Cardiovascular disease is the leading cause of global mortality,with anticoagulant therapy being the main prevention and treatment strategy.Recombinant hirudin(r-hirudin)is a direct thrombin inhibitor that can potenti...Cardiovascular disease is the leading cause of global mortality,with anticoagulant therapy being the main prevention and treatment strategy.Recombinant hirudin(r-hirudin)is a direct thrombin inhibitor that can potentially prevent thrombosis via subcutaneous(SC)and intravenous(IV)administration,but there is a risk of haemorrhage via SC and IV.Thus,microneedle(MN)provides painless and sanitary alternatives to syringes and oral administration.However,the current technological process for the micro mould is complicated and expensive.The micro mould obtained via three-dimensional(3D)printing is expected to save time and cost,as well as provide a diverse range of MNs.Therefore,we explored a method for MNs array model production based on 3D printing and translate it to micro mould that can be used for fabrication of dissolving MNs patch.The results show that r-hirudin-loaded and hyaluronic acid(HA)-based MNs can achieve transdermal drug delivery and exhibit significant potential in the prevention of thromboembolic disease without bleeding in animal models.These results indicate that based on 3D printing technology,MNs combined with r-hirudin are expected to achieve diverse customizableMNs and thus realize personalized transdermal anticoagulant delivery for minimally invasive and long-term treatment of thrombotic disease.展开更多
Millions of people are suffering from Alzheimer’s disease globally,but there is still no effective treatment for this neurodegenerative disease.Thus,novel therapeutic approaches for Alzheimer’s disease are needed,wh...Millions of people are suffering from Alzheimer’s disease globally,but there is still no effective treatment for this neurodegenerative disease.Thus,novel therapeutic approaches for Alzheimer’s disease are needed,which requires further evaluation of the regulato ry mechanisms of protein aggregate degradation.Lysosomes are crucial degradative organelles that maintain cellular homeostasis.Transcription factor EB-mediated lysosome biogenesis enhances autolysosomedependent degradation,which subsequently alleviates neurodege nerative diseases,including Alzheimer’s disease,Parkinson’s disease,and Huntington’s disease.In this review,we start by describing the key features of lysosomes,including their roles in nutrient sensing and degradation,and their functional impairments in different neurodegenerative diseases.We also explain the mechanisms—especially the post-translational modifications—which impact transcription factor EB and regulate lysosome biogenesis.Next,we discuss strategies for promoting the degradation of toxic protein aggregates.We describe Proteolysis-Ta rgeting Chimera and related technologies for the targeted degradation of specific proteins.We also introduce a group of LYsosome-Enhancing Compounds,which promote transcription factor EB-mediated lysosome biogenesis and improve learning,memory,and cognitive function in APP-PSEN1 mice.In summary,this review highlights the key aspects of lysosome biology,the mechanisms of transcription factor EB activation and lysosome biogenesis,and the promising strategies which are emerging to alleviate the pathogenesis of neurodegenerative diseases.展开更多
Prostate cancer(PCa)is the second most prevalent malignancy in males across the world.A greater knowledge of the relationship between protein abundance and drug responses would benefit precision treatment for PCa.Here...Prostate cancer(PCa)is the second most prevalent malignancy in males across the world.A greater knowledge of the relationship between protein abundance and drug responses would benefit precision treatment for PCa.Herein,we establish 35 Chinese PCa primary cell models to capture specific characteristics among PCa patients,including gene mutations,mRNA/protein/surface protein distributions,and pharmaceutical responses.The multi-omics analyses identify Anterior Gradient 2(AGR2)as a pre-operative prognostic biomarker in PCa.Through the drug library screening,we describe crizotinib as a selective compound for malignant PCa primary cells.We further perform the pharmacoproteome analysis and identify 14,372 significant protein-drug correlations.Surprisingly,the diminished AGR2 enhances the inhibition activity of crizotinib via ALK/c-MET-AKT axis activation which is validated by PC3 and xenograft model.Our integrated multi-omics approach yields a comprehensive understanding of PCa biomarkers and pharmacological responses,allowing for more precise diagnosis and therapies.展开更多
The authors of the above-mentioned paper noticed an error in Fig.5a as reported.H&E staining was shown in wrong color during figure processing and DKO-LF group was accidently copied and pasted twice.Original H&...The authors of the above-mentioned paper noticed an error in Fig.5a as reported.H&E staining was shown in wrong color during figure processing and DKO-LF group was accidently copied and pasted twice.Original H&E images have been replaced with the correct color with the accurate grouping information.No text content in figure legend or conclusion is affected by this error.The authors sincerely apologize for any inconvenience caused to the journal and readers.展开更多
Given the opposing effects of Akt and AMP-activated protein kinase(AMPK)on metabolic homeostasis,this study examined the effects of deletion of Akt2 and AMPKα2 on fat diet-induced hepatic steatosis.Akt2–Ampkα2 doub...Given the opposing effects of Akt and AMP-activated protein kinase(AMPK)on metabolic homeostasis,this study examined the effects of deletion of Akt2 and AMPKα2 on fat diet-induced hepatic steatosis.Akt2–Ampkα2 double knockout(DKO)mice were placed on high fat diet for 5 months.Glucose metabolism,energy homeostasis,cardiac function,lipid accumulation,and hepatic steatosis were examined.DKO mice were lean without anthropometric defects.High fat intake led to adiposity and decreased respiratory exchange ratio(RER)in wild-type(WT)mice,which were ablated in DKO but not Akt2^(-/-) and Ampkα2^(-/-) mice.High fat intake increased blood and hepatic triglycerides and cholesterol,promoted hepatic steatosis and injury in WT mice.These effects were eliminated in DKO but not Akt2^(-/-) and Ampkα2^(-/-) mice.Fat diet promoted fat accumulation,and enlarged adipocyte size,the effect was negated in DKO mice.Fat intake elevated fatty acid synthase(FAS),carbohydrate-responsive element-binding protein(CHREBP),sterol regulatory element-binding protein 1(SREBP1),peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC-1α),peroxisome proliferator-activated receptor-α(PPARα),PPARγ,stearoyl-CoA desaturase 1(SCD-1),phosphoenolpyruvate carboxykinase(PEPCK),glucose 6-phosphatase(G6Pase),and diglyceride O-acyltransferase 1(DGAT1),the effect was absent in DKO but not Akt2^(-/-) and Ampkα2^(-/-) mice.Fat diet dampened mitophagy,promoted inflammation and phosphorylation of forkhead box protein O1(FoxO1)and AMPKα1(Ser^(485)),the effects were eradicated by DKO.Deletion of Parkin effectively nullified DKO-induced metabolic benefits against high fat intake.Liver samples from obese humans displayed lowered microtubule-associated proteins 1A/1B light chain 3B(LC3B),Pink1,Parkin,as well as enhanced phosphorylation of Akt,AMPK(Ser^(485)),and FoxO1,which were consolidated by RNA sequencing(RNAseq)and mass spectrometry analyses from rodent and human livers.These data suggest that concurrent deletion of Akt2 and AMPKα2 offers resilience to fat diet-induced obesity and hepatic steatosis,possibly through preservation of Parkin-mediated mitophagy and lipid metabolism.展开更多
Lipids are a large and diverse class of biomolecules that exert multiple biochemical functions,such as fueling energy production,and building blocks for plasma membrane and chemical signals during cellular communication.
