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1.
Plant Physiol ; 2020 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-32245790

RESUMO

The plant hormone jasmonate (JA) promotes resistance to biotic stress by stimulating the degradation of JASMONATE ZIM-DOMAIN (JAZ) proteins, which relieves repression on MYC transcription factors that execute defense programs. JA-triggered depletion of JAZ proteins in Arabidopsis thaliana is also associated with reduced growth and seed production, but the mechanisms underlying these pleiotropic growth effects remain unclear. Here, we investigated this question using an Arabidopsis JAZ-deficient mutant (jazD; jaz1/2/3/4/5/6/7/9/10/13) that exhibits high levels of defense and strong growth inhibition. Genetic suppressor screens for mutations that uncouple growth-defense tradeoffs in the jazD mutant identified nine independent causal mutations in the red-light receptor phytochrome B (phyB). Unlike the ability of the phyB mutations to completely uncouple the mild growth-defense phenotypes in a jaz mutant (jazQ) defective in JAZ1/3/4/9/10, phyB null alleles only weakly alleviated the growth and reproductive defects in the jazD mutant. phyB-independent growth restriction of the jazD mutant was tightly correlated with upregulation of the tryptophan biosynthetic pathway but not changes in central carbon metabolism. Interestingly, jazD and jazD phyB plants were insensitive to a chemical inhibitor of tryptophan biosynthesis, which is a phenotype previously observed in plants expressing hyperactive MYC transcription factors that cannot bind JAZ repressors. These data provide evidence that the mechanisms underlying the JA-mediated growth-defense balance depend on the level of defense, and further establish an association between growth inhibition at high levels of defense and dysregulation of tryptophan biosynthesis.

2.
Acta Cir Bras ; 35(1): e202000105, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32215465

RESUMO

PURPOSE: To investigate whether heat shock protein 90 (HSP90) is involved in complement regulation in ischemic postconditioning (IPC). METHODS: The left coronary artery of rats underwent 30 min of occlusion, followed by 120 min of reperfusion and treatment with IPC via 3 cycles of 30s reperfusion and 30s occlusion. The rats were injected intraperitoneally with 1 mg/kg HSP90 inhibitor geldanamycin (GA) after anesthesia. Eighty rats were randomly divided into four groups: sham, ischemia-reperfusion (I/R), IPC and IPC + GA. Myocardial infarct size, apoptosis index and the expression of HSP90, C3, C5a, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1ß and c-Jun N-terminal kinase (JNK) were assessed. RESULTS: Compared with the I/R injury, the IPC treatment significantly reduced infarct size, release of troponin T, creatine kinase-MB, and lactate dehydrogenase, and cardiomyocyte apoptosis. These beneficial effects were accompanied by a decrease in TNF-α, IL-1ß, C3, C5a and JNK expression levels. However, all these effects were abrogated by administration of the HSP90 inhibitor GA. CONCLUSION: HSP90 exerts a profound effect on IPC cardioprotection, and may be linked to the inhibition of the complement system and JNK, ultimately attenuating I/R-induced myocardial injury and apoptosis.

3.
Microb Pathog ; 142: 104104, 2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32120004

RESUMO

Patients with inflammation in the terminal ileum have high morbidity. In genetically susceptible hosts, chronic intestinal inflammation targeting the resident intestinal microbiota develops, but the microbial signature of the terminal ileum is poorly studied. To improve understanding of the mechanisms underlying the high prevalence of terminal ileum inflammation, we used 16S rRNA sequencing to analyse the mucosa-associated microbiota of the terminal ileum under intestinal homeostasis and inflammation conditions. Mucosal biopsy is the most commonly used sampling technique for assessing microbial communities associated with the intestinal mucosa. Thirty patients (15 with terminal ileum inflammation and 15 controls) underwent colonoscopy and biopsies were taken from the terminal ileum. Diagnosis depended on a combination of endoscopic and histological factors. To determine the composition and diversity of the microbiota, the 16S rRNA was analysed, and a variety of bioinformatics analyses were performed. Among the patients, composition analysis showed that the most abundant phyla identified in the terminal ileum samples were Fusobacteria, Proteobacteria, Firmicutes, Bacteroidetes, and Actinobacteria. At the phylum level, the relative proportion of Bacteroidetes was lower in patients with inflammation than in control patients. In addition, there was an increase in the abundance of the phyla Proteobacteria and Lentisphaerae in patients with inflammation. The abundances of the dominant microbes in the terminal ileum were not significantly different between patients in an inflammatory state and controls. These results confirm that partial dysbiosis of the intestinal mucosa-associated microbiota composition is associated with terminal ileum inflammation.

