Immune checkpoint therapy-elicited sialylation of IgG antibodies impairs antitumorigenic type I interferon responses in hepatocellular carcinoma.

The reinvigoration of anti-tumor T cells in response to immune checkpoint blockade (ICB) therapy is well established. Whether and how ICB therapy manipulates antibody-mediated immune response in cancer environments, however, remains elusive. Using tandem mass spectrometric analysis of modification of immunoglobulin G (IgG) from hepatoma tissues, we identified a role of ICB therapy in catalyzing IgG sialylation in the Fc region. Effector T cells triggered sialylation of IgG via an interferon (IFN)-γ-ST6Gal-I-dependent pathway. DC-SIGN+ macrophages represented the main target cells of sialylated IgG. Upon interacting with sialylated IgG, DC-SIGN stimulated Raf-1-elicited elevation of ATF3, which inactivated cGAS-STING pathway and eliminated subsequent type-I-IFN-triggered antitumorigenic immunity. Although enhanced IgG sialylation in tumors predicted improved therapeutic outcomes for patients receiving ICB therapy, impeding IgG sialylation augmented antitumorigenic T cell immunity after ICB therapy. Thus, targeting antibody-based negative feedback action of ICB therapy has potential for improving efficacy of cancer immunotherapies.

Amplifying hepatic L-aspartate levels suppresses CCl4-induced liver fibrosis by reversing glucocorticoid receptor ß-mediated mitochondrial malfunction.

Liver fibrosis is a determinant-stage process of many chronic liver diseases and affected over 7.9 billion populations worldwide with increasing demands of ideal therapeutic agents. Discovery of active molecules with anti-hepatic fibrosis efficacies presents the most attacking filed. Here, we revealed that hepatic L-aspartate levels were decreased in CCl4-induced fibrotic mice. Instead, supplementation of L-aspartate orally alleviated typical manifestations of liver injury and fibrosis. These therapeutic efficacies were alongside improvements of mitochondrial adaptive oxidation. Notably, treatment with L-aspartate rebalanced hepatic cholesterol-steroid metabolism and reduced the levels of liver-impairing metabolites, including corticosterone (CORT). Mechanistically, L-aspartate treatment efficiently reversed CORT-mediated glucocorticoid receptor ß (GRß) signaling activation and subsequent transcriptional suppression of the mitochondrial genome by directly binding to the mitochondrial genome. Knockout of GRß ameliorated corticosterone-mediated mitochondrial dysfunction and hepatocyte damage which also weakened the improvements of L-aspartate in suppressing GRß signaling. These data suggest that L-aspartate ameliorates hepatic fibrosis by suppressing GRß signaling via rebalancing cholesterol-steroid metabolism, would be an ideal candidate for clinical liver fibrosis treatment.

Targeting inflammatory macrophages rebuilds therapeutic efficacy of DOT1L inhibition in hepatocellular carcinoma.

Epigenetic reprogramming is a promising therapeutic strategy for aggressive cancers, but its limitations in vivo remain unclear. Here, we showed, in detailed studies of data regarding 410 patients with human hepatocellular carcinoma (HCC), that increased histone methyltransferase DOT1L triggered epithelial-mesenchymal transition-mediated metastasis and served as a therapeutic target for human HCC. Unexpectedly, although targeting DOT1L in vitro abrogated the invasive potential of hepatoma cells, abrogation of DOT1L signals hardly affected the metastasis of hepatoma in vivo. Macrophages, which constitute the major cellular component of the stroma, abrogated the anti-metastatic effect of DOT1L targeting. Mechanistically, NF-κB signal elicited by macrophage inflammatory response operated via a non-epigenetic machinery to eliminate the therapeutic efficacy of DOT1L targeting. Importantly, therapeutic strategy combining DOT1L-targeted therapy with macrophage depletion or NF-κB inhibition in vivo effectively and successfully elicited cancer regression. Moreover, we found that the densities of macrophages in HCC determined malignant cell DOT1L-associated clinical outcome of the patients. Our results provide insight into the crosstalk between epigenetic reprogramming and cancer microenvironments and suggest that strategies to influence the functional activities of inflammatory cells may benefit epigenetic reprogramming therapy.

