Ghrelin alleviates intestinal ischemia-reperfusion injury by activating the GHSR-1α/Sirt1/FOXO1 pathway.

Ischemia-reperfusion (IR) injury is primarily characterized by the restoration of blood flow perfusion and oxygen supply to ischemic tissue and organs, but it paradoxically leads to tissue injury aggravation. IR injury is a challenging pathophysiological process that is difficult to avoid clinically and frequently occurs during organ transplantation, surgery, shock resuscitation, and other processes. The major causes of IR injury include increased levels of free radicals, calcium overload, oxidative stress, and excessive inflammatory response. Ghrelin is a newly discovered brain-intestinal peptide with anti-inflammatory and antiapoptotic effects that improve blood supply. The role and mechanism of ghrelin in intestinal ischemia-reperfusion (IIR) injury remain unclear. We hypothesized that ghrelin could attenuate IIR-induced oxidative stress and apoptosis. To investigate this, we established IIR by using a non-invasive arterial clip to clamp the root of the superior mesenteric artery (SMA) in mice. Ghrelin was injected intraperitoneally at a dose of 50 µg/kg 20 min before IIR surgery, and [D-Lys3]-GHRP-6 was injected intraperitoneally at a dose of 12 nmol/kg 20 min before ghrelin injection. We mimicked the IIR process with hypoxia-reoxygenation (HR) in Caco-2 cells, which are similar to intestinal epithelial cells in structure and biochemistry. Our results showed that ghrelin inhibited IIR/HR-induced oxidative stress and apoptosis by activating GHSR-1α. Moreover, it was found that ghrelin activated the GHSR-1α/Sirt1/FOXO1 signaling pathway. We further inhibited Sirt1 and found that Sirt1 was critical for ghrelin-mediated mitigation of IIR/HR injury. Overall, our data suggest that pretreatment with ghrelin reduces oxidative stress and apoptosis to attenuate IIR/HR injury by binding with GHSR-1α to further activate Sirt1.

Metal-free sulfonylation of quinoxalinones to access 2-sulfonyl-oxylated quinoxalines via oxidative O-S cross coupling.

The C2 sulfonylation of quinoxalinones via a metal-free oxidative S-O cross-coupling strategy for synthesizing 2-sulfonyloxylated quinoxalines is established. It effectively solved the long-standing problems in the C2 transformation of quinoxalinones via a metal-free oxidative O-S coupling strategy. Compared with the traditional C2 transformed quinoxalinones-C2 chlorination method, this protocol is mild, facile, and environmentally friendly and exhibits good atomic economy and excellent functional group tolerance. Moreover, the utility of this methodology and the sulfonyloxyl handles was demonstrated through the synthesis of 2-substituted quinoxaline-based bioactive molecules.

A Top-Down Templating Strategy toward Functional Porous Carbons.

Nanostructured carbon materials with high porosity and desired chemical functionalities are of immense interest because of their wide application potentials in catalysis, environment, and energy storage. Herein, a top-down templating strategy is presented for the facile synthesis of functional porous carbons, based on the direct carbonization of diverse organic precursors with commercially available metal oxide powders. During the carbonization, the metal oxide powders can evolve into nanoparticles that serve as in situ templates to introduce nanopores in carbons. The porosity and heteroatom doping of the prepared carbon materials can be engineered by varying the organic precursors and/or the metal oxides. It is further demonstrated that the top-down templating strategy is applicable to prepare carbon-based single-atom catalysts with iron-nitrogen sites, which exhibit a high power density of 545 mW cm-2 in a H2 -air proton exchange membrane fuel cell.

DUBR suppresses migration and invasion of human lung adenocarcinoma cells via ZBTB11-mediated inhibition of oxidative phosphorylation.

Long noncoding RNAs (lncRNAs) are involved in a variety of cancers, but the role of LncRNA DUBR in lung adenocarcinoma (LUAD), the most prevalent form of lung cancer, remains unclear. In this study we investigated the expression of DUBR in LUAD to ascertain its association with the clinical pathology and prognosis of LUAD. Analysis of mRNA expression in The Cancer Genome Atlas (TCGA) LUAD database and in-house LUAD cohort (n = 94) showed that DUBR was significantly downregulated in LUAD, and was associated with poor prognosis. In LUAD cell lines (H1975, A549), overexpression of DUBR significantly suppressed the migration and invasion of the LUAD cells. We demonstrated that c-Myc could bind to the promoter of DUBR, and transcriptionally suppressed its expression. Knockdown of c-Myc almost completely blocked the invasion and migration of LUAD cells, whereas knockdown of DUBR partially rescued c-Myc-knockdown suppressed cell migration and invasion. Furthermore, DUBR overexpression significantly increased the expression of a downstream protein of DUBR, zinc finger, and BTB domain containing 11 (ZBTB11), in H1975 and A549 cells; knockdown of ZBTB11 partially rescued the DUBR-overexpression suppressed cell migration and invasion; knockdown of c-Myc significantly upregulated the expression of ZBTB11 in LUAD cells. Finally, we revealed that DUBR/ZBTB11 axis suppressed oxidative phosphorylation in LUAD cells. In short, we demonstrate that c-Myc/DUBR/ZBTB11 axis suppresses migration and invasion of LUAD by attenuating cell oxidative phosphorylation, which provides new insights into the regulatory mechanism of DUBR.