Micro RNAs(miRNAs) are a class of endogenous non-coding RNAs with regulatory functions. Traditionally, miRNAs are thought to play a negative regulatory role in the cytoplasm by binding to the 30 UTR of target genes to...Micro RNAs(miRNAs) are a class of endogenous non-coding RNAs with regulatory functions. Traditionally, miRNAs are thought to play a negative regulatory role in the cytoplasm by binding to the 30 UTR of target genes to degrade m RNA or inhibit translation. However, it remains a challenge to interpret the potential function of many miRNAs located in the nucleus.Recently, we reported a new type of miRNAs present in the nucleus, which can activate gene expression by binding to the enhancer, and named them nuclear activating miRNAs(NamiRNAs). The discovery of NamiRNAs showcases a complementary regulatory mechanism of mi RNA, demonstrating their differential roles in the nucleus and cytoplasm. Here, we reviewed miRNAs in nucleus to better understand the function of NamiRNAs in their interactions with the enhancers. Accordingly, we propose a Nami RNA–enhancer–target gene activation network model to better understand the crosstalk between NamiRNAs and enhancers in regulating gene transcription.Moreover, we hypothesize that NamiRNAs may be involved in cell identity or cell fate determination during development, although further study is needed to elucidate the underlying mechanisms in detail.展开更多
Accumulating evidence from both animal and human studies suggests that activation of beige fat increases cellular energy expenditure,ultimately reducing adiposity.Here,we report the central role of adipocyte-derived l...Accumulating evidence from both animal and human studies suggests that activation of beige fat increases cellular energy expenditure,ultimately reducing adiposity.Here,we report the central role of adipocyte-derived lysyl oxidase(Lox)in the formation of thermogenic beige fat.Mice exposed to cold or aβ3 agonist showed drastically lower Lox expression in thermogenically activated beige fat.Importantly,inhibition of Lox activity with BAPN stimulated biogenesis of beige fat in inguinal white adipose tissue(iWAT)under housing conditions and potentiated cold-induced adaptive thermogenesis and beiging in both iWAT and epididymal white adipose tissue(eWAT).Notably,white adipocytes with Lox repression undergo transdifferentiation into beige adipocytes which can be suppressed by tumor necrosis factor-α(TNFα)via ERK activation.This work provides new insight into the molecular control to expand beige fat by Lox inhibition and suggest the potential for utilizing inhibitor of Lox to treat the emerging epidemics of obesity and diabetes.展开更多
Long noncoding RNAs(lncRNAs)are functional RNA molecules which are longer than 200 nucleotides in length that do not encode proteins;instead,they regulate target gene expression at transcriptional,posttranscriptional,...Long noncoding RNAs(lncRNAs)are functional RNA molecules which are longer than 200 nucleotides in length that do not encode proteins;instead,they regulate target gene expression at transcriptional,posttranscriptional,and epigenetic levels.LncRNAs play important roles in various biological processes such as dosage compensation,genomic imprinting,cell cycle regulation,and cell differentiation.Although their characterizations have been relatively straightforward with recent advances in modern biology,the functions of lncRNAs are largely unknown.Herein,we discuss the biological functions and research methods of lncRNAs.展开更多
Dear Editor,Bladder cancer is the most common type of genitourinary cancer in China,with an estimated 80,500 new cases and 32,900 related deaths in 2015 alone(Chen et al.,2016).Unlike many other cancers,there has been...Dear Editor,Bladder cancer is the most common type of genitourinary cancer in China,with an estimated 80,500 new cases and 32,900 related deaths in 2015 alone(Chen et al.,2016).Unlike many other cancers,there has been no significant improvement in survival rates for bladder cancer over the last three decades.Specific treatment regimens for bladder cancer and their efficacy vary depending not only on clinical stages,but also on associated risk factors and other personal clinical characteristics.Patients with non-muscle invasive bladder cancer(NMIBC)have a high 5-year recurrence rate of 60%-70%(Berdik,2017)and those with muscle invasive bladder cancer(MIBC)has a relatively poor prognosis with approximately 65%risk of death within 5-year follow-up(Kamat et al.,2016).Therefore,there is an urgent need to develop models for bladder cancer to screen for rational treatment strategies by personalized medicine to improve the clinical assessment and treatment of bladder cancer.展开更多
Lipids and glucose exert many essential physiological functions,such as providing raw materials or energy for cellular biosynthesis,regulating cell signal transduction,and maintaining a constant body temperature.Dysre...Lipids and glucose exert many essential physiological functions,such as providing raw materials or energy for cellular biosynthesis,regulating cell signal transduction,and maintaining a constant body temperature.Dysregulation of lipid and glucose metabolism can lead to glucolipid metabolic disorders linked to various metabolic diseases,such as obesity,diabetes,and cardiovascular disease.Therefore,intervention in glucolipid metabolism is a key therapeutic strategy for the treatment of metabolic diseases.Activating transcription factor 3(ATF3)is a transcription factor that acts as a hub of the cellular adaptive-response network and plays a pivotal role in the regulation of inflammation,apoptosis,DNA repair,and oncogenesis.Emerging evidence has illustrated the vital roles of ATF3 in glucolipid metabolism.ATF3 inhibits intestinal lipid absorption,enhances hepatic triglyceride hydrolysis and fatty acid oxidation,promotes macrophage reverse cholesterol transport,and attenuates the progression of western diet-induced nonalcoholic fatty liver disease and atherosclerosis.In addition to its role in lipid metabolism,ATF3 has also been identified as an important regulator of glucose metabolism.Here,we summarize the recent advances in the understanding of ATF3,mainly focusing on its role in glucose and lipid metabolism and potential therapeutic implications.展开更多
The CRISPR/Cas9 system,originally derived from the prokaryotic adaptive immune system,has been developed as efficient genome editing tools.It enables precise gene manipulation on chromosomal DNA through the specific b...The CRISPR/Cas9 system,originally derived from the prokaryotic adaptive immune system,has been developed as efficient genome editing tools.It enables precise gene manipulation on chromosomal DNA through the specific binding of programmable sgRNA to target DNA,and the Cas9 protein,which has endonuclease activity,will cut a double strand break at specific locus.However,Cas9 is a foreign protein in mammalian cells,and the potential risks associated with its introduction into mammalian cells are not fully understood.In this study,we performed pull-down and mass spectrometry(MS)analysis of Streptococcus pyogenes Cas9(SpyCas9)interacting proteins in HEK293T cells and showed that the majority of Cas9-associated proteins identified by MS were localized in the nucleolus.Interestingly,we further discovered that the Cas9 protein contains a sequence encoding a nucleolus detention signal(NoDS).Compared with wild-type(WT)Cas9,NoDS-mutated variants of Cas9(mCas9)are less stable,although their gene editing activity is minimally affected.Overexpression of WT Cas9,but not mCas9,causes general effects on transcription and protein translation in the host cell.Overall,identification of NoDS in Cas9 will improve the understanding of Cas9's biological function in vivo,and the removal of NoDS in Cas9 may enhance its safety for future clinical use.展开更多
