Magnesium isoglycyrrhizinate ameliorates high fructose-induced liver fibrosis in rat by increasing miR-375-3p to suppress JAK2/STAT3 pathway and TGF-ß1/Smad signaling.

Increasing evidence has demonstrated that excessive fructose intake induces liver fibrosis. Epithelial-mesenchymal transition (EMT) driven by transforming growth factor-ß1 (TGF-ß1)/mothers against decapentaplegic homolog (Smad) signaling activation promotes the occurrence and development of liver fibrosis. Magnesium isoglycyrrhizinate is clinically used as a hepatoprotective agent to treat liver fibrosis, but its underlying molecular mechanism has not been identified. Using a rat model, we found that high fructose intake reduced microRNA (miR)-375-3p expression and activated the janus-activating kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) cascade and TGF-ß1/Smad signaling, which is consistent with the EMT and liver fibrosis. To further verify these observations, BRL-3A cells and/or primary rat hepatocytes were exposed to high fructose and/or transfected with a miR-375-3p mimic or inhibitor or treated with a JAK2 inhibitor, and we found that the low expression of miR-375-3p could induce the JAK2/STAT3 pathway to activate TGF-ß1/Smad signaling and promote the EMT. Magnesium isoglycyrrhizinate was found to ameliorate high fructose-induced EMT and liver fibrosis in rats. More importantly, magnesium isoglycyrrhizinate increased miR-375-3p expression to suppress the JAK2/STAT3 pathway and TGF-ß1/Smad signaling in these animal and cell models. This study provides evidence showing that magnesium isoglycyrrhizinate attenuates liver fibrosis associated with a high fructose diet.

Extracellular miRNAs in the serum and feces of mice exposed to high­dose radiation.

Exposure to high-dose radiation causes life-threatening intestinal damage. Histopathology is the most accurate method of judging the extent of intestinal damage following death. However, it is difficult to predict the extent of intestinal damage. The present study investigated extracellular microRNAs (miRNAs or miRs) in serum and feces using a radiation-induced intestinal injury mouse model. A peak of 25-200 nucleotide small RNAs was detected in mouse serum and feces by bioanalyzer, indicating the presence of miRNAs. Microarray analysis detected four miRNAs expressed in the small intestine and increased by >2-fold in serum and 19 in feces following 10 Gy radiation exposure. Increased miR-375-3p in both serum and feces suggests leakage due to radiation-induced intestinal injury and may be a candidate for high-dose radiation biomarkers.

Possible Role of miR-375-3p in Cervical Lymph Node Metastasis of Oral Squamous Cell Carcinoma.

No clinically useful predictors of latent cervical lymph node metastasis (LNM) in early oral squamous cell carcinoma (OSCC) are available. In this study, we focused on the microRNAs (miRNAs) involved in the expression of numerous genes and explored those associated with latent cervical LNM in early OSCC (eOSCC). First, microarray and RT-PCR analyses revealed a significant downregulation of miR-375-3p expression in primary eOSCC tissues with latent cervical LNM. Next, we examined the effects of miR-375-3p mimics on the growth and migration of four human OSCC cell lines that do not express miR-375-3p. The overexpression of miR-375-3p significantly suppressed the cell proliferation and migration of human OSCC cells in vitro. Furthermore, miR-375-3p mimics markedly inhibited the subcutaneously xenografted human OSCC tumors. Finally, we found the genes involved in the PI3K-AKT pathway and cell migration as target gene candidates of miR-375-3p in human OSCC cells. These findings suggest that miR-375-3p functions as a tumor suppressive-miRNA in OSCC and may serve as a potential biomarker for the prediction of latent cervical LNM in eOSCC and a useful therapeutic target to suppress OSCC progression.

MiR-375-3p mediates reduced pineal function in hypoxia-ischemia brain damage.