4.
J Org Chem ; 85(7): 4740-4752, 2020 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-32162916

RESUMO

A highly regioselective approach to access amide enol carbamates and carbonates 5a-5c', 7a-7h, and 9 was developed through Cu(OTf)2-catalyzed reactions of ynamides 4 with t-butyl carbamates 2 and 8 and t-butyl carbonates 6. Moreover, this strategy was successfully applied to generate amide enol carbamates 11a-11s and 14a-14f from imides 10 and 13 with ynamides through an N-Boc cleavage-addition ring-opening process. A range of substituents was amenable to this transformation, and the desired amide enol carbamates and carbonates were obtained in moderate to good yields.

5.
Cancer Cell ; 37(3): 387-402.e7, 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32142667

RESUMO

We report that neurofibromin, a tumor suppressor and Ras-GAP (GTPase-activating protein), is also an estrogen receptor-α (ER) transcriptional co-repressor through leucine/isoleucine-rich motifs that are functionally independent of GAP activity. GAP activity, in turn, does not affect ER binding. Consequently, neurofibromin depletion causes estradiol hypersensitivity and tamoxifen agonism, explaining the poor prognosis associated with neurofibromin loss in endocrine therapy-treated ER+ breast cancer. Neurofibromin-deficient ER+ breast cancer cells initially retain sensitivity to selective ER degraders (SERDs). However, Ras activation does play a role in acquired SERD resistance, which can be reversed upon MEK inhibitor addition, and SERD/MEK inhibitor combinations induce tumor regression. Thus, neurofibromin is a dual repressor for both Ras and ER signaling, and co-targeting may treat neurofibromin-deficient ER+ breast tumors.

6.
Metab Eng ; 59: 119-130, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32119929

RESUMO

Polyhydroxyalkanoates (PHA) have found widespread medical applications due to their biocompatibility and biodegradability, while further chemical modification requires functional groups on PHA. Halomonas bluephagenesis, a non-model halophilic bacterium serving as a chassis for the Next Generation Industrial Biotechnology (NGIB), was successfully engineered to express heterologous PHA synthase (PhaC) and enoyl coenzyme-A hydratase (PhaJ) from Aeromonas hydrophila 4AK4, along with a deletion of its native phaC gene to synthesize the short chain-co-medium chain-length PHA copolymers, namely poly(3-hydroxybutyrate-co-3-hydroxyhexanoate), poly(3-hydroxybutyrate-co-3-hydroxyhex-5-enoate) and poly(3-hydroxybutyrate-co-3-hydroxyhexanoate-co-3-hydroxyhex-5-enoate). After optimizations of the expression cassette and ribosomal binding site combined with introduction of endogenous acyl-CoA synthetase (fadD), the resulting recombinant strain H. bluephagenesis TDR4 achieved a remarkably high 3-hydroxyhexenoate (3HHxE) molar ratio of 35% when grown on glucose and 5-hexenoic acid as co-substrates. The total ratio of side chain consisting of 3HHx and 3HHxE monomers in the terpolymer can approach 44 mol%. H. bluephagenesis TDR4 was grown to a cell dry mass (CDM) of 30 g/L containing approximately 20% poly(3-hydroxybutyrate-co-22.75 mol% 3-hydroxy-5-hexenoate) in a 48-h of open and unsterile fermentation with a 5-hexenoic acid conversion efficiency of 91%. The resulted functional PHA containing 12.5 mol% 3-hydroxy-5-hexenoate exhibits more than 1000% elongation at break. The engineered H. bluephagenesis TDR4 can be used as an experimental platform to produce functional PHA.