Cancer development is a complicated process controlled by the interplay of multiple signaling pathways and restrained by oxygen and nutrient accessibility in the tumor microenvironment.High plasticity in using diverse...Cancer development is a complicated process controlled by the interplay of multiple signaling pathways and restrained by oxygen and nutrient accessibility in the tumor microenvironment.High plasticity in using diverse nutrients to adapt to metabolic stress is one of the hallmarks of cancer cells.To respond to nutrient stress and to meet the requirements for rapid cell proliferation,cancer cells reprogram metabolic pathways to take up more glucose and coordinate the production of energy and intermediates for biosynthesis.Such actions involve gene expression and activity regulation by the moonlighting function of oncoproteins and metabolic enzymes.The signal−moonlighting protein−metabolism axis facilitates the adaptation of tumor cells under varying environment conditions and can be therapeutically targeted for cancer treatment.展开更多
Summary of main observation and conclusion OSW-1 is a well-known natural saponin with potent antitumor activities.We have designed and pre-pared a small library of 22 OSW-1 analogues with a variety of p-acylamino-benz...Summary of main observation and conclusion OSW-1 is a well-known natural saponin with potent antitumor activities.We have designed and pre-pared a small library of 22 OSW-1 analogues with a variety of p-acylamino-benzoyl groups installed at C2"of the xylose residue,wherein a regioselective(1>3)-glycosylation of arabinoside 3,4-diol has been achieved by manipulatian of the protecting groups on the imidate donors.Bioassays lead to new structure-activity relationships as well as two aplicable fluorescent probes,which are found to localize to lysosomes in HeLa cells and could be used in further antitumor mechanism studies of OSW-1 in living cells.展开更多
Nonalcoholic steatohepatitis(NASH)has emerged as a major cause of liver failure and hepatocellular carcinoma.Investigation into the molecular mechanisms that underlie steatosis-to-NASH progression is key to understand...Nonalcoholic steatohepatitis(NASH)has emerged as a major cause of liver failure and hepatocellular carcinoma.Investigation into the molecular mechanisms that underlie steatosis-to-NASH progression is key to understanding the development of NASH pathophysiology.Here,we present comprehensive multi-omic profiles of preclinical animal models to identify genes,non-coding RNAs,proteins,and plasma metabolites involved in this progression.In particular,by transcriptomics analysis,we identified Growth Differentiation Factor 3(GDF3)as a candidate noninvasive biomarker in NASH.Plasma GDF3 levels are associated with hepatic pathological features in patients with NASH,and differences in these levels provide a high diagnostic accuracy of NASH diagnosis(AUROC=0.90;95%confidence interval:0.85−0.95)with a good sensitivity(90.7%)and specificity(86.4%).In addition,by developing integrated proteomic-metabolomic datasets and performing a subsequent pharmacological intervention in a mouse model of NASH,we show that ferroptosis may be a potential target to treat NASH.Moreover,by using competing endogenous RNAs network analysis,we found that several miRNAs,including miR-582-5p and miR-292a-3p,and lncRNAs,including XLOC-085738 and XLOC-041531,are associated with steatosis-to-NASH progression.Collectively,our data provide a valuable resource into the molecular characterization of NASH progression,leading to the novel insight that GDF3 may be a potential noninvasive diagnostic biomarker for NASH while further showing that ferroptosis is a therapeutic target for the disease.展开更多
Bladder cancer(BLCA)remains a difficult malignancy to manage because of its high recurrence,intense follow-up,and invasive diagnostic and treatment techniques.Immune checkpoint inhibitors(ICIs)have forged a new direct...Bladder cancer(BLCA)remains a difficult malignancy to manage because of its high recurrence,intense follow-up,and invasive diagnostic and treatment techniques.Immune checkpoint inhibitors(ICIs)have forged a new direction for the treatment of BLCA,but it is currently challenging to predict whether an individual patient will be sensitive to ICIs.We collected 43 urine/tumor samples from BLCA patients for primary bladder cancer cells(BCCs)culturing using our previously reported BCC culture platform.We used flow cytometry(FCM)to measure the expression levels of Programmed Death-Ligand 1(PD-L1)on BCCs before and after interferon-gamma(IFN-γ)treatment and found that PD-L1 expression and the sensitivities to IFN-γvaried among patients.RNA-sequencing,western blotting,and programmed death-1(PD-1)binding assays confirmed that the BCC FCM-based PD-L1 detection platform(BC-PD-L1)was reliable and was not hindered by the glycosylation of PD-L1.In the subsequent retrospective study,we found that IFN-γ-stimulated PD-L1(sPD-L1)expression on BCCs detected by BC-PD-L1 could predict the prognosis of BLCA patients.Importantly,the prognostic value was similar or even better in urine-derived BC-PD-L1(UBC-PD-L1).Transcriptome analysis showed that BCCs with high sPD-L1 tended to enrich genes associated with the collagen-containing extracellular matrix,cell–cell adhesion,and positive regulation of the immune system.In addition,the UBC-PD-L1 also exhibited predictive value for ICI response in BLCA patients.In conclusion,as a novel personalized urine-detection method,UBC-PD-L1 may provide a rapid,accurate,and non-invasive tool for monitoring tumor progression,predicting therapeutic responses,and helping improve BLCA clinical treatment in future.展开更多
