Captopril alleviates epilepsy and cognitive impairment by attenuation of C3-mediated inflammation and synaptic phagocytosis.

Evidence from experimental and clinical studies implicates immuno-inflammatory responses as playing an important role in epilepsy-induced brain injury. Captopril, an angiotensin-converting enzyme inhibitor (ACEi), has previously been shown to suppress immuno-inflammatory responses in a variety of neurological diseases. However, the therapeutic potential of captopril on epilepsy remains unclear. In the present study, Sprague Dawley (SD) rats were intraperitoneally subjected to kainic acid (KA) to establish a status epilepticus. Captopril (50 mg/kg, i.p.) was administered daily following the KA administration from day 3 to 49. We found that captopril efficiently suppressed the KA-induced epilepsy, as measured by electroencephalography. Moreover, captopril ameliorated the epilepsy-induced cognitive deficits, with improved performance in the Morris water maze, Y-maze and novel objective test. RNA sequencing (RNA-seq) analysis indicated that captopril reversed a wide range of epilepsy-related biological processes, particularly the glial activation, complement system-mediated phagocytosis and the production of inflammatory factors. Interestingly, captopril suppressed the epilepsy-induced activation and abnormal contact between astrocytes and microglia. Immunohistochemical experiments demonstrated that captopril attenuated microglia-dependent synaptic remodeling presumably through C3-C3ar-mediated phagocytosis in the hippocampus. Finally, the above effects of captopril were partially blocked by an intranasal application of recombinant C3a (1.3 µg/kg/day). Our findings demonstrated that captopril reduced the occurrence of epilepsy and cognitive impairment by attenuation of inflammation and C3-mediated synaptic phagocytosis. This approach can easily be adapted to long-term efficacy and safety in clinical practice.

Could environmental regulations improve the quality of export products? Evidence from China's implementation of pollutant discharge fee.

This study investigates the effect of Chinese environmental regulations on the quality of export products. As the main way for the government to protect the environment, environmental regulations have greatly influenced the production behavior of enterprises. Based on the data of China's pollutant discharge fee implementation and industrial enterprise-pollution panel data, we find that the government's environmental regulations have significantly improved the quality of export products, and this conclusion is still valid after a series of robustness tests. Further analysis shows that the increase in the quality of export products originating from the regulated areas could be attributed to promoting enterprise innovation and reducing resource misallocation. The results in this study provide evidence that the Chinese government could coordinate economic and environmental protection in the new era.

Erratum: microRNA-34a overexpression inhibits cell migration and invasion via regulating SIRT1 in hepatocellular carcinoma.

[This corrects the article DOI: 10.3892/ol.2017.7090.].

Up-regulated long noncoding RNA AB073614 modulates the tumor cell proliferation, invasion and migration in human colorectal cancer.

Colorectal cancer (CRC) is a common cancer and the function of long noncoding RNA (lncRNA) AB073614 in CRC mainly unclear. Here, the expression of lncRNA AB073614 in CRC tissues was evaluated by quantitative real-time PCR (qRT-PCR). CCK-8 assays were conducted to explore the impact of AB073614 on cell proliferation. The effects of AB073614 on cell migration, invasion and apoptosis were evaluated by a Transwell in vitro assay. Apoptosis-related molecular marker expression levels were detected by Western blot analysis. In the present study, we confirmed that AB073614 was significantly upregulated in CRC tissues. A difference analysis in the lncRNA AB073614 expression in CRC patient group suggested that the expression of lncRNA AB073614 was independently associated with higher possibilities of high grade (P = 0.0005), tumor size (> 5 cm) (P = 0.0001), distant metastasis (P = 0.0009), and differentiation level (P = 0.0037). In vitro studies demonstrated that the knockdown of {"type": "entrez-nucleotide", "attrs":{"text": "AB073614", "term_id": "51555790", "term_text": "AB073614"}}AB073614 suppressed SW480 cell proliferation. Meanwhile, the overexpression of {"type": "entrez-nucleotide", "attrs":{"text": "AB073614", "term_id": "51555790", "term_text": "AB073614"}}AB073614 in SW480 cells accelerated cell growth and invasion, and suppressed cell apoptosis. In conclusion, our results suggest that AB073614 may function as a tumor promoter in CRC. Our findings may provide a therapeutic approach for the future treatment of CRC.

LncRNA AB073614 induces epithelial- mesenchymal transition of colorectal cancer cells via regulating the JAK/STAT3 pathway.

