The innate immune sensor NLRP3 assembles an inflammasome complex with NEK7 and ASC to activate caspase‐1 and drive the maturation of proinflammatory cytokines IL‐1β and IL‐18. NLRP3 inflammasome ...activity must be tightly controlled, as its over‐activation is involved in the pathogenesis of inflammatory diseases. Here, we show that NLRP3 inflammasome activation is suppressed by a centrosomal protein Spata2. Spata2 deficiency enhances NLRP3 inflammasome activity both in the macrophages and in an animal model of peritonitis. Mechanistically, Spata2 recruits the deubiquitinase CYLD to the centrosome for deubiquitination of polo‐like kinase 4 (PLK4), the master regulator of centrosome duplication. Deubiquitination of PLK4 facilitates its binding to and phosphorylation of NEK7 at Ser204. NEK7 phosphorylation in turn attenuates NEK7 and NLRP3 interaction, which is required for NLRP3 inflammasome activation. Pharmacological or shRNA‐mediated inhibition of PLK4, or mutation of the NEK7 Ser204 phosphorylation site, augments NEK7 interaction with NLRP3 and causes increased NLRP3 inflammasome activation. Our study unravels a novel centrosomal regulatory pathway of inflammasome activation and may provide new therapeutic targets for the treatment of NLRP3‐associated inflammatory diseases.
Synopsis
NLRP3 inflammasome activation requires the interaction of NLRP3 with centrosomal kinase NEK7. Here we show that the centrosome‐localized deubiquitinase complex Spata2‐CYLD deubiquitinates centrosomal kinase PLK4 to augment its binding to and phosphorylation of NEK7, leading to reduced NEK7‐NLRP3 interaction and NLRP3 inflammasome activation.
Spata2 is localized to the centrosome and suppresses NLRP3 inflammasome activation.
Spata2 recruits CYLD to the centrosome to deubiquitinate PLK4.
Deubiquitination of PLK4 facilitates its binding to and phosphorylation of NEK7.
NEK7 phosphorylation by PLK4 attenuates NEK7‐NLRP3 interaction and NLRP3 inflammasome activation.
The centrosomal protein Spata2 is as a novel regulator of NEK7 phosphorylation and NLRP3‐mediated inflammatory responses.
Small molecules targeting bromodomains of BET proteins possess strong anti-tumor activities and have emerged as potential therapeutics for cancer. However, the underlying mechanisms for the ...anti-proliferative activity of these inhibitors are still not fully characterized. In this study, we demonstrated that BET inhibitor JQ1 suppressed the proliferation and invasiveness of gastric cancer cells by inducing cellular senescence. Depletion of BRD4, which was overexpressed in gastric cancer tissues, but not other BET proteins recapitulated JQ1-induced cellular senescence with increased cellular SA-β-Gal activity and elevated p21 levels. In addition, we showed that the levels of p21 were regulated at the post-transcriptional level by BRD4-dependent expression of miR-106b-5p, which targets the 3'-UTR of p21 mRNA. Overexpression of miR-106b-5p prevented JQ1-induced p21 expression and BRD4 inhibition-associated cellular senescence, whereas miR-106b-5p inhibitor up-regulated p21 and induced cellular senescence. Finally, we demonstrated that inhibition of E2F suppressed the binding of BRD4 to the promoter of miR-106b-5p and inhibited its transcription, leading to the increased p21 levels and cellular senescence in gastric cancer cells. Our results reveal a novel mechanism by which BRD4 regulates cancer cell proliferation by modulating the cellular senescence through E2F/miR-106b-5p/p21 axis and provide new insights into using BET inhibitors as potential anticancer drugs.
International Biological Flora: Ginkgo biloba Lin, Han‐Yang; Li, Wen‐Hao; Lin, Chen‐Feng ...
The Journal of ecology,
April 2022, 2022-04-00, 20220401, Letnik:
110, Številka:
4
Journal Article
Recenzirano
Odprti dostop
This account presents information on all aspects of the biology of Ginkgo biloba L. (Ginkgo, Maidenhair tree) that are relevant to understanding its ecological characteristics. The main topics are ...presented within the standard framework of the International Biological Flora: distribution, habitat, communities, responses to biotic factors, responses to environment, structure and physiology, phenology, reproductive and seed characters, herbivores and disease, history, conservation and global heterogeneity.
Globally, Ginkgo survives a wide range of mean annual temperature (−3.3 to 23.3°C) and annual precipitation (34–3925 mm) conditions, according to a meta‐analysis. It prefers a warm, humid, open‐canopy and a well‐drained environment. The species shows strong tolerance to drought, freezing, fire, air pollution, heavy metals and low‐level salt, whereas it is intolerant to long‐time shade and waterlogging. Six Ginkgo trees even survived the atom bomb in Hiroshima, Japan, during World War II.
