexin type-9 (PCSK9), an enzyme produced mainly by hepatocytes and breaks low-density lipoprotein receptor (LDL-R), inflammatory markers [toll like receptor 4 (TLR4), high mobility group box 1 (HMGB1), tumor necrosis factor alpha (TNFα), c-reactive protein (CRP)], and monocyte subtypes are associated with coronary artery disease (CAD) pathogenesis. The circulating microRNA-218 (miR-218) can relieve CAD through the suppression of HMGB1 in monocyte-derived inflammatory cytokines. Herein, we explored the association between circulatory miR-218 expression and serum levels of PCSK9, inflammatory markers, and monocyte subtypes in statin and non-statin CAD patients. This study involved 91 healthy (control) and 91 stable CAD participants which were subdivided into no-statin (NS, n = 25), low-statin (LS, n = 25), and high-statin (HS, n = 41) groups. low-density lipoprotein cholesterol (LDL-C) and CRP serum levels were calorimetrically determined. Serum levels of PCSK9, TLR4, HMGB1, and TNFα were detected by ELISA, while monocyte subsets [classical (CM), intermediate (IM), non-classical (NC)] were calculated by flow cytometry. Circulatory miR-218 expression was detected by real-time PCR. Results The CAD group had significantly lower miR-218 expression and significantly higher levels of PCSK9, inflammatory markers (HMGB1, CRP, TLR4, and TNFα), and IM% than the control group. Among CAD patients, LS and HS groups had significantly lower miR-218 expression, LDL-C levels, and inflammatory markers and significantly higher levels of PCSK9 than the NS group. The HS group exhibited the lowest miR-218 expression and inflammatory markers and the highest PCSK9 levels. However, there were no significant changes in IM% among statin and non-statin groups. In the three CAD groups, miR-218 showed a significantly negative correlation with PCSK9 and inflammatory markers (HMGB1, CRP, TLR4, and TNFα), while this expression exhibited a significantly negative correlation with CM%, IM%, and NCM% only in the NS group. Results of multivariable linear regression indicated a correlation between miR-218 and five independent variables (PCSK9, HMGB1, CRP, TLR4, and TNFα) in the total statin (LS + HS) group, and eight independent variables (PCSK9, HMGB1, CRP, TLR4, and TNFα, CM%, IM%, NCM%) in the NS group. Provided that all other independent variables are constant, miR-218 expression was significantly correlated to CRP (Beta = 0.234) and PCSK9 (Beta = − 0.875) in the total statin group; TLR4 (Beta = − 0.554) in the LS group; HMGB1 (Beta = − 0.507) in the HS group; and CRP (Beta = − 0.745) in the NS group. Conclusions Statin-treated CAD patients have a unique negative correlation between miR-218 and PCSK9, HMGB1, and TLR4, and subsequently with CAD progress. Therefore, it could be recommended to combine activators of miR-218 and inhibitors of PCSK9, HMGB1, and TLR4 with statin to efficiently treat CAD. 

pdf/association-between-circulatory-microrna-218-expression-50oamc2btt.pdf

Association between circulatory microRNA-218 expression, serum PCSK9 levels, inflammatory markers, and monocyte subsets in coronary artery disease patients: impact of statin therapy

Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT)

CONICYT FONDECYT

1171765
Direccion de Investigacion of the Universidad de La Frontera 

DI19-2018
ANID-Chile Doctoral Scholarship

/pdf/microrna-33b-is-a-potential-non-invasive-biomarker-for-2i1tl0dibf.pdf

MicroRNA-33b is a Potential Non-Invasive Biomarker for Response to Atorvastatin Treatment in Chilean Subjects With Hypercholesterolemia: A Pilot Study.

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MicroRNA-33b is a Potential Non-Invasive Biomarker for Response to Atorvastatin Treatment in Chilean Subjects With Hypercholesterolemia: A Pilot Study.