BACKGROUND: LncRNAs are involved in the metastasis and recurrence of human tumors, including colorectal cancer (CRC). We previously reported that lncRNA AB073614 promotes tumor proliferation and metastasis and predicted a poor clinical outcome of CRC patients. Herein, we investigated the underlying mechanism of lncRNA AB073614-related metastasis in CRC. MATERIAL AND METHODS: The expression of lncRNA AB073614 in CRC tissues were evaluated by quantitative real-time PCR (qRT-PCR). Transwell assay was performed to detect the effects of lncRNA AB073614 on cell migration and invasion. Epithelial-mesenchymal transition (EMT) molecular markers and Janus kinase/signal transducer and activator of transcription (JAK/STAT3) pathway proteins expression levels were detected by Western blot and Immunofluorescence. RESULTS: We confirmed that lncRNA AB073614 was highly expressed in the colorectal cancer tissues. LncRNA AB073614 knockdown in SW480 and HCT116 cells significantly promoted the protein expression levels of E-cadherin and Occludin, and decreased the expressions of N-cadherin and Vimentin, then further decreased the cell migration and invasion ability. Interestingly, the expression of phosphorylated STAT3 was also down-regulated. Furthermore, SW480 and HCT116 cells were transfected with lncRNA AB073614 vector and treated with a JAK inhibitor, AT9283. The results showed that lncRNA AB073614 regulated EMT through JAK-STAT3 signaling pathway. CONCLUSION: All these results indicate that lncRNA AB073614 can induce the expression of EMT cell markers and regulate the process of EMT of CRC cells through regulating the JAK/STAT3 pathway activation.

microRNA-1297 Inhibits the Growth and Metastasis of Colorectal Cancer by Suppressing Cyclin D2 Expression.

microRNAs (miR) can potentially be used for categorizing the various subtypes of colorectal cancer (CRC) and predicting a patient's response to treatment with traditional anti-CRC therapies. We investigated how miR-1297 and its potential target molecule cyclin D2 (CCND2) might affect the progression of CRC. Thirty-two pairs of CRC specimens and corresponding samples of para-tumor tissue were collected and examined for their levels of miR-1297 and CCND2 expression. We also examined miR-1297 and CCND2 expression in cultured SW480 cells. The effects of modulated levels of miR-1297 and CCND2 on cell viability, anchorage-independent growth ability, proliferation, apoptosis, cell cycle distribution, migration, and invasion were detected using specific techniques. The possible regulatory effect of miR-1297 on CCND2 was investigated using dual luciferase assays. Our results showed that miR-1297 expression was downregulated in clinical CRC specimens, and such downregulation was associated with upregulated levels of CCND2 expression. Upregulation of miR-1297 and downregulation of CCND2 reduced the proliferation and metastasis potential of SW480 cells, but did not affect the apoptotic process. In addition, miR-1297 regulated CCND2 function by directly binding to the promoter sequence of the CCND2 gene, which would block CCND2-related signaling at the transcription level. Our findings validate the anti-CRC function of miR-1297 and pro-CRC function of CCND2. Our findings may assist in developing miR-based therapies against CRC.

Therapeutic Effect of Sodium Glucose Co-Transporter 2 Inhibitor Dapagliflozin on Renal Cell Carcinoma.

BACKGROUND Patients with type 2 diabetes mellitus (T2DM) have a high incidence of renal cell carcinoma (RCC) and high sodium glucose co-transporters 2 (SGLT2) expressions. The purpose of this study was to evaluate the anticancer activity of dapagliflozin as an SGLT2 inhibitor on RCC cell lines in vitro and in vivo. MATERIAL AND METHODS qRT-PCR and Western blot were used to detect SGLT2 expression on different human renal cells. Then, flow cytometry and immunofluorescence were used to investigate the effects of dapagliflozin on cell cycle, apoptosis, and SGLT2 expression of CaKi-1 cells. Finally, a xenograft model and immunohistochemical staining were used to investigate the function of dapagliflozin in nude mice. RESULTS We proved that SGLT2 is highly expressed in RCC cell lines. We found that dapagliflozin exerts a higher cytotoxic effect on human RCC than on normal human renal cells, regulates the cell cycle and apoptosis, and reduces the glucose uptake and SGLT2 expression of CaKi-1 cells. Moreover, dapagliflozin inhibits tumor growth and reduces SGLT2 expression in vivo. CONCLUSIONS Our results indicate that dapagliflozin has high efficiency and low toxicity and could be a new therapeutic target for RCC.

LncRNA AB073614 regulates proliferation and metastasis of colorectal cancer cells via the PI3K/AKT signaling pathway.