Kidney disease is manifested in a wide variety of phenotypes,many of which have an important hereditary component.To delineate the genotypic and phenotypic spectrum of pediatric nephropathy,a multicenter registration ...Kidney disease is manifested in a wide variety of phenotypes,many of which have an important hereditary component.To delineate the genotypic and phenotypic spectrum of pediatric nephropathy,a multicenter registration system is being imple-mented based on the Chinese Children Genetic Kidney Disease Database(CCGKDD).In this study,all the patients with kidney and urological diseases were recruited from 2014 to 2020.Genetic analysis was conducted using exome sequencing for families with multiple affected individuals with nephropathy or clinical suspicion of a genetic kidney disease owing to early-onset or extrarenal features.The genetic diagnosis was confirmed in 883 of 2256(39.1%)patients from 23 provinces in China.Phenotypic profiles showed that the primary diagnosis included steroid-resistant nephrotic syndrome(SRNS,23.5%),glomerulonephritis(GN,32.2%),congenital anomalies of the kidney and urinary tract(CAKUT,21.2%),cystic renal disease(3.9%),renal calcinosis/stone(3.6%),tubulopathy(9.7%),and chronic kidney disease of unknown etiology(CKDu,5.8%).The pathogenic variants of 105 monogenetic disorders were identified.Ten distinct genomic disorders were identified as pathogenic copy number variants(CNVs)in 11 patients.The diagnostic yield differed by subgroups,and was highest in those with cystic renal disease(66.3%),followed by tubulopathy(58.4%),GN(57.7%),CKDu(43.5%),SRNS(29.2%),renal calcinosis/stone(29.3%)and CAKUT(8.6%).Reverse phenotyping permitted correct identification in 40 cases with clinical reassessment and unexpected genetic conditions.We present the results of the largest cohort of children with kidney disease in China where diagnostic exome sequencing was performed.Our data demonstrate the utility of family-based exome sequencing,and indicate that the combined analysis of genotype and phenotype based on the national patient registry is pivotal to the genetic diagnosis of kidney disease.展开更多
Protein-biomolecule interactions play pivotal roles in almost all biological processes.For a biomolecule of interest,the identification of the interacting protein(s)is essential.For this need,although many assays are ...Protein-biomolecule interactions play pivotal roles in almost all biological processes.For a biomolecule of interest,the identification of the interacting protein(s)is essential.For this need,although many assays are available,highly robust and reliable methods are always desired.By combining a substrate-based proximity labeling activity from the pupylation pathway of Mycobacterium tuberculosis and the streptavidin(SA)-biotin system,we developed the Specific Pupylation as IDEntity Reporter(SPIDER)method for identifying protein-biomolecule interactions.Using SPIDER,we validated the interactions between the known binding proteins of protein,DNA,RNA,and small molecule.We successfully applied SPIDER to construct the global protein interactome for m^(6)A and m RNA,identified a variety of uncharacterized m^(6)A binding proteins,and validated SRSF7 as a potential m^(6)A reader.We globally identified the binding proteins for lenalidomide and Cob B.Moreover,we identified SARS-CoV-2-specific receptors on the cell membrane.Overall,SPIDER is powerful and highly accessible for the study of proteinbiomolecule interactions.展开更多
Genome-wide association studies(GWASs)have identified over 100 loci associated with rheumatoid arthritis(RA);how-ever,the functionally affected genes and the underlying molecular mechanisms contributing to these assoc...Genome-wide association studies(GWASs)have identified over 100 loci associated with rheumatoid arthritis(RA);how-ever,the functionally affected genes and the underlying molecular mechanisms contributing to these associations are often unknown.In this study,we conducted an integrative genomic analysis incorporating multiple“omics”data and identified a functional regulatory DNA variant,rs56199421,and a plausible mechanism by which it regulates the expression of a puta-tive RA risk gene,ORMDL Sphingolipid Biosynthesis Regulator 3(ORMDL3).The T allele of rs56199421,located in the enhancer region of ORMDL3,exhibited stronger direct binding ability than the other C allele of rs56199421 did in vitro with the transcription factor JunD and demonstrated higher transcriptional activity.Moreover,the T allele of rs56199421 is associated with elevated RA risk,and ORMDL3 expression is increased in RA patients.Thus,these findings suggest that the T allele of rs56199421 enhances JunD transcription factor binding,increases enhancer activity,and elevates the expression of the RA risk gene ORMDL3.展开更多
Scutellaria baicalensis Georgi is important in Chinese traditional medicine where preparations of dried roots,"Huang Qin," are used for liver and lung complaints and as complementary cancer treatments. We re...Scutellaria baicalensis Georgi is important in Chinese traditional medicine where preparations of dried roots,"Huang Qin," are used for liver and lung complaints and as complementary cancer treatments. We report a high-quality reference genome sequence for S. baicalensis where 93% of the 408.14-Mb genome has been assembled into nine pseudochromosomes with a super-N50 of 33.2 Mb. Comparison of this sequence with those of closely related species in the order Lamiales, sesamum indicum and Salvia splendens,revealed that a specialized metabolic pathway for the synthesis of 4'-deoxyflavone bioactives evolved in the genus Scu-tellaria. We found that the gene encoding a specific cinnamate coenzyme A ligase likely obtained its newfunc- tion following recent mutations, and that four genes encoding enzymes in the 4'-deoxyflavone pathway are present as tandem repeats in the genome of S. baicalensis. Further analyses revealed that gene duplications, segmental duplication, gene amplification, and point mutations coupled to gene neo- and subfunctionaliza-tions were involved in the evolution of 4'-deoxyflavone synthesis in the genus Scutellaria. Our study not only provides significant insight into the evolution of specific flavone biosynthetic pathways in the mint family, Lamiaceae, but also will facilitate the development of tools for enhancing bioactive productivity by metabolic engineering in microbes or by molecular breeding in plants. The reference genome of S. baicalensis is also useful for improving the genome assemblies for other members of the mint family and offers an important foundation for decoding the synthetic pathways of bioactive compounds in medicinal plants.展开更多
基金supported by the National Natural Science Foundation of China (NSFC 81902995)the project funded by China Postdoctoral Science Foundation (2018M641936)
文摘Cardiovascular disease is the leading cause of global mortality,with anticoagulant therapy being the main prevention and treatment strategy.Recombinant hirudin(r-hirudin)is a direct thrombin inhibitor that can potentially prevent thrombosis via subcutaneous(SC)and intravenous(IV)administration,but there is a risk of haemorrhage via SC and IV.Thus,microneedle(MN)provides painless and sanitary alternatives to syringes and oral administration.However,the current technological process for the micro mould is complicated and expensive.The micro mould obtained via three-dimensional(3D)printing is expected to save time and cost,as well as provide a diverse range of MNs.Therefore,we explored a method for MNs array model production based on 3D printing and translate it to micro mould that can be used for fabrication of dissolving MNs patch.The results show that r-hirudin-loaded and hyaluronic acid(HA)-based MNs can achieve transdermal drug delivery and exhibit significant potential in the prevention of thromboembolic disease without bleeding in animal models.These results indicate that based on 3D printing technology,MNs combined with r-hirudin are expected to achieve diverse customizableMNs and thus realize personalized transdermal anticoagulant delivery for minimally invasive and long-term treatment of thrombotic disease.