The functional roles of microRNAs (miRNAs) have been studied in various diseases, including hypoxic-ischemic brain damage (HIBD). However, changes in the expression of miRNAs and the underlying mechanisms in the pineal gland during HIBD remain unknown. Based on the previous study by microRNA array, hundreds of miRNAs showed altered expression patterns in the pineal gland in a rat model of HIBD. MiR-375-3p was found to be significantly upregulated and abundant in the pineal gland. Further investigation in an in vitro HI model of pinealocytes showed that miRNA-375 exacerbated the damage to pineal function. After oxygen-glucose deprivation / reoxygenation (OGD/R), miR-375-3p expression increased, while aralkylamine N-acetyltransferase (AANAT) expression and melatonin (MT) secretion decreased. Overexpression of miRNA-375 in pinealocytes aggravated the influence of OGD/R on AANAT expression and MT secretion. Because miRNA-375 overexpression in pinealocytes induced decreased rasd1 mRNA and protein expression, rasd1 may mediate the effect of miR-375-3p on pineal function. Furthermore, miR-375-3p aggravated the cognitive impairment caused by HIBD in rats, as observed by Morris water maze test, and also affected emotion and circadian rhythm in HIBD-treated rats. Thus, miR-375-3p may be a key regulatory molecule in the pineal gland following HIBD, and targeting of miR-375-3p may represent a new strategy for the treatment of HIBD.

MicroRNA-375-3p in endothelial progenitor cells-derived extracellular vesicles relieves myocardial injury in septic rats via BRD4-mediated PI3K/AKT signaling pathway.

OBJECTIVE: Sepsis can induce myocardial dysfunctions and endothelial progenitor cells (EPCs)-derived extracellular vesicles (EVs) can attenuate sepsis. Concerning to that, this article is intended to decode whether microRNA (miR)-375-3p in EPCs-EVs could affect myocardial injury in sepsis. METHODS: Rat bone marrow-derived EPCs and EPCs-EVs were harvested. A rat model of sepsis was established by cecal ligation and puncture. Septic rats were injected with EPCs-EVs that interfered with miR-375-3p, after which cardiac function, inflammatory response, pathological damage, oxidative stress and apoptosis were detected in myocardial tissues. miR-375-3p, bromodomain 4 (BRD4), phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT) expression in myocardial tissues, and their reciprocals were identified. RESULTS: Septic rats expressed reduced miR-375-3p and elevated BRD4 in myocardial tissues. EPCs-EVs improved cardiac function, suppressed inflammation, oxidative stress and apoptosis, as well as attenuated the pathological damage of myocardial tissues in septic rats. Up-regulated/down-regulated miR-375-3p in EPCs-EVs relieved/deteriorated myocardial injury in septic rats. miR-375-3p targeted BRD4 to activate PI3K/AKT pathway, thereafter to ameliorate myocardial injury in septic rats. CONCLUSION: It is illustrated that miR-375-3p in EPCs-EVs activates BRD4-mediated PI3K/AKT signaling pathway to ameliorate myocardial injury in septic rats, which provides a therapeutic target for myocardial injury in sepsis.

miR-375-3p inhibits the progression of laryngeal squamous cell carcinoma by targeting hepatocyte nuclear factor-1ß.

Laryngeal squamous cell carcinoma (LSCC) is one of the most frequently diagnosed head and neck cancers worldwide. Increasing evidence suggests that microRNAs (miRNAs/miRs) regulate the progression of tumorigenesis and the malignant behaviors of cancer cells. The aim of this study was to investigate the function and underlying mechanism of miR-375-3p in LSCC. The expression of miR-375-3p in LSCC tissues and cells was detected using reverse transcription-quantitative PCR. The effects of miR-375-3p on the malignant phenotype of LSCC cells was determined using the Cell Counting Kit-8 assay and flow cytometry. The targets of miR-375-3p were predicted using the miRDB database and confirmed by the luciferase reporter assay. The results of the present study demonstrated that miR-375-3p was downregulated in LSCC tissues and cell lines. Furthermore, overexpression of miR-375-3p significantly suppressed the proliferation and cell cycle progression of LSCC cells. Overexpression of miR-375-3p also increased LSCC cell apoptosis. Mechanistical analysis indicated that miR-375-3p bound the 3'-untranslated region of the hepatocyte nuclear factor 1ß (HNF1ß) and decreased its expression in LSCC cells. Consistent with the role of HNF1ß in glucose metabolism, overexpression of miR-375-3p significantly inhibited glucose consumption and lactate production in LSCC cells. Transfection with HNF1ß notably reversed the inhibitory effect of miR-375-3p on the proliferation of LSCC cells. Collectively, these results indicate the tumor suppressive role of miR-375-3p in LSCC via HNF1ß, suggesting that miR-375-3p may serve as a potential target in the treatment of LSCC.