7.
Bioorg Med Chem Lett ; 30(9): 127097, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32171616

RESUMO

A series of novel rutaecarpine derivatives were synthesized and subjected to pharmacological evaluation as PDE5 inhibitors. The structure-activity relationships were discussed and their binding conformation and simultaneous interaction mode were further clarified by the molecular docking studies. Among the 25 analogues, compound 8i exhibited most potent PDE5 inhibition with IC50 values about 0.086 µM. Moreover, it also produced good effects against scopolamine-induced cognitive impairment in vivo. These results might bring significant instruction for further development of potential PDE5 inhibitors derived from rutaecarpine as a good candidate drug for the treatment of Alzheimer's disease.

8.
Endocrine ; 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32189188

RESUMO

OBJECTIVE: Distant metastases are rarely observed in patients with initial pathologically proven benign follicular nodules of the thyroid. This study aimed to evaluate the clinicopathological features and independent variables associated with survival in such patients with distant metastases. METHODS: In total, 10,992 consecutive differentiated thyroid cancer (DTC) patients treated with 131I after total or near-total thyroidectomy from 2000 to 2018 were retrospectively reviewed. RESULTS: Thirty-nine patients with initial pathologically proven benign follicular nodules of the thyroid were enrolled. Among them, 26 were pathologically diagnosed as thyroid adenoma, 8 as benign nodular goiter, 4 as thyroid adenoma combined with benign nodular goiter, and 1 as normal thyroid tissue. Of 26 patients with the initial pathological slides obtained, eight cases were rediagnosed as minimally invasive thyroid carcinoma (MI-FTC), 10 as follicular tumor of uncertain malignant potential (FT-UMP), and five as well-differentiated tumor of UMP (WDT-UMP). Monitoring of thyroglobulin (Tg) changes after initial thyroidectomy and preablation-stimulated Tg (psTg) level were significantly associated with 5-year OS rate (P = 0.007 and P = 0.005, respectively). The presence of radioactive-refractory DTC (RR-DTC), monitoring of Tg changes after initial thyroidectomy, and psTg level had significant effects on 10-year OS rate (P = 0.002, P < 0.001, and P = 0.005, respectively). Lack of monitoring of Tg changes after initial thyroidectomy and RR-DTC were independent factors associated with poor prognosis (P = 0.003 and P = 0.008, respectively). CONCLUSIONS: MI-FTC, FT-UMP, and WDT-UMP tended to be ignored and/or misdiagnosed as benign follicular lesions. Lack of monitoring of Tg changes after initial thyroidectomy and the presence of RR-DTC were identified as independent factors associated with poor survival.

9.
Crit Care Med ; 48(4): 451-458, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32205590

RESUMO

OBJECTIVES: To evaluate the prevalence of cardiac injury and its association with mortality in hospitalized patients infected with avian influenza A (H7N9) virus. DESIGN: Retrospective cohort study. SETTING: A total of 133 hospitals in 17 provinces, autonomous regions, and municipalities of mainland China that admitted influenza A (H7N9) virus-infected patients between January 22, 2015, and June 16, 2017. PATIENTS: A total of 321 patients with influenza A (H7N9) virus infection were included in the final analysis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographics and clinical characteristics were collected from medical records. Cardiac injury was defined according to cardiac biomarkers, electrocardiography, or echocardiography. Among the 321 patients, 203 (63.2%) showed evidence of cardiac injury. Compared with the uninjured group, the cardiac injury group had lower PaO2/FIO2 (median, 102.0 vs 148.4 mm Hg; p < 0.001), higher Acute Physiology and Chronic Health Evaluation II score (median, 17.0 vs 11.0; p < 0.001), longer stay in the ICU (10.0 vs 9.0 d; p = 0.029), and higher proportion of in-hospital death (64.0% vs 20.3%; p < 0.001). The proportion of virus clearance until discharge or death was lower in the cardiac injury group than in the uninjured group (58.6% vs 86.4%; p < 0.001). Multivariable-adjusted Cox proportional hazards regression analysis showed that cardiac injury was associated with higher mortality (hazards ratio, 2.06; 95% CI, 1.31-3.24) during hospitalization. CONCLUSIONS: Cardiac injury is a frequent condition among hospitalized patients infected with influenza A (H7N9) virus, and it is associated with higher risk of mortality.