基金STI2030-Major Projects,No.2022ZD0213000the National Natural Science Foundation of China,Nos.92057103 and 31872820+1 种基金Shanghai Basic Research Program,No.18ZR1 404000State Key Laboratory of Drug Research,No.SIMM2004KF-09 (all to YL)。
文摘Millions of people are suffering from Alzheimer’s disease globally,but there is still no effective treatment for this neurodegenerative disease.Thus,novel therapeutic approaches for Alzheimer’s disease are needed,which requires further evaluation of the regulato ry mechanisms of protein aggregate degradation.Lysosomes are crucial degradative organelles that maintain cellular homeostasis.Transcription factor EB-mediated lysosome biogenesis enhances autolysosomedependent degradation,which subsequently alleviates neurodege nerative diseases,including Alzheimer’s disease,Parkinson’s disease,and Huntington’s disease.In this review,we start by describing the key features of lysosomes,including their roles in nutrient sensing and degradation,and their functional impairments in different neurodegenerative diseases.We also explain the mechanisms—especially the post-translational modifications—which impact transcription factor EB and regulate lysosome biogenesis.Next,we discuss strategies for promoting the degradation of toxic protein aggregates.We describe Proteolysis-Ta rgeting Chimera and related technologies for the targeted degradation of specific proteins.We also introduce a group of LYsosome-Enhancing Compounds,which promote transcription factor EB-mediated lysosome biogenesis and improve learning,memory,and cognitive function in APP-PSEN1 mice.In summary,this review highlights the key aspects of lysosome biology,the mechanisms of transcription factor EB activation and lysosome biogenesis,and the promising strategies which are emerging to alleviate the pathogenesis of neurodegenerative diseases.
基金supported by National Natural Science Foundation of China(22137002[Y.D.],32071432[M.T.],81872102[H.J.])University Innovation Research Group Project of Chongqing(CXQT21016[Y.D.])+3 种基金High-Level Innovation Platform Project of Chongqing[Y.D.]Talent Program of Chongqing(CQYC202003053[Y.D.])The collaborative project of Chinese Academy of Sciences institutions and universities in Chongqing(HZ2021006[Y.D.])Innovative Research Team of High-Level Local Universities in Shanghai(SSMU-ZDCX20181202[M.T.]).
文摘Prostate cancer(PCa)is the second most prevalent malignancy in males across the world.A greater knowledge of the relationship between protein abundance and drug responses would benefit precision treatment for PCa.Herein,we establish 35 Chinese PCa primary cell models to capture specific characteristics among PCa patients,including gene mutations,mRNA/protein/surface protein distributions,and pharmaceutical responses.The multi-omics analyses identify Anterior Gradient 2(AGR2)as a pre-operative prognostic biomarker in PCa.Through the drug library screening,we describe crizotinib as a selective compound for malignant PCa primary cells.We further perform the pharmacoproteome analysis and identify 14,372 significant protein-drug correlations.Surprisingly,the diminished AGR2 enhances the inhibition activity of crizotinib via ALK/c-MET-AKT axis activation which is validated by PC3 and xenograft model.Our integrated multi-omics approach yields a comprehensive understanding of PCa biomarkers and pharmacological responses,allowing for more precise diagnosis and therapies.
文摘The authors of the above-mentioned paper noticed an error in Fig.5a as reported.H&E staining was shown in wrong color during figure processing and DKO-LF group was accidently copied and pasted twice.Original H&E images have been replaced with the correct color with the accurate grouping information.No text content in figure legend or conclusion is affected by this error.The authors sincerely apologize for any inconvenience caused to the journal and readers.
基金supported in part by the National Key R&D Program of China(2017YFA0506000)National Natural Science Foundation of China(82000351)。
文摘Given the opposing effects of Akt and AMP-activated protein kinase(AMPK)on metabolic homeostasis,this study examined the effects of deletion of Akt2 and AMPKα2 on fat diet-induced hepatic steatosis.Akt2–Ampkα2 double knockout(DKO)mice were placed on high fat diet for 5 months.Glucose metabolism,energy homeostasis,cardiac function,lipid accumulation,and hepatic steatosis were examined.DKO mice were lean without anthropometric defects.High fat intake led to adiposity and decreased respiratory exchange ratio(RER)in wild-type(WT)mice,which were ablated in DKO but not Akt2^(-/-) and Ampkα2^(-/-) mice.High fat intake increased blood and hepatic triglycerides and cholesterol,promoted hepatic steatosis and injury in WT mice.These effects were eliminated in DKO but not Akt2^(-/-) and Ampkα2^(-/-) mice.Fat diet promoted fat accumulation,and enlarged adipocyte size,the effect was negated in DKO mice.Fat intake elevated fatty acid synthase(FAS),carbohydrate-responsive element-binding protein(CHREBP),sterol regulatory element-binding protein 1(SREBP1),peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC-1α),peroxisome proliferator-activated receptor-α(PPARα),PPARγ,stearoyl-CoA desaturase 1(SCD-1),phosphoenolpyruvate carboxykinase(PEPCK),glucose 6-phosphatase(G6Pase),and diglyceride O-acyltransferase 1(DGAT1),the effect was absent in DKO but not Akt2^(-/-) and Ampkα2^(-/-) mice.Fat diet dampened mitophagy,promoted inflammation and phosphorylation of forkhead box protein O1(FoxO1)and AMPKα1(Ser^(485)),the effects were eradicated by DKO.Deletion of Parkin effectively nullified DKO-induced metabolic benefits against high fat intake.Liver samples from obese humans displayed lowered microtubule-associated proteins 1A/1B light chain 3B(LC3B),Pink1,Parkin,as well as enhanced phosphorylation of Akt,AMPK(Ser^(485)),and FoxO1,which were consolidated by RNA sequencing(RNAseq)and mass spectrometry analyses from rodent and human livers.These data suggest that concurrent deletion of Akt2 and AMPKα2 offers resilience to fat diet-induced obesity and hepatic steatosis,possibly through preservation of Parkin-mediated mitophagy and lipid metabolism.
