ABSTRACT
Tanshinone â ¡A (Tâ ¡A), a diterpene quinone with a furan ring, is a bioactive compound found in the medicinal herb redroot sage (Salvia miltiorrhiza Bunge), in which both furan and dihydrofuran analogs are present in abundance. Progress has been made recently in elucidating the tanshinone biosynthetic pathway, including heterocyclization of the dihydrofuran D-ring by cytochrome P450s; however, dehydrogenation of dihydrofuran to furan, a key step of furan ring formation, remains uncharacterized. Here, by differential transcriptome mining, we identified six 2-oxoglutarate-dependent dioxygenase (2-ODD) genes whose expressions corresponded to tanshinone biosynthesis. We showed that Sm2-ODD14 acts as a dehydrogenase catalyzing the furan ring aromatization. In vitro Sm2-ODD14 converted cryptotanshinone to Tâ ¡A and thus was designated Tâ ¡A synthase (SmTâ ¡AS). Furthermore, SmTâ ¡AS showed a strict substrate specificity, and repression of SmTâ ¡AS expression in hairy root by RNAi led to increased accumulation of total dihydrofuran-tanshinones and decreased production of furan-tanshinones. We conclude that SmTâ ¡AS controls the metabolite flux from dihydrofuran- to furan-tanshinones, which influences medicinal properties of S. miltiorrhiza.
Subject(s)
Dioxygenases/genetics , Dioxygenases/metabolism , Diterpenes/metabolism , Furans/metabolism , Plants, Medicinal/metabolism , Salvia miltiorrhiza/genetics , Salvia miltiorrhiza/metabolism , Biosynthetic Pathways , Gene Expression Regulation, Plant , Genes, Plant , Plant Roots/metabolismABSTRACT
Coenzyme Q (CoQ) is vital for energy metabolism in living organisms. In humans, CoQ10 deficiency causes diseases and must be replenished via diet; however, CoQ content in plant foods is primarily low. Here, we report the breeding of high CoQ10 tomato lines by expressing four enzymes with a fruit-specific promoter, which modifies the chloroplast chorismate pathway, enhances cytosolic isoprenoid biosynthesis, and up-regulates the first two reactions in mitochondrion that construct the CoQ10 polyisoprenoid tail. We show that, while the level of the aromatic precursor could be markedly elevated, head group prenylation is the key to increasing the final CoQ10 yield. In the HUCD lines expressing all four transgenes, the highest CoQ10 content (0.15 mg/g dry weight) shows a seven-fold increase from the wild-type level and reaches an extraordinarily rich CoQ10 food grade. Overviewing the changes in other terpenoids by transcriptome and metabolic analyses reveals variable contents of carotenoids and α-tocopherol in the HUCD lines. In addition to the enigmatic relations among different terpenoid pathways, high CoQ10 plants maintaining substantial levels of either vitamin can be selected. Our investigation paves the way for the development of CoQ10-enriched crops as dietary supplements.
Subject(s)
Solanum lycopersicum , Ubiquinone , Carotenoids/metabolism , Fruit/metabolism , Humans , Solanum lycopersicum/genetics , Mitochondria , Ubiquinone/geneticsABSTRACT
The spiro scaffold chiral organocatalyst of 3,2'-pyrrolidinyl spiro-oxindole amine was successfully prepared from racemic spiro-oxindole amine using l-menthol as a chiral pool in 4 steps in 28%-40% overall yields with at least 99% ee in scale-up preparation, and its catalytic activity was evaluated in the enantioselective aldol condensation between 3-(3-hydroxy-1H-pyrazol-1-yl)-oxindole and paraformaldehyde. The spiro organocatalyst showed superior catalytic activity and selectivity compared with its counterparts, and most substrates offered good to excellent results with up to 96% yield in 96% ee.