10.
Mol Brain ; 13(1): 44, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32197621

RESUMO

AIM: A hallmark of classical conditioning is that conditioned stimulus (CS) must be tightly coupled with unconditioned stimulus (US), often requiring temporal overlap between the two, or a short gap of several seconds. In this study, we investigate the temporal requirements for fear conditioning association between a strong artificial CS, high-frequency optogenetic activation of inputs into the lateral amygdala of rats, and a foot-shock to the animal with delays up to many minutes. METHODS: AAV-oChIEF-tdTomato viruses were injected into the auditory cortex and the medial geniculate nucleus of rats. An optical fiber was implanted just above the lateral amygdala of the animal. Optogenetic high-frequency stimuli (oHFS; containing five 1-s trains of 100 Hz laser pulses) were delivered to the lateral amygdala, before or after (with varying intervals) a foot-shock that elicits fear responses in the animal. Pre-trained lever-press behavior was used to assess the degree of fear recall by optogenetic test stimuli (OTS; 10 Hz for 2 min) 24 h after the association experiment. RESULTS: In contrast to the tight temporal requirement for classical conditioning with paired optogenetic moderate-frequency stimuli (oMFS; 10 Hz for 20 s) and foot-shock, oHFS followed by foot-shock with a 5-min or even 1-h (but not 3-h) interval could successfully establish an association to be recalled by OTS the next day. Meanwhile, foot-shock followed by oHFS with a 5-min (but not 1-h) interval could also establish the conditioning. Thus, distant association may be formed between temporally distant stimuli when the CS is strong.

11.
iScience ; 23(3): 100966, 2020 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-32199292

RESUMO

The Suzuki-Miyaura coupling is a fundamentally important transformation in modern organic synthesis. The development of new reaction modes for new chemical accessibility and higher synthetic efficiency is still the consistent pursuance in this field. An efficient Suzuki-Miyaura coupling enabled by a controllable 1,4-palladium migration was realized to afford stereodefined multisubstituted olefins and 1,3-dienes. The reaction exhibits remarkable broad substrate scope, excellent functional-group tolerance, versatile conversion with obtained products, and easy scalability. The practicality of this method is highlighted by the aggregation-induced emission feature of the produced olefins and 1,3-dienes, as well as the capability of affording geometric isomer pairs with a marked difference on photoluminescent quantum yield values.

12.
Chem Commun (Camb) ; 2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-32211708

RESUMO

The synthesis of vinyl sulfones via silver-promoted cross-coupling of vinyl bromides with sulfonyl hydrazides was realized. Water was used as the sole solvent. Multisubstituted vinyl sulfones were easily prepared with excellent alkyl group tolerance. A mechanism involving nucleophilic attack of a sulfinate anion was proposed.