Efficiency Assessment of Bacterial Cellulose on Lowering Lipid Levels In Vitro and Improving Lipid Metabolism In Vivo.

Bacterial cellulose (BC) is well known as a high-performance dietary fiber. This study investigates the adsorption capacity of BC for cholesterol, sodium cholate, unsaturated oil, and heavy metal ions in vitro. Further, a hyperlipidemia mouse model was constructed to investigate the effects of BC on lipid metabolism, antioxidant levels, and intestinal microflora. The results showed that the maximum adsorption capacities of BC for cholesterol, sodium cholate, Pb2+ and Cr6+ were 11.910, 16.149, 238.337, 1.525 and 1.809 mg/g, respectively. Additionally, BC reduced the blood lipid levels, regulated the peroxide levels, and ameliorated the liver injury in hyperlipidemia mice. Analysis of the intestinal flora revealed that BC improved the bacterial community of intestinal microflora in hyperlipidemia mice. It was found that the abundance of Bacteroidetes was increased, while the abundance of Firmicutes and Proteobacteria was decreased at the phylum level. In addition, increased abundance of Lactobacillus and decreased abundance of Lachnospiraceae and Prevotellaceae were obtained at the genus level. These changes were supposed to be beneficial to the activities of intestinal microflora. To conclude, the findings prove the role of BC in improving lipid metabolism in hyperlipidemia mice and provide a theoretical basis for the utilization of BC in functional food.

68Ga-PSMA PET/CT targeted biopsy for the diagnosis of clinically significant prostate cancer compared with transrectal ultrasound guided biopsy: a prospective randomized single-centre study.

PURPOSE: 68Ga-prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) is valuable for detecting primary and recurrent prostatic lesions. This study aimed to evaluate the efficacy of 68Ga-PSMA-11 PET/CT as a triage tool for prostate biopsy (PSMA-TB) and compare with transrectal ultrasound-guided biopsy (TRUS-GB) for the diagnosis of clinically significant prostate cancer (csPCa). METHODS: This single-centre study randomly allocated 120 patients with elevated serum prostate-specific antigen (PSA) levels (> 4 ng/ml) to PSMA-PET or TRUS group. Patients with PSMA-avid lesions (SUVmax ≥ 8.0) underwent PSMA-TB via a single-puncture percutaneous transgluteal approach (n = 25), whilst patients with negative PSMA-PET underwent systematic TRUS-GB (n = 35). All patients in the TRUS group underwent TRUS-GB directly (n = 60). RESULTS: PCa and csPCa were detected in 26/60 (43.3%) and 24/60 (40.0%) patients in the PSMA-PET group and 19/60 (31.6%) and 15/60 (25.0%) in the TRUS group, respectively. In the PSMA-PET group, the detection rate of PCa and csPCa were significantly higher in PSMA-PET-positive than negative patients (PCa, 23/25 (92.0%) vs 3/35 (8.6%), P < 0.01; csPCa, 22/25 (88.0%) vs 2/35 (5.7%), P < 0.01). PSMA-TB detected significantly more PCa and csPCa than TRUS-GB in the TRUS controls (PCa, 21/25 (84.0%) vs 19/60 (31.6%), P < 0.01; csPCa, 20/25 (80.0%) vs 15/60 (25.0%), P < 0.01). PSMA-PET detected significantly more cases of csPCa amongst patients with PSA 4.0-20.0 ng/ml than TRUS (27.02% vs 8.82%, P < 0.05). No haematuria, urinary retention or pelvic infection was observed after PSMA-TB compare with TRUS-GB. CONCLUSIONS: 68Ga-PSMA-11 PET/CT is a feasible imaging technique that may serve as a triage tool for prostate biopsy, and may improve the detection rate of csPCa compared with TRUS-GB, especially in patients with serum PSA 4.0-20.0 ng/ml.

TGFß2-mediated epithelial-mesenchymal transition and NF-κB pathway activation contribute to osimertinib resistance.

Osimertinib (AZD9291) has been widely used for the treatment of EGFR mutant non-small cell lung cancer. However, resistance to osimertinib is inevitable. In this study we elucidated the molecular mechanisms of resistance in osimertinib-resistant NCI-H1975/OSIR cells. We showed that NCI-H1975/OSIR cells underwent epithelial-mesenchymal transition (EMT), which conferred sensitivity to the GPX4 inhibitor 1S, 3R-RSL3 to induce ferroptotic cell death. The EMT occurrence resulted from osimertinib-induced upregulation of TGFß2 that activated SMAD2. On the other hand, we revealed that NCI-H1975/OSIR cells were highly dependent on NF-κB pathway for survival, since treatment with the NF-κB pathway inhibitor BAY 11-7082 or genetic silence of p65 caused much greater cell death as compared with the parental NCI-H1975 cells. In NCI-H1975 cells, osimertinib activated NF-κB pathway, evidenced by the increased p65 nuclear translocation, which was abolished by knockdown of TGFß2. In the cancer genome atlas lung adenocarcinoma data, TGFB2 transcript abundance significantly correlated with EMT-associated genes and NF-κB pathway. In addition, coexistence of EMT and activation of NF-κB pathway was observed in several NCI-H1975/OSIR clones. These findings shed new light on distinct roles of TGFß2 in osimertinib-resistant cells and provide new strategies for treatment of this resistant status.