Subject(s)
Spiro Compounds , Aldehydes , Amines , Formaldehyde , Indoles , Molecular Structure , Oxindoles , Polymers , StereoisomerismABSTRACT
A bifunctional cinchona squaramide catalyzed enantioselective aza-Friedel-Crafts reaction between 2-naphthols and benzothiazolimines has been developed, and a series of chiral 2'-aminobenzothiazolomethyl naphthols with potential antiproliferative and anthelmintic activities have been successfully and effectively prepared in good to excellent yields (up to 98%) with excellent enantioselectivities (up to >99% ee) even in a scale-up preparation under mild conditions.
ABSTRACT
An abnormal [3 + 2]-cycloaddition and highly effective and convenient one-step preparation of tetracyclic bispirooxindoles containing two all-carbon quaternary spirocenters from isatin N,N'-cyclic azomethine imine 1,3-dipole and 3-methyleneoxindole in the presence of catalytic organic base has been disclosed. A variety of bispirooxindoles bearing a dinitrogen heterocycle with four adjacent cycles have been obtained in excellent yields (up to 95%) and diastereoselectivities (>99:1) under mild conditions.
ABSTRACT
A new enantioselective Michael addition between 3-(3-hydroxy-1H-pyrazol-1-yl)oxindole, a new synthon generated from isatin N,N'-cyclic azomethine imine 1,3-dipole, and ß-nitrostyrene has been disclosed. A series of chiral 3-(3-oxo-2,3-dihydro-1H-pyrazol-1-yl) disubstituted oxindoles were obtained in excellent results (up to 97% yield, up to 94% ee) with moderate to good diastereoselectivities (up to 4.3:1 dr).
ABSTRACT
A new base promoted Michael-Michael domino cycloaddition between isoindigos and α-alkylidene succinimides has been developed for highly efficient and one-step convenient preparation of highly steric bispiroxindoles with two adjacent quaternary carbon centers and four consecutive cycles in excellent yields (up to 96%) and diastereoselectivities (up to >20 : 1) under mild conditions within a few minutes. A series of bisprooxindoles were obtained and the synthetic potential of the protocol was evaluated in a scale-up preparation.
ABSTRACT
Objective To explore the associations of non-alcoholic fatty liver disease(NAFLD)with the prevalence,severity,and prognosis of coronary heart disease(CHD). Methods A total of 512 hospitalized patients undergoing coronary angiography in our department from June 2013 to June 2015 were enrolled.Fatty liver was judged by ultrasound screening,and Gensini score was calculated according to the result of coronary angiography.Then the independent predictors of CHD were analyzed.The association between NAFLD and cardiovascular endpoints was analyzed during prospective follow-up among 276 CHD patients. Results The CHD prevalence was 76.8% in NAFLD group and 50.7% in non-NAFLD group(P=0.000),the number of target vessels was 2(1,3)and 1(1,3)(P=0.019),and the Gensini score was(29.02±27.62)and(24.04±20.18)(P=0.022),respectively.NAFLD was an independent predictor of CHD(OR=2.28,95%CI=1.54-3.56,P<0.001).The risk of cardiovascular endpoints was not significantly different between NAFLD group and non-NAFLD group(P>0.1).Cox regression analysis showed that NAFLD was not a predictor of cardiovascular endpoints in patients with CHD(HR=0.95,95%CI=0.62-1.58,P=0.691).Conclusion NAFLD is an independent predictor of CHD,and it is related to severity of coronary artery stenosis.However,it can not predict the clinical outcomes of patients with CHD.
