Autocrine S100B in astrocytes promotes VEGF-dependent inflammation and oxidative stress and causes impaired neuroprotection.

Minimal hepatic encephalopathy (MHE) is strongly associated with neuroinflammation. Nevertheless, the underlying mechanism of the induction of inflammatory response in MHE astrocytes remains not fully understood. In the present study, we investigated the effect and mechanism of S100B, a predominant isoform expressed and released from mature astrocytes, on MHE-like neuropathology in the MHE rat model. We discovered that S100B expressions and autocrine were significantly increased in MHE rat brains and MHE rat brain-derived astrocytes. Furthermore, S100B stimulates VEGF expression via the interaction between TLR2 and RAGE in an autocrine manner. S100B-facilitated VEGF autocrine expression further led to a VEGFR2 and COX-2 interaction, which in turn induced the activation of NFƙB, eventually resulting in inflammation and oxidative stress in MHE astrocytes. MHE astrocytes supported impairment of neuronal survival and growth in a co-culture system. To sum up, a comprehensive understanding of the role of S100B-overexpressed MHE astrocyte in MHE pathogenesis may provide insights into the etiology of MHE.

The activation of spliced X-box binding protein 1 by isorhynchophylline therapy improves diabetic encephalopathy.

The primary symptom of diabetic encephalopathy (DE), a kind of central diabetic neuropathy caused by diabetes mellitus (DM), is cognitive impairment. In addition, the tetracyclic oxindole alkaloid isorhynchophylline (IRN) helps lessen cognitive impairment. However, it is still unclear how IRN affects DM and DE and what mechanisms are involved. The effectiveness of IRN on brain insulin resistance was carefully examined in this work, both in vitro and in vivo. We found that IRN accelerates spliced form of X-box binding protein 1 (sXBP1) translocation into the nucleus under high glucose conditions in vitro. IRN also facilitates the nuclear association of pCREB with sXBP1 and the binding of regulatory subunits of phosphatidylinositol 3-kinase (PI3K) p85α or p85ß with XBP1 to restore high glucose impairment. Also, IRN treatment improves high glucose-mediated impairment of insulin signaling, endoplasmic reticulum stress, and pyroptosis/apoptosis by depending on sXBP1 in vitro. In vivo studies suggested that IRN attenuates cognitive impairment, ameliorating peripheral insulin resistance, activating insulin signaling, inactivating activating transcription factor 6 (ATF6) and C/EBP homology protein (CHOP), and mitigating pyroptosis/apoptosis by stimulation of sXBP1 nuclear translocation in the brain. In summary, these data indicate that IRN contributes to maintaining insulin homeostasis by activating sXBP1 in the brain. Thus, IRN is a potent antidiabetic agent as well as an sXBP1 activator that has promising potential for the prevention or treatment of DE.

Induction of the mitochondrial NDUFA4L2 protein by HIF-1a regulates heart regeneration by promoting the survival of cardiac stem cell.

The adult mammalian heart doesn't regenerate after cardiomyocyte injury, which was mainly caused by the severe and persistent effects of cardiomyopathy. Recently, some studies reported that the mammalian heart can regenerate under low oxygen environment. However, the mechanism that the mammalian heart can regenerate remains unknown. Here, we used cardiac stem cells (CSCs) to be planted in serum-free medium under hypoxia environment to understand the mechanism of HIF1α/NDUFA4L2 in the regulation of hypoxia-alleviated apoptosis. Our results revealed that hypoxia can alleviated CSCs apoptosis. Hypoxia inhibited the level of cleaved-caspase3 and stimulated the expression of stabilized HIF-1α. DMOG promotes the survival of CSCs and the protein expression of NDUFA4L2. 2-ME repressed the survival of CSCs and the protein expression of NDUFA4L2. CHIP assay showed that HIF-1α regulated the survival of CSCs by augmenting the combination of HIF-1α and NDUFA4L2's HRE. Knockdown of NDUFA4L2 reversed the role of hypoxia in the survival of CSCs. Taken together, hypoxia promotes the viability of CSCs in serum-free medium by HIF-1α/NDUFA4L2 signaling pathway.

TRIM27 ameliorates ischemic stroke by regulating NLRP3 inflammasome-mediated pyroptosis via the Akt/Nrf2/HO-1 signaling.