Ginkgo is susceptible to few diseases. Those occurring in nursery seedlings and juvenile trees involve stem rot and leaf blight. The former is caused by Macrophomina phaseoli, which could lead to a mortality rate of 5%–12% (up to 31.8%) for seedlings. This disease can be mitigated by a 4‐h shading treatment and applying organic fertilisers. The pathogens inducing leaf blight include Alternaria alternata, Colletotrichum gloeosporioides and Pestalotia ginkgo, which may infect 100% juvenile trees in some regions. The application of 45% carbendazim or 50% Tuzet can effectively prevent leaf blight.
Ginkgo biloba is one of the world’s most distinctive trees with an important position in plant evolution and human society. It is a tall deciduous dioecious tree native to China. Refugial populations were identified in three glacial refugia located in eastern, southern and south‐western China, respectively, with a patchy distribution pattern and a small population size. It typically grows along flood‐disturbed streamsides in warm‐temperate deciduous (and evergreen mixed) broadleaved forests. Ginkgo may have been introduced repeatedly out of China since the sixth century. It has been planted as a landscape tree world‐wide, except in Antarctica. Ginkgo is also of great value for edible nuts, herbal medicine, religion and art. It is a natural and cultural symbol of China.
摘要
本文系统总结了活化石树种银杏(Ginkgo biloba L.)的生物学和生态学特性。根据本刊“国际生物学植物志”的标准框架，我们从以下十一个方面进行了全面描述:分布、生境、群落、生物响应、环境响应、结构与生理、物候、繁殖和种子特征、植食动物与疾病、进化历史、保护、全球异质性。
银杏具有突出的环境适应性和抗逆性。荟萃分析表明，银杏可适应变异范围极广的年均温(−3.3 至 23.3 °C)和年降水量(34至3925 mm)环境，但喜温暖、湿润、郁闭度低、排水状况良好的生境。银杏对干旱、霜冻、火、大气污染、重金属和低浓度的盐分具较强的耐受性，但不耐受长时间荫蔽和水淹。日本广岛市的六株银杏甚至经历第二次世界大战原子弹轰炸后仍存活至今。
银杏也具很强的抗病性。大树病害极少，在幼苗和幼树中仅发现茎腐病和叶枯病。茎腐病由菜豆壳球孢(Macrophomina phaseoli)引起，幼苗致死率为5%–12%(最高达31.8%)，4小时遮荫处理外加施用有机肥可有效减轻症状。叶枯病的病原菌包括链格孢(Alternaria alternata)、盘长孢状刺盘孢(Colletotrichum gloeosporioides)和银杏盘多毛孢(Pestalotia ginkgo)。某些地区幼树的叶枯病发病率可达100%，但喷洒45%多菌灵或50%退菌特可有效预防叶枯病。
作为全世界最独特的树种之一，银杏在植物进化和人类社会中扮演着重要角色。这种高大落叶乔木雌雄异株，原产中国，共有三处冰期避难所，分别位于华东、西南和华南。避难所种群分布零散，且种群大小较小。在暖温带落叶阔叶林和常绿落叶阔叶混交林中，常分布于沟谷两侧。自公元六世纪以来，银杏不断被引种至中国之外的世界各地，作为一种景观树种，目前银杏被栽培于除南极洲外的其余六大洲。它还具有很高的食用、药用、宗教和艺术价值。银杏是中国的自然和文化符号之一。
The living fossil Ginkgo biloba is one of the world’s most distinctive trees with an important position in plant evolution and human society. It is a tall deciduous dioecious tree with masses of golden fan‐shaped leaves in autumn. It grows world‐wide except in Antarctica and even survived the atomic bombing of Hiroshima. The extreme longevity of over 1000 years results in part from its prominent tolerance and resistance to both biotic and abiotic stresses as well as from outstanding regeneration potential due to sprouts, suckers or air roots. Refugial and natural populations still persist along flood‐disturbed streamsides in subtropical China.