Subject(s)
Coronary Disease/complications , Non-alcoholic Fatty Liver Disease/complications , Coronary Angiography , Humans , Prevalence , Prognosis , Prospective Studies , Risk FactorsABSTRACT
Objective To explore the relationship between serum uric acid (SUA) level and coronary heart disease(CHD) in male and female patients. Methods A total of 760 hospitalized patients undergoing coronary angiography in our department from June 2013 to June 2017 were enrolled. Gensini score was calculated according to the result of coronary angiography,and SUA was tested.Patients were divided according to SUA quartiles. The relationship between SUA level and the prevalence of CHD in male and female patients was analyzed. Results Among females,there was significant difference in SUA level between patients with and without CHD (t=4.415,P=0.000). Univariate logistic regression analysis showed that SUA level was independently associated with CHD (OR=1.32,95%CI:1.12-1.58,P=0.002). The prevalence of CHD was 31.2%,52.6%,47.4%,and 59.7%,respectively,in four quartile groups (χ2=13.652,P=0.003);in addition,female patients displayed significantly higher prevalence of CHD in the quartile 2 (P=0.007),3(P=0.038),and 4(P=0.000) groups than in quartile 1 group. Among female patients with CHD,there were significant differences in number of target vessels (Z=4.627,P=0.008),number of lesion vessels (χ2=18.522,P=0.005),and Gensini score (Z=3.683,P=0.029) in four groups. The Gensini scores of coronary artery were significantly higher in the quartile 4 group than in quartile 1 (P=0.012) and 2 (P=0.014) groups. Multiple linear regression analysis showed that there was a dose-response relationship between SUA level and Gensini score (B=1.105,SE=0.365,P=0.003). Among males,however,there was no significant difference in SUA level between patients with and without CHD(t=1.271,P=0.205). The prevalence of CHD in four quartile groups was 77.9%,69.0%,61.7%,and 79.6%,respectively,showing no significant difference(χ2=4.514,P=0.211). Conclusion sSUA is an independent risk fact for female CHD patients. High SUA level is correlated with severity of CHD only in women.
Subject(s)
Coronary Disease/blood , Uric Acid/blood , Coronary Angiography , Coronary Vessels/pathology , Female , Humans , Male , Prevalence , Risk FactorsABSTRACT
Objective To investigate the correlation between CYP2C19 gene polymorphism and elderly cerebral infarction.Methods Two polymorphisms including rs4244285 and rs4986893 of the CYP2C19 gene were detected by gene chip technology in 72 elderly patients with acute cerebral infarction (stroke group) and 77 otherwise healthy controls. The clinical data and the polymorphism distribution of CYP2C19 were compared,and the potential association between genetic polymorphism and cerebral infarction was analyzed by Logistic regression.Results The frequencies of rs4244285 GG (45.83% vs. 63.64%,Χ 2=4.766,P=0.029) and rs4244285 A allele (34.03% vs. 22.73%,Χ 2=4.695,P=0.030) were significantly higher in stroke group than in control group. There were no significant differences in the distribution of the alleles of rs4986893 or the rs4244285 GA and AA between these two groups (all P>0.05). After the conventional cerebrovascular risk factors including gender,age,body mass index,smoking,and total cholesterol were adjusted,Logistic regression analysis showed that rs4244285 A allele significantly increased the stroke risk [the additive model AA vs. GG:OR=2.564,95%CI=1.181-5.566,P=0.017;the dominant model AA/AG vs. GG:OR=2.763,95%CI=1.343-5.685,P=0.006].Conclusion CYP2C19 genetic polymorphism may be associated with the increased risk of cerebral infarction in the elderly,although future well-designed studies with larger sample sizes are warranted.
