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The relationship between circular RNAs (circRNAs) and many types of cancer has been of great interest. A novel circRNA, circBFAR, has been identified, but the functions of circBFAR and its underlying mechanism in gastric cancer (GC) have not been reported. This study was designed to investigate the role of circBFAR in GC and its downstream miRNA targets. Quantitative real-time polymerase reaction was used to detect the expression of circBFAR and miRNAs. Cell counting kit-8 and EdU were used to detect the proliferation of GC cells. Measurement of the extracellular acidification rate, oxygen consumption rate and lactate acid production were performed to assess the glycolysis levels. The results showed that circBFAR exhibited higher expression in GC tissues and cell lines. circBFAR was proven to promote GC proliferation by targeting the miR-513a-3p/hexokinase 2 (HK2) axis. Inhibition of circBFAR also led to a significant decrease in the glycolysis levels. In this study, we found a circBFAR/miR-513a-3p/HK2 axis in GC and revealed the relationship between circBFAR and glycolysis for the first time. circBFAR may serve as a novel target of GC individualized therapy. • Identification of the circBFAR functions in proliferation of gastric cancer. • miR-513a-3p/hexokinase 2 axis as the critical target of circBFAR. • Glycolysis driven by circBFAR in gastric cancer. • Potentials of circBFAR knockdown in the treatment of gastric cancer. [ABSTRACT FROM AUTHOR]

Propofol, a commonly used intravenous anesthetic in tumor surgery, has recently garnered attention for its anti-cancer activity. We previously demonstrated that propofol inhibits migration and invasion of esophageal squamous cell carcinoma cells. However, the effects of propofol in tumor angiogenesis are inconclusive. The current study investigated the effects of propofol on the biological functions of lung cancer associated endothelial cells (LC-EC) and colon cancer associated endothelial cells (CC-EC) that represent in vitro tumor angiogenesis. We showed that propofol inhibited tubular structure formation of both LC-EC and CC-EC, particularly the early stages of angiogenesis. In addition, propofol inhibited migration, adhesion, proliferation, and survival of tumor associated endothelial cells. Mechanism studies revealed that propofol disrupted tumor angiogenesis microenvironment via suppressing expression and secretion of multiple pro-angiogenic factors by tumor cells. Propofol also inhibited VEGF/VEGFR2-and mTOR/eIF4E-mediated signaling pathways in endothelial cells. Our findings demonstrate the inhibitory effects of propofol on tumor angiogenesis and support the anti-cancer properties of propofol. Our work provides preclinical evidence into the potential mechanisms by which propofol may negatively affect tumor growth and metastasis. • Propofol inhibits tumor angiogenesis. • Propofol inhibits tumor endothelial cell migration, adhesion and growth. • Propofol disrupts tumor angiogenesis microenvironment. • Propofol inhibits VEGF/VEGFR- and mTOR/eIF4E-mediated signaling. [ABSTRACT FROM AUTHOR]

Fear- and anxiety-related psychiatric disorders have been one of the major chronic diseases afflicting patients for decades, and new compounds for treating such disorders remain to be developed. (+)-Borneol, a bicyclic monoterpene found in several species of Artemisia and Dipterocarpaceae, is widely used for anxiety, pain and anesthesia in Chinese medicine. Meanwhile, it can potentiate GABA (γ-aminobutyric acid) activity directly in recombinant GABAA receptors. The present study was to investigate the effects of (+)-Borneol on both contextual and cued fear recall. Interestingly, microinjection of (+)-Borneol into the dorsal hippocampus inhibited 24 h and 7 d contextual fear, whereas its infusion into ventral hippocampus only reduced 24 h cued fear responses. Moreover, microinjection of (+)-Borneol into dorsal but not ventral hippocampus suppressed anxiety-like behaviors in the open field test, light/dark exploration and the elevated plus maze test. As selective GABA A receptor antagonist bicuculline reversed the effect of (+)-Borneol on contextual fear paradigm and the drug potentiated GABA-evoked currents in acute hippocampus slices, modulation of the GABAergic neurotransmission may explain the effects of (+)-Borneol. Our findings suggest that (+)-Borneol can serve as a new therapeutic in fear- and anxiety-related disorders. [ABSTRACT FROM AUTHOR]

