Celastrol mitigates inflammation in sepsis by inhibiting the PKM2-dependent Warburg effect

Background: Sepsis involves life-threatening organ dysfunction and is caused by a dysregulated host response to infection. No specific therapies against sepsis have been reported. Celastrol(Cel) is a natural anti-inflammatory compound that shows potential against systemic inflammatory diseases. This study aimed to investigate the pharmacological activity and molecular mechanism of Cel in models of endotoxemia and sepsis.Methods: We evaluated the anti-inflammatory efficacy of Cel against endotoxemia and sepsis in mice and macrophage cultures treated with lipopolysaccharide(LPS). We screened for potential protein targets of Cel using activity-based protein profiling(ABPP). Potential targets were validated using biophysical methods such as cellular thermal shift assays(CETSA) and surface plasmon resonance(SPR). Residues involved in Cel binding to target proteins were identified through point mutagenesis, and the functional effects of such binding were explored through gene knockdown.Results: Cel protected mice from lethal endotoxemia and improved their survival with sepsis, and it significantly decreased the levels of pro-inflammatory cytokines in mice and macrophages treated with LPS(P <0.05). Cel bound to Cys424 of pyruvate kinase M2(PKM2), inhibiting the enzyme and thereby suppressing aerobic glycolysis(Warburg effect). Cel also bound to Cys106 in high mobility group box 1(HMGB1) protein, reducing the secretion of inflammatory cytokine interleukin(IL)-1β. Cel bound to the Cys residues in lactate dehydrogenase A(LDHA).Conclusions: Cel inhibits inflammation and the Warburg effect in sepsis via targeting PKM2 and HMGB1 protein.

Three source rocks discovered in the Mid-Lower Jurassic,Dunhuang Basin in China

1.Objective Dunhuang Basin is the largest area and the third hydrocarbon resources potential basin among the basins of Hexi Corridor,and also a low exploration degree basin.The source rock position,characteristics and hydrocarbon generating potential of residual Mid-Lower Jurassic are still unknown.The project is to ascertain the source rock development and hydrocarbon generating capacity of Mid-Lower Jurassic,to find out the resource potential,to delineate the resource prospect area and to optimize the favorable areas.It may direct the petroleum exploration in Dunhuang Basin.

Crocus genome reveals the evolutionary origin of crocin biosynthesis

Crocus sativus (saffron) is a globally autumn-flowering plant, and its stigmas are the most expensive spice and valuable herb medicine. Crocus specialized metabolites, crocins, are biosynthesized in distant species, Gardenia (eudicot) and Crocus (monocot), and the evolution of crocin biosynthesis remains poorly understood. With the chromosome-level Crocus genome assembly, we revealed that two rounds of lineage-specific whole genome triplication occurred, contributing important roles in the production of carotenoids and apocarotenoids. According to the kingdom-wide identification, phylogenetic analysis, and functional assays of carotenoid cleavage dioxygenases (CCDs), we deduced that the duplication, site positive selection, and neofunctionalization of Crocus-specific CCD2 from CCD1 members are responsible for the crocin biosynthesis. In addition, site mutation of CsCCD2 revealed the key amino acids, including I143, L146, R161, E181, T259, and S292 related to the catalytic activity of zeaxanthin cleavage. Our study provides important insights into the origin and evolution of plant specialized metabolites, which are derived by duplication events of biosynthetic genes.

可持续发展情景下丝绸之路沿线国家土地利用及其对陆地碳库影响

可持续发展目标(SDGs)呼吁全世界共同采取行动,促进繁荣并保护地球.本研究面向SDGs构建了环境、粮食和经济等可持续发展情景,预测2020~2030年丝绸之路沿线国家的土地利用变化,并分析其对陆地碳库的影响。研究表明:未来土地利用变化及其对陆地碳库的影响在不同情景下存在显著差异。在可持续环境情景下,林地得到了有效保护,相较于2020年中国林地碳储量增加了约0.60%;在可持续粮食情景下,耕地流失得到了缓解,尤其在南亚及东南亚地区的耕地面积呈现上升趋势:在可持续经济情景下,城市扩张速度加快,引起的碳损失量最多这项研究有助于推进丝绸之路沿线甚至全球可持续发展进程,为探寻可持续发展路径提供了科学依据。

Celastrol induces ferroptosis in activated HSCs to ameliorate hepatic fibrosis via targeting peroxiredoxins and HO-1

Ferroptosis is a form of regulated cell death, characterized by excessive membrane lipid peroxidation in an iron-and ROS-dependent manner. Celastrol, a natural bioactive triterpenoid extracted from Tripterygium wilfordii, shows effective anti-fibrotic and anti-inflammatory activities in multiple hepatic diseases. However, the exact molecular mechanisms of action and the direct protein targets of celastrol in the treatment of liver fibrosis remain largely elusive. Here, we discover that celastrol exerts anti-fibrotic effects via promoting the production of reactive oxygen species(ROS) and inducing ferroptosis in activated hepatic stellate cells(HSCs). By using activity-based protein profiling(ABPP) in combination with bio-orthogonal click chemistry reaction and cellular thermal shift assay(CETSA), we show that celastrol directly binds to peroxiredoxins(PRDXs), including PRDX1, PRDX2, PRDX4 and PRDX6,through the active cysteine sites, and inhibits their anti-oxidant activities. Celastrol also targets to heme oxygenase 1(HO-1) and upregulates its expression in activated-HSCs. Knockdown of PRDX1, PRDX2,PRDX4, PRDX6 or HO-1 in HSCs, to varying extent, elevated cellular ROS levels and induced ferroptosis. Taken together, our findings reveal the direct protein targets and molecular mechanisms via which celastrol ameliorates hepatic fibrosis, thus supporting the further development of celastrol as a promising therapeutic agent for liver fibrosis.

武威盆地武地1井石炭系烃源岩地球化学特征及地质意义

以武威盆地北部坳陷武地1井为基础,通过烃源岩有机质丰度、类型、成熟度及生物标志化合物等参数的综合研究,系统评价了武威盆地石炭系烃源岩的生烃潜力。研究认为武威盆地北部坳陷石炭系太原组烃源岩有机碳含量高,是一套“较好—好”的烃源岩;有机质类型以Ⅲ型为主,Ⅱ2型次之,生物标志化合物中正构烷烃峰型完整,主峰碳数多为17,姥植比及伽马蜡烷参数均表明其生物来源于微咸水的海陆过渡相沉积环境;孕甾烷系列含量低而规则生物构型甾烷含量高,规则生物构型甾烷C_(27)、C_(28)和C_(29)呈不对称“V”型,C_(29)相对含量高于C_(27),生物来源以高等植物为主,低等水生生物也有贡献;三环萜烷和C_(30)重排藿烷含量低,C_(30)藿烷及C_(29)Ts含量高,Ts含量小于Tm,整体上处于成熟—高成熟阶段;有机质类型及成熟度决定了石炭系烃源岩以生成天然气为主。研究结果表明武威盆地石炭系勘探应以寻找天然气为主。