13.
Artigo em Inglês | MEDLINE | ID: mdl-32129850

RESUMO

AIMS: To investigate the effects of aspirin-omitted dual antithrombotic therapy on myocardial infarction and stent thrombosis in nonvalvular atrial fibrillation (NVAF) patients presenting with acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS: A systematic review and meta-analysis were performed using PubMed to search for randomized clinical trials comparing dual antithrombotic therapy (DAT) with triple antithrombotic therapy (TAT) in this setting. Three trials involving 8845 patients were included (4802 and 4043 patients treated with DAT and TAT, respectively). There were no significant differences in all-cause death and stroke between the aspirin-omitted DAT group and TAT group. Otherwise, the incidence of myocardial infarction was significantly higher with aspirin-omitted DAT versus TAT (odds ratio [OR]: 1.29, 95% confidence interval [CI]: 1.02-1.63; P = 0.04; I2=0%). Similarly, the incidence of stent thrombosis increased in patients treated with aspirin-omitted DAT versus TAT (OR: 1.61, 95% CI: 1.02-2.53; P = 0.04; I2=0%). The occurrence of major bleeding and clinically relevant nonmajor bleeding events, as defined by the International Society on Thrombosis and Hemostasis, was significantly lower with aspirin-omitted DAT versus TAT (OR: 0.61, 95% CI: 0.48-0.78; P = 0.02; I2=76%). Similar results were found according to the International Society on Thrombosis and Hemostasis major bleeding, Thrombolysis in Myocardial Infarction major or minor bleeding, and Thrombolysis in Myocardial Infarction major bleeding scales. CONCLUSION: Aspirin-omitted DAT reduces the occurrence of bleeding episodes, with a higher rate of myocardial infarction and stent thrombosis in NVAF patients presenting with ACS or undergoing PCI.

14.
Retina ; 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32134802

RESUMO

PURPOSE: To evaluate the safety and efficacy of Brimonidine Drug Delivery System (Brimo DDS), a biodegradable intravitreal implant, in the treatment of geographic atrophy (GA) secondary to age-related macular degeneration. METHODS: Phase 2, randomized, multicenter, double-masked, 24-month study. Study eyes were treated (Day 1; Month 6 retreatment) with Brimo DDS 132 µg (n = 49), Brimo DDS 264 µg (n = 41), or sham procedure (n = 23). The primary timepoint for efficacy analysis was Month 12. RESULTS: Mean GA area growth at Month 12 was 1.78 mm, 1.59 mm, and 2.19 mm in the Brimo DDS 132 µg, 264 µg, and sham groups, respectively. Geographic atrophy area growth was consistently smaller with Brimo DDS 132 and 264 µg than sham; between-group differences were significant (P ≤ 0.032) at Month 3. In patients with baseline lesion area ≥6 mm (two-thirds of patients), GA lesion area and effective radius growth was reduced with Brimo DDS 132 and 264 µg at Month 12 (P ≤ 0.050 vs. sham). Treatment-related adverse events were usually injection procedure-related. CONCLUSION: Brimo DDS demonstrated a favorable safety profile and reduced GA lesion area growth at Month 3. Lesion growth at Month 12 was reduced in patients with baseline GA lesion area ≥6 mm. The results support Phase 3 development.

17.
J Clin Anesth ; 62: 109742, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32088534

RESUMO

STUDY OBJECTIVES: The aim of the present study was to assess the quality of recovery from anesthesia on patients subjected to laparoscopic radical resection of colorectal cancer under epidural block combined with general anesthesia or general anesthesia by means of Quality of Recovery-15 (QoR-15) questionnaire. DESIGN: Prospective randomized trial. SETTING: The setting is at an operating room, a post-anesthesia care unit, and a hospital ward. PATIENTS: Seventy patients, aging from 65 to 79 years with an American Society of Anesthesiologists physical status II or III, were scheduled to undergo laparoscopic radical resection of colorectal cancer. INTERVENTIONS: Epidural block combined with general anesthesia or general anesthesia. MEASUREMENTS: The QoR-15 was administered by an investigator blind to group allocation before surgery (T0), at 24 and 72h after surgery (T1 and T2), and on postoperative day 7 (T3). The quality of recovery, as assessed by the score on the QoR-15, was compared between the groups. Besides, the consumption of anesthetics, respiratory recovery time, response time, extubation time, flatus time, the incidence of nausea or vomiting, the consumption of antiemetic and analgesic agents, and the duration of the hospital stay were also recorded. MAIN RESULTS: The QoR-15 scores at T1 and T2 were significantly higher in the E + G group compared with the G group (P < 0.05). Among the five dimensions of the QoR-15, physiological comfort, physiological independence, pain, and emotional dimension were significantly better at T1 in the E + G group, and physiological comfort and pain were significantly better at T2 in the E + G group. CONCLUSION: This study demonstrates that epidural block combined with general anesthesia can improve the early recovery of elderly patients after laparoscopic radical resection of colorectal cancer from the perspective of patients.