Post-translational modifications (PTMs) play pivotal roles in controlling the stability and activity of the tumor suppressor p53 in response to distinct stressors. Here we report an unexpected finding of a short chain fatty acid modification of p53 in human cells. Crotonic acid (CA) treatment induces p53 crotonylation, but surprisingly reduces its protein, but not mRNA level, leading to inhibition of p53 activity in a dose dependent fashion. Surprisingly this crotonylation targets serine 46, instead of any predicted lysine residues, of p53, as detected in TCEP-probe labeled crotonylation and anti-crotonylated peptide antibody reaction assays. This is further confirmed by substitution of serine 46 with alanine, which abolishes p53 crotonylation in vitro and in cells. CA increases p53-dependent glycolytic activity, and augments cancer cell proliferation in response to metabolic or DNA damage stress. Since serine 46 is only found in human p53, our studies unveil an unconventional PTM unique for human p53, impairing its activity in response to CA. Because CA is likely produced by the gut microbiome, our results also predict that this type of PTM might play a role in early human colorectal neoplasia development by negating p53 activity without mutation of this tumor suppressor gene. • p53 in human cells is crotonylated in response to crotonic acid. • This crotonylation is detected independently by a Pan anti-crotonylated peptide antibody and a TCEP probe. • This crotonylation surprisingly occurs at the serine 46 residue of p53. • Substitution of serine 46, but not any of predicted lysines, by alanine abolishes this p53 crotonylation. • Crotonic acid increases glycolytic activity and cancer cell proliferation by impairing p53 activity in human cancer cells. [ABSTRACT FROM AUTHOR]

Neuronal nitric oxide synthase (nNOS) 1 , mainly responsible for NO release in central nervous system (CNS) 2 , plays a significant role in multiple physiological functions. However, the function of nNOS + interneurons in fear learning has not been much explored. Here we focused on the medial ganglionic eminences (MGE) 3 -derived nNOS + interneurons in fear learning. To determine the origin of nNOS + interneurons, we cultured neurons in vitro from MGE, cortex, lateral ganglionic eminence (LGE) 4 , caudal ganglionic eminences (CGE) 5 and preoptic area (POA) 6 . The results showed that MGE contained the most abundant precursors of nNOS + interneurons. Moreover, donor cells from E12.5 embryos demonstrated the highest positive rate of nNOS + interneurons compared with other embryonic periods (E11.5, E12, E13, E13.5 and E14). Additionally, these cells from E12.5 embryos showed long axonal and abundant dendritic arbors after 10 days culture, indicating the capability to disperse and integrate in host neural circuits after transplantation. To investigate the role of MGE-derived nNOS + interneurons in fear learning, donor MGE cells were transplanted into dentate gyrus (DG) 7 of nNOS knock-out (nNOS −/− ) or wild-type mice. Results showed that the transplantation of MGE cells promoted the acquisition of nNOS −/− but not the wild-type mice, suggesting the importance of nNOS + neurons in fear acquisition. Moreover, we transplanted MGE cells from nNOS −/− mice or wild-type mice into DG of the nNOS −/- mice and found that only MGE cells from wild-type mice but not the nNOS −/− mice rescued the deficit in acquisition of the nNOS −/− mice, further confirming the positive role of nNOS + neurons in fear learning. [ABSTRACT FROM AUTHOR]

