MiR-34a affects dexmedetomidine-inhibited chronic inflammatory visceral pain by targeting to HDAC2.

BACKGROUND: Dexmedetomidine (DEX) has been used as an anesthetic for decades. The present investigation aimed to elucidate the analgesic impact of DEX on 2,4,6-Trinitrobenzenesulfonic acid (TNBS)-induced chronic inflammatory visceral pain (CIVP) in rats. METHODS: TNBS with or without DEX to Male Sprague-Dawley SD rats were randomly divided into four groups: normal, CIVP, DEX, and vehicle. Pain behaviors were assessed and the abdominal withdrawal reflex, mechanical withdrawal threshold, and thermal withdrawal latency were recorded. Quantitative polymerase chain reaction data showed increased expressions of pro-inflammatory cytokines (IL-6, IL-1ß and TNF-α) in the spinal cord tissues of rats. RESULTS: RNA microarray and quantitative polymerase chain reaction results indicated that miR-34a was downregulated by TNBS induction, but it was upregulated by DEX administration. Further studies showed that transfection of adenovirus-miR-34a inhibitor reversed the effect of DEX on the pain behaviors and spinal-cord pro-inflammatory-cytokine generation in CIVP rats. Additionally, we found that miR-34a targeted the 3'-UTR of the HDAC2 gene, as evinced by the increased HDAC2 expression in the CIVP and DEX + miR-34a inhibitor groups, and decreased HDAC2 signaling in the DEX group. Moreover, knock-down of HDAC2 restored DEX-attenuated pain behaviors and reduced pro-inflammatory cytokine production. CONCLUSIONS: DEX thus exhibited an analgesic effect on CIVP rats through the miR-34a-mediated HDAC2 pathway and suppressed visceral hypersensitivity.

Interleukin-17 promotes the development of cisplatin resistance in colorectal cancer.

Cisplatin (DDP)-based anticancer therapy is an important chemotherapeutic strategy for the treatment of colorectal cancer. However, its beneficial effect is largely compromised by adverse reactions, and more importantly, by the development of drug resistance. Therefore, it is crucial to determine the potential mechanism underlying the development of DDP resistance in colorectal cancer. Interleukin-17 (IL-17) is a proinflammatory cytokine that has been found to serve an important role in the host defense during cancer development. It has been suggested that IL-17 is key to promoting the development of resistance to DDP in several major types of cancer. However, the role of IL-17 in DDP resistance in colorectal cancer has not been extensively investigated. In the present study, it was observed that IL-17 was significantly upregulated in colorectal tumor samples, compared with the adjacent tissues. Furthermore, IL-17 was found to promote the viability of HCT116 colorectal cells treated with DDP, whilst blocking IL-17 signaling leading to HCT116 cell apoptosis. IL-17 was also shown to regulate the expression of several apoptosis-related proteins, including phosphorylated-protein kinase B (p-Akt), apoptosis regulator BAX (Bax), apoptosis regulator Bcl-2 (Bcl-2) and serine/threonine-protein kinase mTOR (mTOR). These findings indicated that IL-17 facilitates the development of DDP resistance in colorectal cancer by inhibiting cancer cell apoptosis through targeting p-Akt, Bax, Bcl-2 and mTOR. Overall, the findings of the present study suggest that a combination of DDP and an IL-17 inhibitor may prove to be a highly efficient strategy for colorectal cancer treatment.

Systems Pharmacology Dissection of the Protective Effect of Myricetin Against Acute Ischemia/Reperfusion-Induced Myocardial Injury in Isolated Rat Heart.

In this paper, we investigated the multi-target effect of myricetin as a therapeutic for cardiovascular disease, using an acute ischemia/reperfusion-induced myocardial injury model to gain insight into its mechanism of action. The compound-target interaction profiles of myricetin were determined using a combination of text mining, chemometric and chemogenomic methods. The effect of myricetin on cardiac function was investigated by carrying out experiments in rats subjected to ischemia/reperfusion (I/R) using Langendorff retrograde perfusion technology. Compared to the I/R group, pretreatment with 5 µM myricetin was observed to improve the maximum up/down rate of left ventricular pressure (dp/dt max) and coronary flow, raise left ventricular developed pressure, and decrease creatine kinase and lactate dehydrogenase levels in coronary flow. In addition, myricetin treatment was shown to have beneficial effects through its ability to reduce both infarct size and levels of cardiomyocyte apoptosis. Myricetin was also observed to have antioxidant properties, as evidenced by its ability to reduce MDA levels, while increasing both SOD levels and the GSH/GSSG ratio. Finally, an upregulation of 6-phosphogluconate dehydrogenase and fatty acid synthase expression and a downregulation of cyclooxygenase-2, cytochrome P450 and p38 mitogen-activated protein kinase expression suggest that myricetin acts through mechanisms which alter relevant signaling pathways. In summary, our results demonstrate that myricetin has protective cardiovascular effects against I/R-induced myocardial injury.