18.
Molecules ; 25(4)2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32075151

RESUMO

Marine sponges are well known as rich sources of biologically natural products. Growing evidence indicates that sponges harbor a wealth of microorganisms in their bodies, which are likely to be the true producers of bioactive secondary metabolites. In order to promote the study of natural product chemistry and explore the relationship between microorganisms and their sponge hosts, in this review, we give a comprehensive overview of the structures, sources, and activities of the 774 new marine natural products from sponge-derived microorganisms described over the last two decades from 1998 to 2017.

19.
J Cell Mol Med ; 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32040269

RESUMO

Cartilage endplate (CEP) degeneration has been considered as one of important factors related to intervertebral disc degeneration (IVDD). Previous researches have showed that Rac1 played a pivotal role in chondrocyte differentiation. However, the effect of Rac1 during the process of CEP degeneration remains unclear. Herein, we explored the effect of Rac1 on CEP degeneration and elucidated the underlying molecular mechanism. We found expression of Rac1-GTP increased in human-degenerated CEP tissue and IL-1ß-stimulated rat endplate chondrocytes (EPCs). Our study revealed that Rac1 inhibitor NSC23766 treatment promoted the expression of collagen II, aggrecan and Sox-9, and decreased the expression of ADTAMTS5 and MMP13 in IL-1ß-stimulated rat EPCs. Moreover, we also found that NSC23766 could suppress the activation of Wnt/ß-catenin pathway, suggesting that the beneficial effects of Rac1 inhibition in EPCs are mediated through the Wnt/ß-catenin signalling. Besides, puncture-induced rats models showed that NSC23766 played a protective role on CEP and disc degeneration. Collectively, these findings demonstrated that Rac1 inhibition delayed the EPCs degeneration and its potential mechanism may be associated with Wnt/ß-catenin pathway regulation, which may help us better understand the association between Rac1 and CEP degeneration and provide a promising strategy for delaying the progression of IVDD.

20.
Ther Adv Respir Dis ; 14: 1753466620905274, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32043429

RESUMO

BACKGROUND: Angiopoietin-2 (Ang-2), as one of the ligands of endothelial receptor Tie2, is known to be significant for vessel maturation and stabilization after birth. Previous studies showed the relationship between Ang-2 level and the risk of mortality in patients with acute respiratory distress syndrome (ARDS). However, the link between circulating Ang-2 and the risk of mortality in patients with ARDS varied in different investigations. RESULTS: We performed a systematic review and meta-analysis of all available cohort studies regarding the association between baseline circulating Ang-2 and mortality in patients with ARDS. Among the 10 eligible studies, pooled odds ratio (OR) showed that high Ang-2 level contributed to ARDS mortality [OR = 1.56, 95% confidence interval (CI): 1.30-1.89, I2 = 76.2%]. Stratified analysis revealed that higher circulating Ang-2 was related to a 30% higher risk in the high-quality scores group (OR = 1.68, 95% CI: 1.33-2.68, I2 = 62.4%). The I2 of the bad compliance group decreased from 76.2% to 8.5%, which suggested that compliance is a significant source of heterogeneity. This association may be blunted by potential bias, although the results was not meaningfully changed by omitting only one study at a time. Further subgroup analysis and meta-regression support that compliance of patients also affects the results significantly, compared with the publication year, follow-up duration, the samples, or population characteristics. CONCLUSION: Participants with higher baseline Ang-2 were at a higher risk for future risk of mortality in patients with ARDS. Higher circulating Ang-2 levels could independently predict the risk of mortality in patients with ARDS. However, further large scale prospective cohorts or even interventional studies are warranted to evaluate the diagnostic power of Ang-2 and its causative role on ARDS outcome. The reviews of this paper are available via the supplemental material section.

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