Tripartite motif-containing 27 (TRIM27) is a member of TRIM family that exerts a protective effect against cardiac and hepatic ischemia/reperfusion (I/R) injury; however, little is known about its role in ischemic stroke. In our experiment, mice were intracerebroventricular injected with recombinant lentiviruses carrying TRIM27 or empty vector, and then they were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) 2 weeks after the injection. Mouse microglial BV-2 cells were infected with lentiviruses carrying TRIM27 or empty vector before exposure to oxygen-glucose deprivation/reoxygenation (OGD/R). TRIM27's role was assessed in vivo and in vitro. TRIM27 overexpression reduced infarct size, improved neurological function, inhibited activation of NLRP3 inflammasome, and activated the Akt/Nrf2/HO-1 pathway in mice subjected to MCAO/R. Furthermore, TRIM27 overexpression suppressed activation of NLRP3 inflammasome and activated this signaling pathway in OGD/R-exposed microglial cells. GSK690693 or ML385 treatment partially reversed the effect of TRIM27 overexpression in vitro. These findings indicate that TRIM27 overexpression ameliorates ischemic stroke by regulating NLRP3 inflammasome and Akt/Nrf2/HO-1 signaling. This study provides a novel target for treatment of ischemic stroke.

NAD+ repletion inhibits the endothelial-to-mesenchymal transition induced by TGF-ß in endothelial cells through improving mitochondrial unfolded protein response.

Endothelial-to-mesenchymal transition (EndMT) plays an important role in the progression of cardiac fibrosis but its mechanism and treatment need to be further understood. Herein, we have found that mitochondrial unfolded protein response (mtUPR) played a critical role in transforming growth factor beta 1 (TGF-ß1)-induced EndMT in endothelial cells (ECs). MtUPR was repressed in endothelial cells after exposure to TGF-ß1. NAD + precursor nicotinamide riboside (NR) could attenuate TGF-ß1-induced EndMT and improve the levels of mtUPR. Significantly, prohibitin proteins (PHB and PHB2) was also regulated by nicotinamide riboside. Moreover, we found that inhibition of prohibitin proteins could prevent the protective effect of nicotinamide riboside on mtUPR and TGF-ß1-induced EndMT. Overexpression of prohibitin proteins could alleviate mitochondrial function and TGF-ß1-induced EndMT through improving mtUPR. In vivo, The EndMT of ECs induced by Transverse aortic constriction (TAC) in mouse was inhibited by NR. In conclusion, our results indicate that nicotinamide riboside improved the expression of prohibitin proteins to ameliorate EndMT via promotion of mtUPR. Nicotinamide riboside is a potential therapeutic target for cardiac fibrosis.

Inflammatory cytokines in cardiac pacing patients with atrial fibrillation and asymptomatic atrial fibrillation.

BACKGROUND: To investigate the changes of inflammatory cytokines in cardiac pacing patients with atrial fibrillation and asymptomatic atrial fibrillation and the effects of metoprolol on them. METHODS: A total of 92 cardiac pacing patients with atrial fibrillation and asymptomatic atrial fibrillation in our hospital from April 2015 to March 2017 were selected and randomly divided into the control group and the observation group, with 46 cases in each group. Three months after pacemaker implantation, the control group was treated with aspirin, the observation group was treated with metoprolol on the basis of aspirin, and the curative effects were compared between the two groups. After treatment, the heart rate, the frequency and duration of atrial fibrillation and the atrial fibrillation load were observed. P-wave dispersion (PD) and cardiac function of the two groups of patients at 6 months after treatment were compared. The changes of serum levels of tumor necrosis factor-α (TNF-α), high sensitive C-reactive protein (Hs-CRP) and interleukin-6 (IL-6) in patients were compared before treatment and at 1, 3 and 6 months after treatment. The quality of life of the two groups of patients was observed. RESULTS: After treatment, the effective rate of treatment in the observation group was significantly higher than that in the control group (P<0.05). After treatment, the average heart rate and atrial fibrillation load in the observation group were significantly improved compared with those in the control group, and the frequency and duration of atrial fibrillation were significantly lower than those in the control group (P<0.05). After treatment, the maximum P-wave duration (Pmax), the minimum P-wave duration (Pmin) and PD in the observation group were significantly lower than those in the control group (P<0.05). The left ventricular ejection fraction (LVEF) in the observation group was significantly higher than that in the control group, and the left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV) and E/A in the observation group were significantly lower than those in the control group (P<0.05). After treatment, the levels of TNF-α, Hs-CRP and IL-6 in the two groups of patients were decreased significantly, and those in the observation group were significantly lower than those in the control group (P<0.05). The quality of life score in the observation group was significantly higher than that in the control group (P<0.05). CONCLUSIONS: Metoprolol can effectively reduce the incidence of atrial fibrillation, atrial fibrillation loadand inflammatory cytokine levels in cardiac pacing patients with atrial fibrillation and asymptomatic atrial fibrillation, and improve cardiac function of the patients and their quality of life. It has an important clinical significance.