Unacylated ghrelin attenuates acute liver injury and hyperlipidemia via its anti-inflammatory and anti-oxidative activities.

Objectives: Liver injury and hyperlipidemia are major issues that have drawn more and more attention in recent years. The present study aimed to investigate the effects of unacylated ghrelin (UAG) on acute liver injury and hyperlipidemia in mice. Materials and Methods: UAG was injected intraperitoneally once a day for three days. Three hours after the last administration, acute liver injury was induced by intraperitoneal injection of carbon tetrachloride (CCl4), and acute hyperlipidemia was induced by intraperitoneal injection of poloxamer 407, respectively. Twenty-four hours later, samples were collected for serum biochemistry analysis, histopathological examination, and Western blotting. Results: In acute liver injury mice, UAG significantly decreased liver index, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), reduced malondialdehyde (MDA) concentration and increased superoxide dismutase(SOD) in liver tissue. NF-kappa B (NF-κB) protein expression in the liver was down-regulated. In acute hyperlipidemia mice, UAG significantly decreased serum total cholesterol (TC), triglyceride (TG), ALT, and AST, as well as hepatic TG levels. Meanwhile, hepatic MDA decreased and SOD increased significantly. Moreover, UAG improved the pathological damage in the liver induced by CCl4 and poloxamer 407, respectively. Conclusion: Intraperitoneal injection of UAG exhibited hepatoprotective and lipid-lowering effects on acute liver injury and hyperlipidemia, which is attributed to its anti-inflammatory and anti-oxidant activities.

Modularly Integrated System for Spatiotemporally Separated Solar Energy Storage and Release.

The sun is regarded as an endless source of clean energy. However, the intermittent supply and dynamically changeable demand of solar energy, as well as its uneven regional distribution, have been continually motivating the technological research of practical strategies to realize the spatiotemporally separated solar energy harvest and utilization. Accordingly, we here developed an integrated system for efficient solar energy capture, stable storage, and on-demand release, which corresponds to the intricate design of three distinct modules, namely, a photothermal conversion module, a latent heat storage module, and a mechanical trigger module. Moreover, efficient heat transfer and long-term supercooled stability necessitate interfacial passivation to coordinate the physical coupling of different modules. In addition to providing an integrated prototype that demonstrates a closed energy cycle in practice, this study may further inspire a new paradigm for advanced solar utilization in both theory and methodology.

CAU-Net: A Deep Learning Method for Deep Gray Matter Nuclei Segmentation.

The abnormal iron deposition of the deep gray matter nuclei is related to many neurological diseases. With the quantitative susceptibility mapping (QSM) technique, it is possible to quantitatively measure the brain iron content in vivo. To assess the magnetic susceptibility of the deep gray matter nuclei in the QSM, it is mandatory to segment the nuclei of interest first, and many automatic methods have been proposed in the literature. This study proposed a contrast attention U-Net for nuclei segmentation and evaluated its performance on two datasets acquired using different sequences with different parameters from different MRI devices. Experimental results revealed that our proposed method was superior on both datasets over other commonly adopted network structures. The impacts of training and inference strategies were also discussed, which showed that adopting test time augmentation during the inference stage can impose an obvious improvement. At the training stage, our results indicated that sufficient data augmentation, deep supervision, and nonuniform patch sampling contributed significantly to improving the segmentation accuracy, which indicated that appropriate choices of training and inference strategies were at least as important as designing more advanced network structures.

SIRT1 regulates Tat-induced HIV-1 transactivation through activating AMP-activated protein kinase.