Potential of Marine Bacterial Metalloprotease A69 in the Preparation of Peanut Peptides with Angiotensin-Converting Enzyme (ACE)-Inhibitory and Antioxidant Properties.

Marine bacterial proteases have rarely been used to produce bioactive peptides, although many have been reported. This study aims to evaluate the potential of the marine bacterial metalloprotease A69 from recombinant Bacillus subtilis in the preparation of peanut peptides (PPs) with antioxidant activity and angiotensin-converting enzyme (ACE)-inhibitory activity. Based on the optimization of the hydrolysis parameters of protease A69, a process for PPs preparation was set up in which the peanut protein was hydrolyzed by A69 at 3000 U g-1 and 60 °C, pH 7.0 for 4 h. The prepared PPs exhibited a high content of peptides with molecular weights lower than 1000 Da (>80%) and 3000 Da (>95%) and contained 17 kinds of amino acids. Moreover, the PPs displayed elevated scavenging of hydroxyl radical and 1,1-diphenyl-2-picryl-hydrazyl radical, with IC50 values of 1.50 mg mL-1 and 1.66 mg mL-1, respectively, indicating the good antioxidant activity of the PPs. The PPs also showed remarkable ACE-inhibitory activity, with an IC50 value of 0.71 mg mL-1. By liquid chromatography mass spectrometry analysis, the sequences of 19 ACE inhibitory peptides and 15 antioxidant peptides were identified from the PPs. These results indicate that the prepared PPs have a good nutritional value, as well as good antioxidant and antihypertensive effects, and that the marine bacterial metalloprotease A69 has promising potential in relation to the preparation of bioactive peptides from peanut protein.

[2-DG improves lung ischemia/reperfusion injury by inhibiting NLRP3-mediated pyroptosis in rats].

The aim of this study was to investigate whether the protective effect of 2-deoxyglucose (2-DG) on lung ischemia/reperfusion (I/R) injury is mediated by inhibiting nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-mediated pyroptosis in rats. Male Sprague-Dawley rats were randomly divided into control group, 2-DG group, lung I/R injury group (I/R group) and 2-DG+I/R group. 2-DG (0.7 g/kg) was intraperitoneally injected 1 h prior to lung ischemia. The tissue structure was measured under light microscope. Lung injury parameters were detected. The contents of malondialdehyde (MDA), myeloperoxidase (MPO) and lactate were determined by commercially available kits. ELISA was used to detect the levels of IL-1ß and IL-18. Western blot, qRT-PCR and immunofluorescence staining were used to measure the expression changes of glycolysis and pyroptosis related indicators. The results showed that there was no significant difference in the parameters between the control group and the 2-DG group. However, the lung injury parameters, oxidative stress response, lactic acid content, IL-1ß, and IL-18 levels were significantly increased in the I/R group. The protein expression levels of glycolysis and pyroptosis related indicators including hexokinase 2 (HK2), pyruvate kinase 2 (PKM2), NLRP3, Gasdermin superfamily member GSDMD-N, cleaved-Caspase1, cleaved-IL-1ß and cleaved-IL-18, and the gene expression levels of HK2, PKM2 and NLRP3 were markedly up-regulated in the I/R group compared with those in the control group. The expression of HK2 and NLRP3 was also increased detected by immunofluorescence staining. Compared with the I/R group, the 2-DG+I/R group exhibited significantly improved alveolar structure and inflammatory infiltration, reduced lung injury parameters, and decreased expression of glycolysis and pyroptosis related indicators. These results suggest that 2-DG protects against lung I/R injury possibly by inhibiting NLRP3-mediated pyroptosis in rats.

Host Plant Determines the Population Size of an Obligate Symbiont (Buchnera aphidicola) in Aphids.