α-Helical antimicrobial peptides (AMPs) generally have facially amphiphilic structures that may lead to undesired peptide interactions with blood proteins and self-aggregation due to exposed ...hydrophobic surfaces. Here we report the design of a class of cationic, helical homo-polypeptide antimicrobials with a hydrophobic internal helical core and a charged exterior shell, possessing unprecedented radial amphiphilicity. The radially amphiphilic structure enables the polypeptide to bind effectively to the negatively charged bacterial surface and exhibit high antimicrobial activity against both gram-positive and gram-negative bacteria. Moreover, the shielding of the hydrophobic core by the charged exterior shell decreases nonspecific interactions with eukaryotic cells, as evidenced by low hemolytic activity, and protects the polypeptide backbone from proteolytic degradation. The radially amphiphilic polypeptides can also be used as effective adjuvants, allowing improved permeation of commercial antibiotics in bacteria and enhanced antimicrobial activity by one to two orders of magnitude. Designing AMPs bearing this unprecedented, unique radially amphiphilic structure represents an alternative direction of AMP development; radially amphiphilic polypeptides may become a general platform for developing AMPs to treat drug-resistant bacteria.
Gut dysbiosis has been found to be involved in the pathogenesis of energy metabolic disorders and might be a new strategy for these ailments. Berberine (BBR), a botanical medicine, shows therapeutic ...efficacy in patients with metabolic diseases. Numerous reports have shown BBR's modulating effect on gut microbiota, opening a new avenue to understand BBR's mechanism. In this study, a colon‐specific delivery system, BBR‐CS/PT‐NP, is investigated by the assembly of pH/gut microflora dual stimuli‐responsive nanoparticles for enhancing the interaction between BBR and gut microbiota. After oral administration, the delivering system remains stable in the stomach and small intestine, followed by a burst release of BBR after reaching the colon segment rich in intestinal bacteria. The enzymes produced by bacteria degrade the nanoparticle, causing direct exposure of BBR to gut microbiota. In the high fat diet‐induced obese hamsters, BBR‐CS/PT‐NP intervention inhibits weight‐gain and fat deposition, decreases plasma lipids and glucose levels, improves inflammation condition and insulin resistance, alleviates hepatic steatosis, at a level significantly higher than the pure BBR does. The mechanisms might be attributable to the enhanced interaction between BBR and the gut flora. The results provide a novel proof‐of‐concept for drug delivery targeting gut microbiota to ameliorate metabolic disorders.
Gut dysbiosis is involved in the pathogenesis of energy metabolic disorders and represents a new strategy for treating these ailments. In this study, a pH/gut microflora dual stimuli‐responsive system, berberine (BBR)‐CS/PT‐NP with colon‐homing and microbiota‐targeting characteristics, is investigated to enhance the interaction between BBR and the gut microbiota. It provides a novel proof‐of‐concept for drug delivery targeting gut microbiota to ameliorate metabolic diseases.
Acetylation of transcriptional regulators is normally dynamically regulated by nutrient status but is often persistently elevated in nutrient‐excessive obesity conditions. We investigated the ...functional consequences of such aberrantly elevated acetylation of the nuclear receptor FXR as a model. Proteomic studies identified K217 as the FXR acetylation site in diet‐induced obese mice. In vivo studies utilizing acetylation‐mimic and acetylation‐defective K217 mutants and gene expression profiling revealed that FXR acetylation increased proinflammatory gene expression, macrophage infiltration, and liver cytokine and triglyceride levels, impaired insulin signaling, and increased glucose intolerance. Mechanistically, acetylation of FXR blocked its interaction with the SUMO ligase PIASy and inhibited SUMO2 modification at K277, resulting in activation of inflammatory genes. SUMOylation of agonist‐activated FXR increased its interaction with NF‐κB but blocked that with RXRα, so that SUMO2‐modified FXR was selectively recruited to and trans‐repressed inflammatory genes without affecting FXR/RXRα target genes. A dysregulated acetyl/SUMO switch of FXR in obesity may serve as a general mechanism for diminished anti‐inflammatory response of other transcriptional regulators and provide potential therapeutic and diagnostic targets for obesity‐related metabolic disorders.
Synopsis
Acetylation levels of many transcriptional regulators are aberrantly elevated in obesity but the functional consequences are unclear. Elevated acetylation of the mouse nuclear Farnesoid X receptor (FXR) in obesity is found to inhibit its SUMOylation, constituting a molecular switch that promotes hepatic inflammation and metabolic dysfunction in vivo.
Agonist‐activated FXR is SUMO2‐modified at lysine 277 by the PIASy SUMO E3 ligase.
FXR SUMOylation inhibits inflammatory gene expression upon inflammatory signaling.
Selective inflammatory gene trans‐repression results from increased NF‐κB and decreased RXRα interaction of SUMO2‐FXR.
In obese mice, FXR acetylation at lysine 217 inhibits its SUMOylation and diminishes SUMO2‐dependent FXR anti‐inflammatory action.
Elevated acetylation of the mouse nuclear Farnesoid X receptor (FXR) in obesity inhibits its SUMOylation, which promotes hepatic inflammation and metabolic dysfunction in vivo.
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