Subject(s)
Cerebral Infarction/genetics , Cytochrome P-450 CYP2C19/genetics , Aged , Alleles , Brain Ischemia/genetics , Case-Control Studies , Gene Frequency , Genetic Predisposition to Disease , Genotype , Humans , Polymorphism, Single Nucleotide , Stroke/geneticsABSTRACT
Host reproduction can be manipulated by bacterial symbionts in various ways. Parthenogenesis induction is the most effective type of reproduction manipulation by symbionts for their transmission. Insect sex is determined by regulation of doublesex (dsx) splicing through transformer2 (tra2) and transformer (tra) interaction. Although parthenogenesis induction by symbionts has been studied since the 1970s, its underlying molecular mechanism is unknown. Here we identify a Wolbachia parthenogenesis-induction feminization factor gene (piff) that targets sex-determining genes and causes female-producing parthenogenesis in the haplodiploid parasitoid Encarsia formosa. We found that Wolbachia elimination repressed expression of female-specific dsx and enhanced expression of male-specific dsx, which led to the production of wasp haploid male offspring. Furthermore, we found that E. formosa tra is truncated and non-functional, and Wolbachia has a functional tra homolog, termed piff, with an insect origin. Wolbachia PIFF can colocalize and interact with wasp TRA2. Moreover, Wolbachia piff has coordinated expression with tra2 and dsx of E. formosa. Our results demonstrate the bacterial symbiont Wolbachia has acquired an insect gene to manipulate the host sex determination cascade and induce parthenogenesis in wasps. This study reveals insect-to-bacteria horizontal gene transfer drives the evolution of animal sex determination systems, elucidating a striking mechanism of insect-microbe symbiosis.
Subject(s)
Gene Transfer, Horizontal , Symbiosis , Wasps , Wolbachia , Animals , Wolbachia/physiology , Wolbachia/genetics , Wasps/physiology , Wasps/microbiology , Wasps/genetics , Symbiosis/genetics , Female , Male , Parthenogenesis/genetics , Insect Proteins/genetics , Insect Proteins/metabolism , Sex Determination Processes/geneticsABSTRACT
Prostate cancer (PCa) is one of the most common malignancies in men; recently, PCa-related mortality has increased worldwide. Although androgen deprivation therapy (ADT) is the standard treatment for PCa, patients often develop aggressive castration-resistant PCa (CRPC), indicating the presence of an alternative source of androgen. Clostridium scindens is a member of the gut microbiota and can convert cortisol to 11ß-hydroxyandrostenedione (11ß-OHA), which is a potent androgen precursor. However, the effect of C. scindens on PCa progression has not been determined. In this study, androgen-dependent PCa cells (LNCaP) were employed to investigate whether C. scindens-derived metabolites activate androgen receptor (AR), which is a pivotal step in the development of PCa. Results showed that cortisol metabolites derived from C. scindens-conditioned medium promoted proliferation and enhanced migration of PCa cells. Furthermore, cells treated with these metabolites presented activated AR and stimulated AR-regulated genes. These findings reveal that C. scindens has the potential to promote PCa progression via the activation of AR signaling. Further studies on the gut-prostate axis may help unravel an alternative source of androgen that triggers CRPC exacerbation.
Subject(s)
Prostatic Neoplasms, Castration-Resistant , Receptors, Androgen , Male , Humans , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Prostate/metabolism , Androgens/metabolism , Androgens/pharmacology , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/metabolism , Androgen Antagonists/metabolism , Androgen Antagonists/pharmacology , Hydrocortisone/metabolism , Hydrocortisone/pharmacology , Cell Line, TumorABSTRACT
BACKGROUND: Dyspnea is one of the most common symptoms of chronic respiratory disease (CRD) and is closely related to increased functional disability and mortality, resulting in substantial adverse outcomes on patients and imposing great social and economic burden. Although multiple clinical trials and systematic reviews have suggested that acupuncture could be effective in treating COPD and lung cancer, little is known about its effects on dyspnea relief in patients with CRD. The present study aimed to use a systematic review approach to evaluate the effectiveness and safety of acupuncture in the treatment of dyspnea in patients with CRD. METHODS: We will search the following 9 databases from inception to June 30, 2022, PubMed, Web of Science, EMBASE, Cochrane Central Register of Controlled Trials, Chinese National Knowledge Infrastructure, WANFANG Database, Chinses Scientific and Technological Periodical Database, and Chinese Biomedical Database, and the Cochrane Library Database. Clinical randomized controlled trials in English or Chinese that evaluate invasive acupuncture versus control group in treatment of CRD with dyspnea will be included. The primary outcome will be dyspnea scores, breathing physiological function, and the secondary outcomes include exercise tolerance by six-minute walk distance quality of life, quality of life and adverse events. Two reviewers will independently conduct study selection, data extraction and quality assessment. The Review Manager software will be used for meta-analysis. This protocol will be carried out in accordance with the PRISMA-P guidance. CONCLUSION: This systematic review and meta-analysis will provide the evidence of whether acupuncture is an effective and safe intervention for CRD with dyspnea. The results will be disseminated through peer-reviewed publication.