文摘Lipids are a large and diverse class of biomolecules that exert multiple biochemical functions,such as fueling energy production,and building blocks for plasma membrane and chemical signals during cellular communication.
基金supported by the National Natural Science Foundation of China (Grant No. 31671308)the Ministry of Science and Technology of China (Grant No. 2016YFC0900300)
文摘Micro RNAs(miRNAs) are a class of endogenous non-coding RNAs with regulatory functions. Traditionally, miRNAs are thought to play a negative regulatory role in the cytoplasm by binding to the 30 UTR of target genes to degrade m RNA or inhibit translation. However, it remains a challenge to interpret the potential function of many miRNAs located in the nucleus.Recently, we reported a new type of miRNAs present in the nucleus, which can activate gene expression by binding to the enhancer, and named them nuclear activating miRNAs(NamiRNAs). The discovery of NamiRNAs showcases a complementary regulatory mechanism of mi RNA, demonstrating their differential roles in the nucleus and cytoplasm. Here, we reviewed miRNAs in nucleus to better understand the function of NamiRNAs in their interactions with the enhancers. Accordingly, we propose a Nami RNA–enhancer–target gene activation network model to better understand the crosstalk between NamiRNAs and enhancers in regulating gene transcription.Moreover, we hypothesize that NamiRNAs may be involved in cell identity or cell fate determination during development, although further study is needed to elucidate the underlying mechanisms in detail.
基金This research was supported by National Natural Science Foundation(No.81770844,82070870 and 81170781 to H.Y.Huang).
文摘Accumulating evidence from both animal and human studies suggests that activation of beige fat increases cellular energy expenditure,ultimately reducing adiposity.Here,we report the central role of adipocyte-derived lysyl oxidase(Lox)in the formation of thermogenic beige fat.Mice exposed to cold or aβ3 agonist showed drastically lower Lox expression in thermogenically activated beige fat.Importantly,inhibition of Lox activity with BAPN stimulated biogenesis of beige fat in inguinal white adipose tissue(iWAT)under housing conditions and potentiated cold-induced adaptive thermogenesis and beiging in both iWAT and epididymal white adipose tissue(eWAT).Notably,white adipocytes with Lox repression undergo transdifferentiation into beige adipocytes which can be suppressed by tumor necrosis factor-α(TNFα)via ERK activation.This work provides new insight into the molecular control to expand beige fat by Lox inhibition and suggest the potential for utilizing inhibitor of Lox to treat the emerging epidemics of obesity and diabetes.
文摘Long noncoding RNAs(lncRNAs)are functional RNA molecules which are longer than 200 nucleotides in length that do not encode proteins;instead,they regulate target gene expression at transcriptional,posttranscriptional,and epigenetic levels.LncRNAs play important roles in various biological processes such as dosage compensation,genomic imprinting,cell cycle regulation,and cell differentiation.Although their characterizations have been relatively straightforward with recent advances in modern biology,the functions of lncRNAs are largely unknown.Herein,we discuss the biological functions and research methods of lncRNAs.
基金The work was supported by grants from National Natural Science Foundation of China(Grant Nos.31270830 and 21572038)Shanghai Association for Science and Technology(Grant No.17401930400)and Development Fund for Shanghai Talents.
文摘Dear Editor,Bladder cancer is the most common type of genitourinary cancer in China,with an estimated 80,500 new cases and 32,900 related deaths in 2015 alone(Chen et al.,2016).Unlike many other cancers,there has been no significant improvement in survival rates for bladder cancer over the last three decades.Specific treatment regimens for bladder cancer and their efficacy vary depending not only on clinical stages,but also on associated risk factors and other personal clinical characteristics.Patients with non-muscle invasive bladder cancer(NMIBC)have a high 5-year recurrence rate of 60%-70%(Berdik,2017)and those with muscle invasive bladder cancer(MIBC)has a relatively poor prognosis with approximately 65%risk of death within 5-year follow-up(Kamat et al.,2016).Therefore,there is an urgent need to develop models for bladder cancer to screen for rational treatment strategies by personalized medicine to improve the clinical assessment and treatment of bladder cancer.
基金the National Natural Science Foundation of China(32271218 to Y.X.)in part by grants from the National Natural Science Foundation of China(81670519 to J.L.)the Science and Technology Commission of Shanghai Municipality(22ZR1414300 to H.W.).
文摘Lipids and glucose exert many essential physiological functions,such as providing raw materials or energy for cellular biosynthesis,regulating cell signal transduction,and maintaining a constant body temperature.Dysregulation of lipid and glucose metabolism can lead to glucolipid metabolic disorders linked to various metabolic diseases,such as obesity,diabetes,and cardiovascular disease.Therefore,intervention in glucolipid metabolism is a key therapeutic strategy for the treatment of metabolic diseases.Activating transcription factor 3(ATF3)is a transcription factor that acts as a hub of the cellular adaptive-response network and plays a pivotal role in the regulation of inflammation,apoptosis,DNA repair,and oncogenesis.Emerging evidence has illustrated the vital roles of ATF3 in glucolipid metabolism.ATF3 inhibits intestinal lipid absorption,enhances hepatic triglyceride hydrolysis and fatty acid oxidation,promotes macrophage reverse cholesterol transport,and attenuates the progression of western diet-induced nonalcoholic fatty liver disease and atherosclerosis.In addition to its role in lipid metabolism,ATF3 has also been identified as an important regulator of glucose metabolism.Here,we summarize the recent advances in the understanding of ATF3,mainly focusing on its role in glucose and lipid metabolism and potential therapeutic implications.
基金This work was supported by the National Key Research and Development Program of China(No.2018YFC0310900)the National Natural Science Foundation of China grants(No.31270830,21572038,21877016 to Y.D,No.31671386 to Q.H,81972621 to W.J)+1 种基金the Development Fund for Shanghai Talents,Fund of State Key Laboratory of Bioorganic and Natural Products Chemistry,Fund of State Key Laboratory of Drug Research,Chinese Academy of Science(No.SIMM1601KF-08)Fudan University Graduate Student Research Grant.