Granule cells in the dentate gyrus regenerate constantly in adult hippocampus and then integrate into neural circuits in the hippocampus thereby providing the neural basis for learning and memory. Promoting the neurogenesis in the hippocampus facilitates learning and memory such as spatial learning, object identification, and extinction learning. The interaction between neuronal nitric oxide synthase (nNOS) and postsynaptic density protein-95 (PSD-95) is reported to negatively regulate neurogenesis in brain, so we hypothesized that disrupting this interaction might facilitate the neurogenesis in the dentate gyrus (DG) and thus enhance the extinction memory retrieval of fear learning. We found that uncoupling the nNOS-PSD-95 complex in remote contextual fear condition promoted both neuronal proliferation and survival in the DG, contributing to an enhanced retrieval of the extinction memory. Moreover, the nNOS-PSD-95 uncoupling-induced neurogenesis may be mediated by the extracellular signal-regulated kinase (ERK) as the phosphorylation level of ERK1/2 was increased after uncoupling. These findings suggest that the nNOS-PSD-95 complex may serve as a novel target for the treatment of post-traumatic stress disorder (PTSD). [ABSTRACT FROM AUTHOR]

The neuroprotective effects of hydrogen have been demonstrated, but the mechanism is still poorly understood. In a clinical trial of inhaled hydrogen in patients with subarachnoid hemorrhage (SAH), we found that hydrogen reduced the accumulation of lactic acid in the nervous system. There are no studies demonstrating the regulatory effect of hydrogen on lactate and in this study we hope to further clarify the mechanism by which hydrogen regulates lactate metabolism. In cell experiments, PCR and Western Blot showed that HIF-1α was the target related to lactic acid metabolism that changed the most before and after hydrogen intervention. HIF-1α levels were suppressed by hydrogen intervention treatment. Activation of HIF-1α inhibited the lactic acid-lowering effect of hydrogen. We have also demonstrated the lactic acid-lowering effect of hydrogen in animal studies. Our work clarifies that hydrogen can regulate lactate metabolism via the HIF-1αpathway, providing new insights into the neuroprotective mechanisms of hydrogen. • In clinical trials, hydrogen therapy reduced cerebrospinal fluid lactate levels in patients with subarachnoid hemorrhage. • HIF-1α is the target associated with the greatest change in lactate metabolism before and after hydrogen intervention. • Hydrogen regulates lactate metabolism after SAH via the HIF-1α pathway. [ABSTRACT FROM AUTHOR]

Abstract Specific study about the inhibitory effect of costunolide (CN) and relevant mechanism is of great significance for the treatment of pulmonary fibrosis. Here, the pharmacological activity of costunolide on the treatment of pulmonary fibrosis was investigated in vivo and in vitro. The in vivo mice study, mice were received intratracheal injection of bleomycin (BLM, 5 mg/kg) on 0 day to obtain BLM-induced pulmonary fibrosis firstly. From 2 day to 21 day, mice were orally administered with different dose of CN (low dose(CNL): 10 mg/kg, high dose(CNH): 20 mg/kg) and pirfenidone (PFD)(positive control, 50 mg/kg). The in vitro cells model, cells were incubated with recombinant human TGF-β1 for 24 h to get TGF-β 1 -induced pulmonary fibrosis. Cells were treated differently for 24 h and divided into five groups. Then, the activity of CN was evaluated by the expression level of related protein and the factors of oxidative stress in vivo and in vitro, and the mechanism was tested from the involved channel protein aspect. As a result, from the comparison of multiple factors (α-SMA, collagen type I/III, HYP, MDA, SOD) between pirfenidone group and CN group, it revealed the beneficial effects of CN against BLM-induced and TGF-β 1 -induced pulmonary fibrosis. In addition, our study also proved that CN exerted its effects through suppressing the NF-kB dependent inflammation and regulated TGF-β 1 /Smad 2 / NOX 4 -Nrf 2 signaling pathways. In conclusion, CN could be a potential theraputic candidate for the treatment pulmonary fibrosis in the future. Highlights • The study showed that the NF-kB and TGF-β 1 /Smad 2 /NOX 4 -Nrf 2 signaling pathway may play a significant role in PF. • CN inhibited TGF-β1-induced PF in HELF cells. • CN attenuates BLM-induced PF in mice. • CN inhibited attenuated oxidative stress. [ABSTRACT FROM AUTHOR]