Stroke is a major public health problem leading to high rates of death and disability in adults. Excessive stimulation of N-methyl-D-aspartate receptors (NMDARs) and the resulting neuronal nitric oxide synthase (nNOS) activation are crucial for neuronal injury after stroke insult. However, directly inhibiting NMDARs or nNOS can cause severe side effects because they have key physiological functions in the CNS. Here we show that cerebral ischemia induces the interaction of nNOS with postsynaptic density protein-95 (PSD-95). Disrupting nNOS-PSD-95 interaction via overexpressing the N-terminal amino acid residues 1-133 of nNOS (nNOS-N(1-133)) prevented glutamate-induced excitotoxicity and cerebral ischemic damage. Given the mechanism of nNOS-PSD-95 interaction, we developed a series of compounds and discovered a small-molecular inhibitor of the nNOS-PSD-95 interaction, ZL006. This drug blocked the ischemia-induced nNOS-PSD-95 association selectively, had potent neuroprotective activity in vitro and ameliorated focal cerebral ischemic damage in mice and rats subjected to middle cerebral artery occlusion (MCAO) and reperfusion. Moreover, it readily crossed the blood-brain barrier, did not inhibit NMDAR function, catalytic activity of nNOS or spatial memory, and had no effect on aggressive behaviors. Thus, this new drug may serve as a treatment for stroke, perhaps without major side effects.

Emerging studies demonstrate that long noncoding RNAs (lncRNA) participate in the regulation of various cancers. In the current study, a novel has been identified and explored in esophageal squamous cell carcinoma (ESCC). To discover a new regulatory circuitry in which RNAs crosstalk with each other, the transcriptome of lncRNA-miRNA-mRNA from ESCC and adjacent nonmalignant specimens were analyzed using multiple microarrays and diverse bioinformatics platforms. The functional role and mechanism of a novel were further investigated by gain-of-function and loss-of-function assays and An ESCC biomarker panel, consisting of, , and, was validated by qRT-PCR and hybridization using samples from 148 patients. as an oncogene is highly expressed in ESCC tissues and cell lines, and promotes ESCC cell proliferation and metastasis. Mechanistically, promotes expression of transcription factor Snail1 by competitively binding, resulting in the epithelial-mesenchymal transition (EMT) cascade. Moreover, also induces FSCN1 expression by sponging and upregulation of mRNA-stabilizing protein HuR, which further promotes ESCC invasion cascades. We also discovered and validated a clinically applicable ESCC biomarker panel, consisting of ,, and , that is significantly associated with overall survival and provides additional prognostic evidence for ESCC patients. As a novel regulator, plays an important role in ESCC cell proliferation and metastasis. The regulatory axis provides bona fide targets for anti-ESCC therapies. .

The long non-coding RNA, HOTTIP, has an important role in tumorigenesis. It is known that HOTTIP regulates HOX gene family; however, its regulatory mechanism in esophageal squamous cell carcinoma (ESCC) remains elusive. In this study, we investigated the role of HOTTIP in ESCC and observed that HOTTIP/HOXA13 was upregulated in ESCC and promoted cell proliferation and metastasis in vivo and in vitro. Interestingly, harboring a miR-30b-binding site, HOTTIP as a molecular sponge mainly regulated miR-30b level in the nucleus and modulated the repression of HOXA13 mediated by miR-30b in the cytoplasm, resulting in the positive HOTTIP/HOXA13 correlation. In addition, HOTTIP upregulated snail1 by competitively binding miR-30b, subsequently promoting epithelial-mesenchymal transition (EMT) and invasion. HOTTIP directly bound the adaptor protein WDR5 and drove histone H3 lysine 4 trimethylation and HOXA13 gene transcription in ESCC cells. In conclusion, our findings indicated that HOTTIP modulated HOXA13 at both the transcriptional and posttranscriptional levels in ESCC cells and HOTTIP-miR-30b-HOXA13 axis may serve as potential diagnostic markers or drug targets for ESCC therapies.

Background/purposeLong noncoding RNAs (lncRNAs) have emerged as important regulators and biomarkers of tumor development and progression. This study investigated the clinical significance, biological functions, and underlying mechanisms of long intergenic non-protein-coding RNA 1296 (LINC01296) in prostate cancer.Materials and methodsLINC01296 expression in prostate cancer tissues and cell lines was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The correlation between LINC01296 expression and clinicopathologic characteristics of prostate cancer was analyzed using Kaplan–Meier analysis and the Cox proportional-hazard model. Small interfering RNA was used to suppress LINC01296, and knockdown efficiency was examined by qRT-PCR. Cell Counting Kit 8 assay, colony-formation assay, migration and invasion assays, and Western blot assay were used to explore the role of LINC01296 in tumor progression further.ResultsLINC01296-expression level was higher in prostate cancer tissues and prostate cancer cells than in adjacent nontumor tissues and immortalized normal prostate stromal WPMY1 cells. LINC01296 expression was correlated with preoperative prostate specific antigen (P=0.002), lymph-node metastasis (P=0.035), Gleason score (P<0.001), and tumor stage (P=0.036). Patients with higher LINC01296 expression displayed advanced clinical features and shorter biochemical recurrence-free survival time than those with lower LINC01296 expression. Multivariate analysis showed that LINC01296 expression was an independent predictor of biochemical recurrence-free survival in prostate cancer. Additionally, LINC01296 knockdown inhibited prostate cancer-cell proliferation, migration, and invasion, demonstrated in an in vitro study involving regulation of PI3K–Akt–mTOR signaling and epithelial–mesenchymal transition.ConclusionThe results demonstrated that LINC01296 is a novel molecule involved in prostate cancer development and progression, and thus is a potential biomarker of prognosis.