Health assistant: answering your questions anytime from biomedical literature.

MOTIVATION: With the abundant medical resources, especially literature available online, it is possible for people to understand their own health status and relevant problems autonomously. However, how to obtain the most appropriate answer from the increasingly large-scale database, remains a great challenge. Here, we present a biomedical question answering framework and implement a system, Health Assistant, to enable the search process. METHODS: In Health Assistant, a search engine is firstly designed to rank biomedical documents based on contents. Then various query processing and search techniques are utilized to find the relevant documents. Afterwards, the titles and abstracts of top-N documents are extracted to generate candidate snippets. Finally, our own designed query processing and retrieval approaches for short text are applied to locate the relevant snippets to answer the questions. RESULTS: Our system is evaluated on the BioASQ benchmark datasets, and experimental results demonstrate the effectiveness and robustness of our system, compared to BioASQ participant systems and some state-of-the-art methods on both document retrieval and snippet retrieval tasks. AVAILABILITY AND IMPLEMENTATION: A demo of our system is available at https://github.com/jinzanxia/biomedical-QA.

CD4+CD38+ central memory T cells contribute to HIV persistence in HIV-infected individuals on long-term ART.

BACKGROUND: Despite the effective antiretroviral treatment (ART) of HIV-infected individuals, HIV persists in a small pool. Central memory CD4+ T cells (Tcm) make a major contribution to HIV persistence. We found that unlike HLA-DR, CD38 is highly expressed on the Tcm of HIV-infected subjects receiving ART for > 5 years. It has been reported that the half-life of total and episomal HIV DNA in the CD4+CD38+ T cell subset, exhibits lower decay rates at 12 weeks of ART. Whether CD38 contributes to HIV latency in HIV-infected individuals receiving long-term ART is yet to be addressed. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from the whole blood of HIV-infected subjects receiving suppressive ART. The immunophenotyping, proliferation and apoptosis of CD4+ T cell subpopulations were detected by flow cytometry, and the level of CD38 mRNA and total HIV DNA were measured using real-time PCR and digital droplet PCR, respectively. A negative binomial regression model was used to determine the correlation between CD4+CD38+ Tcm and total HIV DNA in CD4+ T cells. RESULTS: CD38 was highly expressed on CD4+ Tcm cells from HIV infected individuals on long-term ART. Comparing with HLA-DR-Tcm and CD4+HLA-DR+ T cells, CD4+CD38+ Tcm cells displayed lower levels of activation (CD25 and CD69) and higher levels of CD127 expression. The proportion of CD38+ Tcm, but not CD38- Tcm cells can predict the total HIV DNA in the CD4+ T cells and the CD38+ Tcm subset harbored higher total HIV DNA copy numbers than the CD38- Tcm subset. After transfected with CD38 si-RNA in CD4+ T cells, the proliferation of CD4+ T cells was inhibited. CONCLUSION: The current date indicates that CD4+CD38+ Tcm cells contribute to HIV persistence in HIV-infected individuals on long-term ART. Our study provides a potential target to resolve HIV persistence.

Nagilactone D ameliorates experimental pulmonary fibrosis in vitro and in vivo via modulating TGF-ß/Smad signaling pathway.

Pulmonary fibrosis is a prototypic chronic progressive lung disease with high morbidity and mortality worldwide. Novel effective therapeutic agents are urgently needed owing to the limited treatment options in clinic. Herein, nagilactone D (NLD), a natural dinorditerpenoid obtained from Podocarpus nagi, was found to suppress transforming growth factor-ß1 (TGF-ß1)-mediated fibrotic process in vitro and bleomycin (BLM)-induced pulmonary fibrosis in vivo. NLD attenuated TGF-ß1-induced expression of fibrotic markers including type I and III collagen, fibronectin, α-SMA, and CTGF in human pulmonary fibroblasts (WI-38 VA-13 and HLF-1 cells). Mechanism study indicated that NLD suppressed TGF-ß1-induced up-regulation of TßR I, and Smad2 phosphorylation, nuclear translocation, and transcriptional activation. Moreover, NLD ameliorated BLM-induced histopathological abnormalities in the lungs of experimental fibrotic mice, suppressed synthesis of relative fibrotic markers and fibroblast-to-myofibroblast transition, as well as BLM-induced up-regulation of TßR I expression and Smad signaling in mouse lungs. These data collectively support NLD to be a potential therapeutic agent for pulmonary fibrosis.