Buchnera aphidicolais an obligate endosymbiont that provides aphids with several essential nutrients. Though much is known about aphid-Buchnera interactions, the effect of the host plant on Buchnera population size remains unclear. Here we used quantitative PCR (qPCR) techniques to explore the effects of the host plant on Buchnera densities in the cotton-melon aphid, Aphis gossypii Buchneratiters were significantly higher in populations that had been reared on cucumber for over 10 years than in populations maintained on cotton for a similar length of time. Aphids collected in the wild from hibiscus and zucchini harbored more Buchnera symbionts than those collected from cucumber and cotton. The effect of aphid genotype on the population size of Buchnera depended on the host plant upon which they fed. When aphids from populations maintained on cucumber or cotton were transferred to novel host plants, host survival and Buchnera population size fluctuated markedly for the first two generations before becoming relatively stable in the third and later generations. Host plant extracts from cucumber, pumpkin, zucchini, and cowpea added to artificial diets led to a significant increase in Buchnera titers in the aphids from the population reared on cotton, while plant extracts from cotton and zucchini led to a decrease in Buchnera titers in the aphids reared on cucumber. Gossypol, a secondary metabolite from cotton, suppressed Buchnera populations in populations from both cotton and cucumber, while cucurbitacin from cucurbit plants led to higher densities. Together, the results suggest that host plants influence Buchnera population processes and that this may provide phenotypic plasticity in host plant use for clonal aphids.

Co-Delivery of paclitaxel and doxorubicin in folate-Targeted pluronic/ploy (D,L-lactide-b-glycolide) polymersomes.

Drugs with different solubility can be selectively embedded into polymersomes with the hydrophilic core and hydrophobic bilayer. Novel folate-targeted Pluronic/poly (D,L-lactide-b-glycolide) polymersomes were constructed and used for the co-delivery of paclitaxel (PTX) and doxorubicin (DOX) to improve their inhibitory effect over cancer cells. The particle size of blank polymersomes was mainly distributed below 125 nm. The release of PTX and DOX from polymersomes showed an initial burst release followed by a sustained and slow release. The in vitro cytotoxicity data showed that the targeted co-loaded polymersomes (PTX&DOX FA-Ps) exhibited better inhibitory effect than single-loaded polymersomes and free drugs did. Furthermore, PTX&DOX FA-Ps showed the synergistic therapeutic effect over OVCAR-3 cancer cells. The cellular uptake results also showed that folate modified polymersomes had excellent targeting performance. Therefore, the folate-targeted Pluronic/poly (D,L-lactide-b-glycolide) polymersomes have potential application value as novel drug carriers to co-deliver PTX and DOX.

[Theoretical basis of ecology for the influence of global change on resources, environment, and ecosystems.] / å ¨çƒå˜åŒ–å¯¹èµ„æºçŽ¯å¢ƒåŠç”Ÿæ€ç³»ç»Ÿå½±å“çš„ç”Ÿæ€å­¦ç†è®ºåŸºç¡€.

With the deepening of global change research, the applied problems such as global change risk and response for social sustainable development, temporal and spatial allocation of resources and environmental elements and impact assessment of ecosystem are becoming a new trend in the research field of global change. Based on the ecological framework, we focused on clarifying the connotations of resources and the environment and their components. Resources refer to all substances consumed by organisms in the process of producing organic matter from inorganic matter and transferring energy and matter among organisms. These include inorganic resources (e.g., solar radiation, CO2, O2, water, and mineral elements) and organic resources (as a source of food for other organisms). In contrast, the environment can not be consumed or depleted by organisms. In addition, we described the components of global change and the associated variations of resources and environmental factors, as well as current research progress on the responses of ecosystem to global change. We scientifically described the processes and mechanisms of global change in terms of their influence on resources, the environment, and ecosystems within a theoretical framework based on ecological principles. Our goal was to provide a strong theoretical foundation for future research on coping with the risks of global change.

[Soil stoichiometry characteristics under different land use types in the Horqin Sandy Land, China]. / 科尔沁沙地不同土地利用类型土壤化学计量特征.