Subject(s)
Acupuncture Therapy , Quality of Life , Acupuncture Therapy/methods , Dyspnea/etiology , Dyspnea/therapy , Humans , Meta-Analysis as Topic , Randomized Controlled Trials as Topic , Research Design , Systematic Reviews as TopicABSTRACT
The widely cultivated medicinal and ornamental plant sage (Salvia officinalis L.) is an evergreen shrub of the Lamiaceae family, native to the Mediterranean. We assembled a high-quality sage genome of 480 Mb on seven chromosomes, and identified a biosynthetic gene cluster (BGC) encoding two pairs of diterpene synthases (diTPSs) that, together with the cytochromes P450 (CYPs) genes located inside and outside the cluster, form two expression cascades responsible for the shoot and root diterpenoids, respectively, thus extending BGC functionality from co-regulation to orchestrating metabolite production in different organs. Phylogenomic analysis indicates that the Salvia clades diverged in the early Miocene. In East Asia, most Salvia species are herbaceous and accumulate diterpenoids in storage roots. Notably, in Chinese sage S. miltiorrhiza, the diterpene BGC has contracted and the shoot cascade has been lost. Our data provide genomic insights of micro-evolution of growth type-associated patterning of specialized metabolite production in plants.
Subject(s)
Diterpenes , Salvia , Multigene Family , Phylogeny , Plants/genetics , Salvia/genetics , Salvia/metabolismABSTRACT
A new and crucial synthon of 3-((diphenylmethylene)-amino)-oxindole was designed and synthesized, for which an organocatalytic and enantioselective Michael/cyclization reaction with a terminal vinyl ketone catalyzed by a cinchona base was disclosed. A wide variety (28 examples) of almost all new chiral spiro[oxindol-3,2'-pyrrols] were prepared in excellent yields (up to 99%) with excellent enantioselectivities (95-99% ee), of which a typical chiral spiro product was further reduced to chiral spiro[oxindole-3,2'-pyrrolidine].
Subject(s)
Cinchona/chemistry , Oxindoles/chemistry , Schiff Bases/chemistry , Spiro Compounds/chemistry , Cyclization , Ketones/chemistry , Molecular Structure , StereoisomerismABSTRACT
Coenzyme Q (CoQ) is an electron transporter in the mitochondrial respiratory chain, yet the biosynthetic pathway in eukaryotes remains only partially resolved. C6-hydroxylation completes the benzoquinone ring full substitution, a hallmark of CoQ. Here, we show that plants use a unique flavin-dependent monooxygenase (CoqF), instead of di-iron enzyme (Coq7) operating in animals and fungi, as a C6-hydroxylase. CoqF evolved early in eukaryotes and became widely distributed in photosynthetic and related organisms ranging from plants, algae, apicomplexans, and euglenids. Independent alternative gene losses in different groups and lateral gene transfer have ramified CoqF across the eukaryotic tree with predominance in green lineages. The exclusive presence of CoqF in Streptophyta hints at an association of the flavoenzyme with photoautotrophy in terrestrial environments. CoqF provides a phylogenetic marker distinguishing eukaryotes and represents a previously unknown target for drug design against parasitic protists.