The expression profiles of long noncoding RNAs (lncRNAs) in colorectal cancer (CRC) have remained unclear. LncRNA AB073614 is known to be upregulated in ovarian cancer and glioma tissues, and is associated with the occurrence and progression of those cancers. In the present study, we investigated the lncRNA AB073614 gene expression patterns in CRC cell lines and tissue samples from CRC patients, and then analyzed them for possible associations with various clinicopathological characteristics. Furthermore, the roles played by lncRNA AB073614 in CRC cell proliferation, apoptosis, cell cycle progression, migration, and invasion were examined in vitro by using gene knockdown and overexpression techniques. We detected the levels of lncRNA AB073614 in 28 paired CRC tissues and adjacent normal tissues by qRT-PCR, and our results revealed that AB073614 expression in 85.7% (24/28) of the CRC tissues was significantly higher than those in the paired normal tissues. Furthermore, the levels of AB073614 were closely related to tumor grade, size, cell differentiation status, and the presence of distant metastases. Knockdown of AB073614 expression significantly inhibited the proliferation, migration, and invasion of SW480 cells, and resulted in their increased rates of apoptosis and G1 phase cell cycle arrest, whereas overexpression of AB073614 produced the opposite effects. Finally, results of studies which used an agonist (740Y-P) and an inhibitor (LY294002) of the PI3K/AKT signaling pathway, as well as the results of western blot assays, indicated that lncRNA AB073614 exerts its effects by targeting the PI3K/AKT-mediated signaling pathway. Taken together, our data indicate that lncRNA AB073614 acts to prevent CRC progression by affecting the PI3K/AKT signaling pathway, and may be useful as a novel prognostic or treatment agent for CRC.

microRNA-34a overexpression inhibits cell migration and invasion via regulating SIRT1 in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) remains one of the most common types of malignancy with high mortality and morbidity rates. Previous studies have suggested that microRNAs (miRs) serve pivotal functions in various types of tumor. The aim of the present study was to assess the association between miR-34a expression and HCC cell migration and invasion, and the potential underlying mechanisms. The miR-34a overexpression vector or scramble control was transfected into human Hep3B and Huh7 cell lines. Transwell assays, and Matrigel and wound healing assays were used to detect the effects of miR-34a expression on HCC cell invasion and migration, respectively. The expression of miR-34a and the mRNA expression of other associated proteins were detected using quantitative reverse transcription polymerase chain reaction, and protein levels were measured using western blot analysis. Compared with the control, miR-34a expression was significantly downregulated in Hep3B and Huh7 cells, but this was reversed by the transfection with exogenous miR-34a (P<0.01). The number of migrated or invaded cells was significantly reduced by the overexpression of miR-34a in Hep3B or Huh7 cells (P<0.01). The expression of sirtuin 1 was upregulated, while the level of acetylate-p53 was downregulated by overexpression of miR-34a. Taken together, the results of the present study suggested that the overexpression of miR-34a may have suppressed HCC metastasis via inhibited cell migration and invasion.

Resolvin D1 and E1 alleviate the progress of hepatitis toward liver cancer in long-term concanavalin A-induced mice through inhibition of NF-κB activity.

Resolvins, an endogenous lipid mediator derived from eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) of fish oil, has been reported to have anti-inflammatory and antitumor effect in various pathogenic processes. However, there are no studies about the effects of resolvin D1 and E1 on concanavalin A-induced hepatitis. Hence, the present study is to illustrate whether resolvin D1 and E1 inhibit concanavalin A-induced liver injury, liver cancer and underlying mechanisms by which they may recover. C57BL/6 mice were pretreated with resolvin D1 and E1 for 4 h, and then injected with concanavalin A for 12 h. Subsequently, blood and liver tissue were collected at 0, 2, 4, 8 and 12 h for different analysis. Analysis of inflammatory cytokines indicated that the inhibition of necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-2, IL-1ß and IL-6 could be performed by resolvin D1 and E1. Moreover, Toll-like receptor (TLR) 4 expression, NF-κB and AP-1 activity also have been confirmed to have key roles in the development of liver injury. They were significantly suppressed in the treatment group, compared to model. In addition, resolvin D1 and E1 markedly downregulated CD4+ and CD8+ cell infiltration in the liver. A long-term concanavalin A treatment for 32 weeks was performed to analyze the changes of hepatitis to liver cancer and the antitumor effect of resolving D1 and E1. These results indicated that resolvin D1 and E1 prevent concanavalin A-induced liver injury and the changes of hepatitis to liver cancer in mice through inhibition of inflammatory cytokine secretion and NF-κB/AP-1 activity. Thus, they could be novel target to be considered in the process of finding sufficient drug to protect against various forms of hepatitis and liver cancer.