The stoichiometry characteristics of carbon (C), nitrogen (N), and phosphorus (P) is an important indicator of soil quality and ecosystem nutrient limitations. Exploring the effects of land use type and soil depth on soil nutrient stoichiometry can clarify soil nutrient cycling. In this study, we collected soil samples from sites with five different land use types (irrigated cropland, rainfed cropland, sandy grassland, fixed dunes, and mobile dunes) in the Horqin Sandy Land, and evaluated the influences of land use type and soil depth on the contents and stoichiometry characteristics of soil organic carbon (SOC), total nitrogen (TN), and total phosphorus (TP). We found that: 1) SOC (3.23 g·kg-1), TN (0.37 g·kg-1), and TP (0.15 g·kg-1) contents and stoichiometry characteristics (C:N, C:P, N:P was 9.07, 25.56, 2.97, respectively) to a depth of 10 cm in the Horqin Sandy Land were significantly lower than the mean values of soils in China. 2) Soil stoichiometry characteristics differed significantly among land use types. The contents of SOC, TN, and TP to a depth of 100 cm were highest in irrigated cropland, followed by sandy grassland, rainfed cropland, fixed dunes, and mobile dunes. The C:N ratios in sandy grassland, irrigated cropland, and rainfed cropland were significantly higher than those in the fixed dune and mobile dune sites. C:P ratios in the sandy grassland, fixed dunes, irrigated cropland, and rainfed cropland were significantly higher than that in the mobile dunes. The N:P ratio differed little among the five land use types. 3) SOC and TN contents in the sandy grassland, fixed dunes, irrigated cropland, and rainfed cropland decreased with increasing soil depth. SOC, TN, and C:P in the mobile dunes and TP and C:N in all land use types showed no variation among depths. The C:P ratio of sandy grassland, fixed dunes, irrigated cropland, and rainfed cropland and the N:P ratio of sandy grassland decreased with increasing soil depth. 4) SOC, TN, and TP contents and the C:N ratio were significantly negatively correlated with the contents of medium and fine sands and with soil bulk density, but significantly positively correlated with silt+clay, and very fine sand contents. Desertification led to losses of SOC and nutrients in the Horqin Sandy Land, and exacerbated soil N deficiency. Inputs of water and ferti-lizer helped cropland to maintain a relatively high level of soil nutrients.

[Evaluation of cerebrovascular reserve by xenon computed tomography in patients with ischemic stroke].

OBJECTIVE: To evaluate the cerebrovascular reserve (CVR) in patients of ischemic stroke with cerebrovascular stenosis by Xenon-enhanced CT. METHODS: Twenty subjects of ischemic stroke with cerebrovascular stenosis were recruited. All subjects were examined by Xenon-enhanced CT before and after acetazolamide (ACZ) challenge test to quantitatively measure the regional cerebral blood flow (rCBF) and CVR. RESULTS: We compared the rCBF in the corresponding region supplied with stenosed artery (divided manually) with that in the region of normal side. There was no significant difference in resting rCBF but in CVR [ipsilateral side vs. normal side (5.9 ± 24.3)% vs (25.9 ± 32.6)%, P < 0.05]. CONCLUSION: Impaired CVR is an important character of the patients with cerebrovascular stenosis suffered from ischemic stroke.

Global White Matter Hypoperfusion on CT Predicts Larger Infarcts and Hemorrhagic Transformation after Acute Ischemia.

INTRODUCTION: Presence of white matter hyperintensity (WMH) on MRI is a marker of cerebral small vessel disease and is associated with increased small vessel stroke and increased risk of hemorrhagic transformation (HT) after thrombolysis. AIM: We sought to determine whether white matter hypoperfusion (WMHP) on perfusion CT (CTP) was related to WMH, and if WMHP predisposed to acute lacunar stroke subtype and HT after thrombolysis. METHODS: Acute ischemic stroke patients within 12 h of symptom onset at 2 centers were prospectively recruited between 2011 and 2013 for the International Stroke Perfusion Imaging Registry. Participants routinely underwent baseline CT imaging, including CTP, and follow-up imaging with MRI at 24 h. RESULTS: Of 229 ischemic stroke patients, 108 were Caucasians and 121 Chinese. In the contralateral white matter, patients with acute lacunar stroke had lower cerebral blood flow (CBF) and cerebral blood volume (CBV), compared to those with other stroke subtypes (P = 0.041). There were 46 patients with HT, and WMHP was associated with increased risk of HT (R(2) = 0.417, P = 0.002). Compared to previously reported predictors of HT, WMHP performed better than infarct core volume (R(2) = 0.341, P = 0.034), very low CBV volume (R(2) = 0.249, P = 0.026), and severely delayed perfusion (Tmax>14 second R(2) = 0.372, P = 0.011). Patients with WMHP also had larger acute infarcts and increased infarct growth compared to those without WMHP (mean 28 mL vs. 13 mL P < 0.001). CONCLUSION: White matter hypoperfusion remote to the acutely ischemic region on CTP is a marker of small vessel disease and was associated with increased HT, larger acute infarct cores, and greater infarct growth.