文摘The CRISPR/Cas9 system,originally derived from the prokaryotic adaptive immune system,has been developed as efficient genome editing tools.It enables precise gene manipulation on chromosomal DNA through the specific binding of programmable sgRNA to target DNA,and the Cas9 protein,which has endonuclease activity,will cut a double strand break at specific locus.However,Cas9 is a foreign protein in mammalian cells,and the potential risks associated with its introduction into mammalian cells are not fully understood.In this study,we performed pull-down and mass spectrometry(MS)analysis of Streptococcus pyogenes Cas9(SpyCas9)interacting proteins in HEK293T cells and showed that the majority of Cas9-associated proteins identified by MS were localized in the nucleolus.Interestingly,we further discovered that the Cas9 protein contains a sequence encoding a nucleolus detention signal(NoDS).Compared with wild-type(WT)Cas9,NoDS-mutated variants of Cas9(mCas9)are less stable,although their gene editing activity is minimally affected.Overexpression of WT Cas9,but not mCas9,causes general effects on transcription and protein translation in the host cell.Overall,identification of NoDS in Cas9 will improve the understanding of Cas9's biological function in vivo,and the removal of NoDS in Cas9 may enhance its safety for future clinical use.
基金This work was supported by the Ministry of Science and Technology(No.2019YFA0801703)the National Natural Science Foundation of China(Nos.81790250,81790253,91959202,81902823,and 81972620)the Innovation Program of Shanghai Municipal Education Commission(No.N173606).
文摘Cancer development is a complicated process controlled by the interplay of multiple signaling pathways and restrained by oxygen and nutrient accessibility in the tumor microenvironment.High plasticity in using diverse nutrients to adapt to metabolic stress is one of the hallmarks of cancer cells.To respond to nutrient stress and to meet the requirements for rapid cell proliferation,cancer cells reprogram metabolic pathways to take up more glucose and coordinate the production of energy and intermediates for biosynthesis.Such actions involve gene expression and activity regulation by the moonlighting function of oncoproteins and metabolic enzymes.The signal−moonlighting protein−metabolism axis facilitates the adaptation of tumor cells under varying environment conditions and can be therapeutically targeted for cancer treatment.
基金We acknowledge the financial support from the National Natural Science Foundation of China(21672248 and 21621002)E-Institutes of Shanghai Municipal Education Commission(E09013)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB20020000)。
文摘Summary of main observation and conclusion OSW-1 is a well-known natural saponin with potent antitumor activities.We have designed and pre-pared a small library of 22 OSW-1 analogues with a variety of p-acylamino-benzoyl groups installed at C2"of the xylose residue,wherein a regioselective(1>3)-glycosylation of arabinoside 3,4-diol has been achieved by manipulatian of the protecting groups on the imidate donors.Bioassays lead to new structure-activity relationships as well as two aplicable fluorescent probes,which are found to localize to lysosomes in HeLa cells and could be used in further antitumor mechanism studies of OSW-1 in living cells.
基金This study was supported by the National Key Research and Development Program of China(2018YFA0800402)the National Natural Science Foundation of China(81974119,82070887 and 81900771)+2 种基金the Shanghai Outstanding Academic Leaders Projects and Basic Research of Science and Technology Innovation Action Plan by Shanghai Municipal Science and Technology Committee(21XD1423400 and 21JC1401300)Excellent Youth Cultivation Program of Shanghai Sixth People’s Hospital(ynjq202202)the Shenzhen Science and technology R&D Foundation(KCXFZ202002011010445).
文摘Nonalcoholic steatohepatitis(NASH)has emerged as a major cause of liver failure and hepatocellular carcinoma.Investigation into the molecular mechanisms that underlie steatosis-to-NASH progression is key to understanding the development of NASH pathophysiology.Here,we present comprehensive multi-omic profiles of preclinical animal models to identify genes,non-coding RNAs,proteins,and plasma metabolites involved in this progression.In particular,by transcriptomics analysis,we identified Growth Differentiation Factor 3(GDF3)as a candidate noninvasive biomarker in NASH.Plasma GDF3 levels are associated with hepatic pathological features in patients with NASH,and differences in these levels provide a high diagnostic accuracy of NASH diagnosis(AUROC=0.90;95%confidence interval:0.85−0.95)with a good sensitivity(90.7%)and specificity(86.4%).In addition,by developing integrated proteomic-metabolomic datasets and performing a subsequent pharmacological intervention in a mouse model of NASH,we show that ferroptosis may be a potential target to treat NASH.Moreover,by using competing endogenous RNAs network analysis,we found that several miRNAs,including miR-582-5p and miR-292a-3p,and lncRNAs,including XLOC-085738 and XLOC-041531,are associated with steatosis-to-NASH progression.Collectively,our data provide a valuable resource into the molecular characterization of NASH progression,leading to the novel insight that GDF3 may be a potential noninvasive diagnostic biomarker for NASH while further showing that ferroptosis is a therapeutic target for the disease.
基金supported by the National Natural Science Foundation of China(No.82073413 to S.J.)the Clinical and Research Fund of Wu Jieping Medical Foundation(No.320.6750.2020-01-12 to S.J.)+1 种基金the National Natural Science Foundation of China(No.22137002 to Y.D.)the China Postdoctoral Science Foundation(No.2020TQ0068 to J.W.).
文摘Bladder cancer(BLCA)remains a difficult malignancy to manage because of its high recurrence,intense follow-up,and invasive diagnostic and treatment techniques.Immune checkpoint inhibitors(ICIs)have forged a new direction for the treatment of BLCA,but it is currently challenging to predict whether an individual patient will be sensitive to ICIs.We collected 43 urine/tumor samples from BLCA patients for primary bladder cancer cells(BCCs)culturing using our previously reported BCC culture platform.We used flow cytometry(FCM)to measure the expression levels of Programmed Death-Ligand 1(PD-L1)on BCCs before and after interferon-gamma(IFN-γ)treatment and found that PD-L1 expression and the sensitivities to IFN-γvaried among patients.RNA-sequencing,western blotting,and programmed death-1(PD-1)binding assays confirmed that the BCC FCM-based PD-L1 detection platform(BC-PD-L1)was reliable and was not hindered by the glycosylation of PD-L1.In the subsequent retrospective study,we found that IFN-γ-stimulated PD-L1(sPD-L1)expression on BCCs detected by BC-PD-L1 could predict the prognosis of BLCA patients.Importantly,the prognostic value was similar or even better in urine-derived BC-PD-L1(UBC-PD-L1).Transcriptome analysis showed that BCCs with high sPD-L1 tended to enrich genes associated with the collagen-containing extracellular matrix,cell–cell adhesion,and positive regulation of the immune system.In addition,the UBC-PD-L1 also exhibited predictive value for ICI response in BLCA patients.In conclusion,as a novel personalized urine-detection method,UBC-PD-L1 may provide a rapid,accurate,and non-invasive tool for monitoring tumor progression,predicting therapeutic responses,and helping improve BLCA clinical treatment in future.