Transcription of human immunodeficiency virus (HIV-1) is activated by viral Tat protein which regulates HIV-long terminal repeat (LTR) transcription and elongation. HIV-1 Tat protein is a substrate for the deacetylase activity of sirtuin 1 (SIRT1). Here we investigate the signaling pathway involved in Tat-induced HIV-1 transactivation through SIRT1. Western blot analysis showed a significant reduction in AMPK activation and downstream acetyl-CoA carboxylase (ACC) activation in response to Tat treatment. NAD(+) levels and SIRT1 activity were also decreased with Tat treatment. SIRT1 activator resveratrol reversed Tat-mediated reduction in AMPK activation and downstream ACC activation; while SIRT1 inhibitor nicotinamide or knockdown of SIRT1 by siRNA potentiated Tat-mediated reduction in AMPK activation and downstream ACC activation. Consistent with this association, AMPK activator AICAR as well as resveratrol inhibited Tat-induced HIV-1 transactivation. On the contrary, AMPK inhibitor compound C, knockdown of AMPK by siRNA as well as nicotinamide or knockdown of SIRT1 by siRNA potentiated Tat-induced HIV-1 transactivation. Collectively, our data provide new insights into understanding of the molecular mechanisms of Tat-regulated transcription, suggesting that targeting SIRT1-AMPK pathway could serve as a new target for the development of new anti HIV-1 agents.

Resveratrol inhibited Tat-induced HIV-1 LTR transactivation via NAD(+)-dependent SIRT1 activity.

AIMS: Tat protein plays a pivotal role in both the human immunodeficiency virus type 1 (HIV-1) replication cycle and the pathogenesis of HIV-1 infection. Sirtuins 1 (SIRT1) is a possible candidate for redox modulation because its activity is regulated by nicotinamide adenine dinucleotide (NAD(+)) or NAD(+)/NADH ratio. The aim of the present study was to determine whether the redox status and SIRT1 expression are related to HIV-1 Tat protein-induced transactivation. MAIN METHODS: HeLa-CD4-long terminal repeat (LTR)-beta-gal (MAGI) cells were transfected with Tat plasmid. Tat-induced HIV-1 LTR transactivation was determined by MAGI cell assay. The NAD(+) or NADH levels and SIRT1 activity were measured. In addition, the protein expression of SIRT1 was assayed by western blotting. KEY FINDINGS: Pretreatment with resveratrol increased intracellular NAD(+) levels and SIRT1 protein expression after Tat plasmid transfection in a concentration-dependent manner. Pretreatment with resveratrol attenuated Tat-induced HIV-1 transactivation in MAGI cells. These effects of resveratrol were largely abolished by knockdown of SIRT1 by short interfering RNA (siRNA). Pretreatment with nicotinamide, a SIRT1 inhibitor, potentiated Tat-induced HIV-1 transactivation in MAGI cells, and overexpression of SIRT1 attenuated Tat-induced HIV-1 transcription in MAGI cells. SIGNIFICANCE: Inhibition of SIRT1 activity by Tat is considered a critical step of Tat transactivation. Resveratrol and related compounds represent potential candidates for novel anti-HIV therapeutics.

Nrf2 is involved in inhibiting Tat-induced HIV-1 long terminal repeat transactivation.

HIV-1 Tat is one of six regulatory proteins that are required for viral replication and is an attractive target for the development of new anti-HIV agents. The induction of oxidative stress, as shown with Tat, may have a bearing on the transactivation mechanism of transcription. The transcription factor Nrf2 is a key player in the regulation of genes encoding many antioxidative response enzymes. Thus, the effect of Nrf2 on Tat-induced HIV-1 transcription was studied in MAGI cells. We found, for the first time, that Tat enhanced cellular expression of Nrf2 at the transcriptional and protein levels in these cells, and Tat activated antioxidant response element-driven gene expression. Tat simultaneously decreased the intracellular glutathione (GSH) levels and increased reactive oxygen species (ROS) production. The coordinated induction of ROS production, GSH depletion, and nuclear Nrf2 accumulation induced by Tat suggests that Nrf2 activation induced by Tat is not sufficient for protection against Tat-induced oxidative stress. Furthermore, when cells were pretreated with scavengers of hydrogen peroxide such as N-acetylcysteine, or overexpression of Nrf2, or Keap1 knockdown by siRNA, Tat-induced HIV-1 LTR transactivation was suppressed, whereas buthionine sulfoximine or Nrf2 knockdown by siRNA potentiated Tat-induced HIV-1 LTR transactivation. Similar results were found in HIV-IIIB virus infection. Taken together, these data clearly show that Nrf2 inhibits Tat-induced HIV-1 LTR transactivation. This negative regulation of Tat-induced HIV-1 LTR transactivation by Nrf2 might be an important mechanism leading to its anti-HIV-1 replicative activity.