The centenary of insulin discovery represents an important opportunity to transform diabetes from a fatal diagnosis into a medically manageable chronic condition. Insulin is a key peptide hormone and mediates the systemic glucose metabolism in different tissues. Insulin resistance (IR) is a disordered biological response for insulin stimulation through the disruption of different molecular pathways in target tissues. Acquired conditions and genetic factors have been implicated in IR. Recent genetic and biochemical studies suggest that the dysregulated metabolic mediators released by adipose tissue including adipokines, cytokines, chemokines, excess lipids and toxic lipid metabolites promote IR in other tissues. IR is associated with several groups of abnormal syndromes that include obesity, diabetes, metabolic dysfunction-associated fatty liver disease (MAFLD), cardiovascular disease, polycystic ovary syndrome (PCOS), and other abnormalities. Although no medication is specifically approved to treat IR, we summarized the lifestyle changes and pharmacological medications that have been used as efficient intervention to improve insulin sensitivity. Ultimately, the systematic discussion of complex mechanism will help to identify potential new targets and treat the closely associated metabolic syndrome of IR.

Background: Depression is a common mental disease that mainly manifests as bad mood, decreased interest, pessimism, slow thinking, lack of initiative, poor diet and sleep. Patients with severe depression have suicidal tendencies. Exosomes are small vesicles released by the fusion of a multivesicular body and membranes, and they contain specific proteins, nucleic acids, and lipids related to the cells from which they originate. MicroRNAs (miRNAs) are 20-24 nt RNAs that can be packaged into exosomes and can play important regulatory roles. Astrocytes are the most abundant cell population in the central nervous system and have a close link to depression. Astrocyte activation could result in the release of inflammatory cytokines, including IL-1β, IL-6, and TNFα, which could promote the symptoms of depression. In previous research, our team confirmed that NK cells regulate depression in mice. Here, we propose that miRNA in the exosomes from NK cells performs this antidepressant function.Methods: Exosomes from NK cells were shown by in vivo and in vitro experiments to alleviate symptoms of chronic mild stress in mice and decrease pro-inflammatory cytokines release from astrocytes. The production of pro-inflammatory cytokines was assessed by ELISA. Microarray analysis was used to identify critical miRNAs. Luciferase reporter assays, qPCR, and other experiments were used to prove that exosomal miR-207 has an important role in alleviating the symptoms of stress in mice.Results: MiRNA-containing exosomes from NK cells could alleviate symptoms of chronic mild stress in mice. In vivo experiments showed that these exosomes decreased the levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNFα) released by astrocytes. By microarray analysis of exosome miRNA profiles, miR-207 was found to be overexpressed in exosomes derived from unstressed mice. Experiments confirmed that miR-207 directly targets TLR4 interactor with leucine-rich repeats (Tril) and inhibits NF-κB signaling in astrocytes. MiR-207 could decrease the release of pro-inflammatory cytokines and inhibit expression of Tril in vitro. In vivo experiments revealed that exosomes with low miR-207 levels showed decreased antidepressant activity.(Continued on next page) Conclusion: Collectively, our findings revealed that exosomal miR-207 alleviated symptoms of depression in stressed mice by targeting Tril to inhibit NF-κB signaling in astrocytes.

It has been reported that an endostatin-derived synthetic peptide, named ES-2, that contains the amino acids 60-70 of endostatin from its N terminus, efficiently inhibits basic fibroblast growth factor-induced directional migration and tubular morphogenesis of microvascular endothelial cells. We found that the peptide had no effects on tumor growth in vivo. However, when the peptide Arg-Gly-Asp (RGD) was introduced into ES-2, the modified ES-2 showed significant antitumor results in animal models. Histochemical and immunohistochemical analysis showed that RGD-modified ES-2 induced large areas of continuous necrosis within tumors and significantly reduced the vessel density compared to control. Furthermore, only the peptides with RGD were able to bind tumor cells in vitro, suggesting that additional RGD domains may help in improving the receptor-binding ability and pharmacokinetic properties of ES-2 and preventing organic clearance, as well as enzymatic degradation of the peptide, thus enabling a greater fraction of the administered dose to be biologically available.

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