基金J.R.is supported by National Natural Science Foundation of China(NSFC-8182207)Shanghai Academic/Technology Research Leader(19XD1420600)Chinese Academy of Medical Sciences(2019-RC-HL_020).
文摘Kidney disease is manifested in a wide variety of phenotypes,many of which have an important hereditary component.To delineate the genotypic and phenotypic spectrum of pediatric nephropathy,a multicenter registration system is being imple-mented based on the Chinese Children Genetic Kidney Disease Database(CCGKDD).In this study,all the patients with kidney and urological diseases were recruited from 2014 to 2020.Genetic analysis was conducted using exome sequencing for families with multiple affected individuals with nephropathy or clinical suspicion of a genetic kidney disease owing to early-onset or extrarenal features.The genetic diagnosis was confirmed in 883 of 2256(39.1%)patients from 23 provinces in China.Phenotypic profiles showed that the primary diagnosis included steroid-resistant nephrotic syndrome(SRNS,23.5%),glomerulonephritis(GN,32.2%),congenital anomalies of the kidney and urinary tract(CAKUT,21.2%),cystic renal disease(3.9%),renal calcinosis/stone(3.6%),tubulopathy(9.7%),and chronic kidney disease of unknown etiology(CKDu,5.8%).The pathogenic variants of 105 monogenetic disorders were identified.Ten distinct genomic disorders were identified as pathogenic copy number variants(CNVs)in 11 patients.The diagnostic yield differed by subgroups,and was highest in those with cystic renal disease(66.3%),followed by tubulopathy(58.4%),GN(57.7%),CKDu(43.5%),SRNS(29.2%),renal calcinosis/stone(29.3%)and CAKUT(8.6%).Reverse phenotyping permitted correct identification in 40 cases with clinical reassessment and unexpected genetic conditions.We present the results of the largest cohort of children with kidney disease in China where diagnostic exome sequencing was performed.Our data demonstrate the utility of family-based exome sequencing,and indicate that the combined analysis of genotype and phenotype based on the national patient registry is pivotal to the genetic diagnosis of kidney disease.
基金supported by the National Key Research and Development Program of China(2020YFE0202200)the National Natural Science Foundation of China(31900112,21907065,31970130 and 31670831)。
文摘Protein-biomolecule interactions play pivotal roles in almost all biological processes.For a biomolecule of interest,the identification of the interacting protein(s)is essential.For this need,although many assays are available,highly robust and reliable methods are always desired.By combining a substrate-based proximity labeling activity from the pupylation pathway of Mycobacterium tuberculosis and the streptavidin(SA)-biotin system,we developed the Specific Pupylation as IDEntity Reporter(SPIDER)method for identifying protein-biomolecule interactions.Using SPIDER,we validated the interactions between the known binding proteins of protein,DNA,RNA,and small molecule.We successfully applied SPIDER to construct the global protein interactome for m^(6)A and m RNA,identified a variety of uncharacterized m^(6)A binding proteins,and validated SRSF7 as a potential m^(6)A reader.We globally identified the binding proteins for lenalidomide and Cob B.Moreover,we identified SARS-CoV-2-specific receptors on the cell membrane.Overall,SPIDER is powerful and highly accessible for the study of proteinbiomolecule interactions.
基金supported by the grants from the National Natural Science Foundation of China(No.31771451 to YL)Shanghai Municipal Science and Technology Major Project(No.2017SHZDZX01 to YL)the National Key R&D Program of China(No.2021YFC2701001 to YL).
文摘Genome-wide association studies(GWASs)have identified over 100 loci associated with rheumatoid arthritis(RA);how-ever,the functionally affected genes and the underlying molecular mechanisms contributing to these associations are often unknown.In this study,we conducted an integrative genomic analysis incorporating multiple“omics”data and identified a functional regulatory DNA variant,rs56199421,and a plausible mechanism by which it regulates the expression of a puta-tive RA risk gene,ORMDL Sphingolipid Biosynthesis Regulator 3(ORMDL3).The T allele of rs56199421,located in the enhancer region of ORMDL3,exhibited stronger direct binding ability than the other C allele of rs56199421 did in vitro with the transcription factor JunD and demonstrated higher transcriptional activity.Moreover,the T allele of rs56199421 is associated with elevated RA risk,and ORMDL3 expression is increased in RA patients.Thus,these findings suggest that the T allele of rs56199421 enhances JunD transcription factor binding,increases enhancer activity,and elevates the expression of the RA risk gene ORMDL3.
基金National Key R&D Program of China (2018YFC1706200,2018YFD1000701-4)the National Natural Science Foundation of China (31870282, 31700268 and 31788103)+2 种基金the Fund of Chinese Academy of Sciences (QYZDY-SSW-SMC026 and 153D31KYSB20160074)the Chenshan Special Fund for Shanghai Landscaping Administration Bureau Program (G182401, G172402, G182402, G192413, and G192414)the CAS/JIC and Center of Excellence for Plant and Microbial Sciences (CEPAMS) joint foundation through support to Q.Z., X.Y.C., J.Y., and C.M. Q.Z. and J.Y. were also supported by the Youth Innovation Promotion Association, Chinese Academy of Sciences.
文摘Scutellaria baicalensis Georgi is important in Chinese traditional medicine where preparations of dried roots,"Huang Qin," are used for liver and lung complaints and as complementary cancer treatments. We report a high-quality reference genome sequence for S. baicalensis where 93% of the 408.14-Mb genome has been assembled into nine pseudochromosomes with a super-N50 of 33.2 Mb. Comparison of this sequence with those of closely related species in the order Lamiales, sesamum indicum and Salvia splendens,revealed that a specialized metabolic pathway for the synthesis of 4'-deoxyflavone bioactives evolved in the genus Scu-tellaria. We found that the gene encoding a specific cinnamate coenzyme A ligase likely obtained its newfunc- tion following recent mutations, and that four genes encoding enzymes in the 4'-deoxyflavone pathway are present as tandem repeats in the genome of S. baicalensis. Further analyses revealed that gene duplications, segmental duplication, gene amplification, and point mutations coupled to gene neo- and subfunctionaliza-tions were involved in the evolution of 4'-deoxyflavone synthesis in the genus Scutellaria. Our study not only provides significant insight into the evolution of specific flavone biosynthetic pathways in the mint family, Lamiaceae, but also will facilitate the development of tools for enhancing bioactive productivity by metabolic engineering in microbes or by molecular breeding in plants. The reference genome of S. baicalensis is also useful for improving the genome assemblies for other members of the mint family and offers an important foundation for decoding the synthetic pathways of bioactive compounds in medicinal plants.