ABSTRACT
The tyrosine metabolism pathway serves as a starting point for the production of a variety of structurally diverse natural compounds in plants, such as tocopherols, plastoquinone, ubiquinone, betalains, salidroside, benzylisoquinoline alkaloids, and so on. Among these, tyrosine-derived metabolites, tocopherols, plastoquinone, and ubiquinone are essential to plant survival. In addition, this pathway provides us essential micronutrients (e.g., vitamin E and ubiquinone) and medicine (e.g., morphine, salidroside, and salvianolic acid B). However, our knowledge of the plant tyrosine metabolism pathway remains rudimentary, and genes encoding the pathway enzymes have not been fully defined. In this review, we summarize and discuss recent advances in the tyrosine metabolism pathway, key enzymes, and important tyrosine-derived metabolites in plants.
ABSTRACT
A cinchona alkaloid squaramide promoted enantioselective [4+2] cyclization between hydroxymaleimides and ortho-hydroxyphenyl p-QMs has been disclosed, and a wide range of chiral hemiketals containing chromane and succinimide frameworks with two adjacent quaternary stereogenic centers have been prepared for the first time with excellent results (up to 99% yield, up to 99 : 1 dr, up to >99% ee) under mild conditions.
ABSTRACT
Helicobacter pylori infection is associated with several gastrointestinal diseases, including gastritis, peptic ulcer, and gastrointestinal adenocarcinoma. Two major cytotoxins, vacuolating cytotoxin A (VacA) and cytotoxin-associated gene A (CagA), interact closely with lipid rafts, contributing to H. pylori-associated disease progression. The Campylobacter jejuni cytolethal distending toxin consists of three subunits: CdtA, CdtB, and CdtC. Among them, CdtA and CdtC bind to membrane lipid rafts, which is crucial for CdtB entry into cells. In this study, we employed recombinant CdtC (rCdtC) to antagonize the functions of H. pylori cytotoxin in cells. Our results showed that rCdtC alleviates cell vacuolation induced by H. pylori VacA. Furthermore, rCdtC reduces H. pylori CagA translocation, which decreases nuclear factor kappa-B activation and interleukin-8 production, resulting in the mitigation of gastric epithelial cell inflammation. These results reveal that CdtC hijacks cholesterol to compete for H. pylori cytotoxin actions via lipid rafts, ameliorating H. pylori-induced pathogenesis.
ABSTRACT
BACKGROUND: Chinese herbal medicine (CHM) has been shown to be effective in the treatment of stable chronic obstructive pulmonary disease (COPD) by published meta-analyses. However, disease outcomes were inconsistent and heterogeneity was observed attributed to placebo-controlled studies. We present a protocol for a systematic review aiming to evaluate the clinical efficacy and safety of CHM comparing to placebo in the treatment of stable COPD, to provide robust evidence for the use of CHM in COPD. METHODS: We will comprehensively search the following 9 databases from inception to March 2019: Web of Science, PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Chinese National Knowledge Infrastructure (CNKI), WANFANG Database, Chinese Scientific and Technological Periodical Database (VIP) and Chinese Biomedical Database (CBM), and the Cochrane Library database. All clinical randomized controlled trials comparing CHM to placebo for the treatment of stable COPD in English or Chinese will be included. The primary outcome will be quality of life, symptom score and exacerbation frequency, and the secondary outcomes include traditional Chinese medicine syndrome score and effective rate, lung function, 6-minute walk distance, and adverse events. Data extraction and quality assessment will be performed independently by 2 reviewers. Data synthesis and risk of bias will be assessed using the Review Manager software. This protocol will be conducted according to the Preferred Reporting Item for Systematic Review and Meta-analysis Protocols (PRISMA-P) guidance. RESULTS: This systematic review and meta-analysis will provide a high-quality comprehensive evaluation of the efficacy and safety based on current literature evidence of CHM intervention for stable COPD. CONCLUSION: The conclusion of this study will present the evidence of whether CHM is an effective and safe intervention for stable COPD patients.