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1.
J Hazard Mater ; 421: 126690, 2022 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-34315019

RESUMO

Shellfish toxins are derived from harmful algae and are easily accumulated in environment and marine food through the food chain, exposing high risks on human health. Preliminary rapid screening is one of the most effective monitoring ways to reduce the potential risks; however, the traditional methods encounter with many limitations, such as complicated procedures, low sensitivity and specificity, and ethical problems. Alternatively, bioaffinity sensors are proposed and draw particular attention. Among them, the aptasensors are springing up and emerging as superior alternatives in recent years, exhibiting high practicability to analyze shellfish toxins in real samples in the marine food chain. Herein, the latest research progresses of aptasensors towards shellfish toxins in the marine food chain in the past five years was reviewed for the first time, in terms of the aptamers applied in these aptasensors, construction principles, signal transduction techniques, response types, individual performance properties, practical applications, and advantages/disadvantages of these aptasensors. Synchronously, critical discussions were given and future perspectives were prospected. We hope this review can serve as a powerful reference to promote further development and application of aptasensors to monitor shellfish toxins, as well as other analytes with similar demands.


Assuntos
Aptâmeros de Nucleotídeos , Técnicas Biossensoriais , Contaminação de Alimentos/análise , Toxinas Marinhas/análise , Cadeia Alimentar , Humanos , Frutos do Mar
2.
J Affect Disord ; 296: 434-442, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34606808

RESUMO

BACKGROUND: Preventive intervention can significantly reduce the human and economic costs of postpartum depression (PPD) compared with treatment post-diagnosis. However, identifying women with a high PPD risk and making a judgement as to the benefits of preventive intervention is a major challenge. METHODS: This is a retrospective study of parturients that underwent a cesarean delivery. Control group was used as development cohort and validation cohort to construct the risk prediction model of PPD and determine a risk threshold. Ketamine group and development cohort were used to verify the risk classification of parturients by evaluating whether the incidence of PPD decreased significantly after ketamine treatment in high-risk for PPD population. RESULTS: The AUC for the development cohort and validation cohort of the PPD prediction model were 0.751 (95%CI:0.700-0.802) and 0.748 (95%CI:0.680-0.816), respectively. A threshold of 19% PPD risk probability was determined, with a specificity and sensitivity in the validation cohort are 0.766 and 0.604, respectively. After matching the high-risk group and the low-risk group by propensity score, the results demonstrated that PPD incidence significantly reduced in the high-risk group following ketamine, versus non-ketamine, intervention (p < 0.01). In contrast, intervention in the low-risk group showed no significant difference in PPD outcomes (p > 0.01). LIMITATION: Randomized trials are needed to further verify the feasibility of the model and the thresholds proposed. CONCLUSION: This prediction model developed in this study shows utility in predicting PPD risk. Ketamine intervention significantly lowers PPD incidence in parturients with a risk classification threshold greater than 19%.

3.
Artigo em Inglês | MEDLINE | ID: mdl-34721642

RESUMO

Objective: This study aimed to explore the clinical efficacy and relevant mechanism of Tripterygium glycosides combined with low molecular weight heparin calcium (LMWH) in the treatment of Henoch-Schönlein purpura nephritis (HSPN) in children. Methods: 64 cases of children patients with HSPN treated at Qilu Hospital (Qingdao) from January 2015 to May 2020 were selected and randomly divided into the control group and the observation group and 32 cases in each group. Conventional medical treatment was applied in the two groups, besides which the control group was given LMWH while the observation group was given Tripterygium glycosides based on the control group. The clinical efficacy and the indexes of clinical symptoms of the two groups were compared. Immune globulin level, fibrinogen content (FIB), prothrombin time (PT), platelet level (PLT), and activated partial thromboplastin time (APTT) level of the two groups were compared before and after the treatment. Results: The total effective rate in the observation group was significantly higher than that of the control group, and the recurrence rate in the observation group was lower than that in the control group. After treatment, urine red blood cell count and 24 h urine protein were obviously better than those of the control group. There was no statistically significant difference in PT between the two groups of children before and after treatment. The levels of PLT and FIB in the two groups of patients after treatment were significantly lower than before treatment, and the PLT levels in the observation group were lower than those in the control group. Conclusion: The combination of Tripterygium glycosides and LMWH had good clinical effects in the treatment of children with HSPN, and it could improve the clinical symptoms, the mechanism of which might be related to the increase of PT, a decrease of PLT, and the improvement of coagulation function.

4.
ACS Infect Dis ; 2021 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-34735113

RESUMO

Dengue virus (DENV) non-structural protein 5 (NS5) is critical for viral RNA synthesis within endoplasmic reticulum (ER)-derived replication complexes in the cytoplasm; however a proportion of NS5 is known to be localized to the nucleus of infected cells. The importance of nuclear DENV NS5 on viral replication and pathogenesis is still unclear. We recently discovered a nuclear localization signal (NLS) residing in the C-terminal 18 amino acid (Cter18) region of DENV NS5 and that a single NS5 P884T amino acid substitution adjacent to the NLS is sufficient to relocalize a significant proportion of DENV2 NS5 from the nucleus to the cytoplasm of infected cells. Here, in vitro studies show that the DENV2 NS5 P884T mutant replicates similarly to the parental wild-type infectious clone-derived virus while inducing a greater type I interferon and inflammatory cytokine response, in a manner independent of NS5's ability to degrade STAT2 or regulate SAT1 splicing. In both AG129 mouse and Aedes aegypti mosquito infection models, the P884T virus exhibits lower levels of viral replication only at early timepoints. Intriguingly, there appears to be a tendency for selection pressure to revert to the wild-type proline in P884T-infected Ae. aegypti, in agreement with the high conservation of the proline at this position of NS5 in DENV2, 3, and 4. These results suggest that the predominant nuclear localization of DENV NS5, while not required for viral RNA replication, may play a role in pathogenesis and modulation of the host immune response and contribute to viral fitness in the mosquito host.

5.
J Med Chem ; 64(21): 16187-16204, 2021 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-34723530

RESUMO

Targeting P-glycoprotein (ABCB1 or P-gp) has been recognized as a promising strategy to overcome multidrug resistance. Here, we reported our medicinal chemistry efforts that led to the discovery of the triazolo[1,5-a]pyrimidine derivative WS-898 as a highly effective ABCB1 inhibitor capable of reversing paclitaxel (PTX) resistance in drug-resistant SW620/Ad300, KB-C2, and HEK293/ABCB1 cells (IC50 = 5.0, 3.67, and 3.68 nM, respectively), more potent than verapamil and zosuquidar. WS-898 inhibited the efflux function of ABCB1, thus leading to decreased efflux and increased intracellular PTX concentration in SW620/Ad300 cells. The cellular thermal shift assay indicated direct engagement of WS-898 to ABCB1. Furthermore, WS-898 stimulated the ATPase activity of ABCB1 but had minimal effects on cytochrome P450 3A4 (CYP3A4). Importantly, WS-898 increased PTX sensitization in vivo without obvious toxicity. The results suggest that WS-898 is a highly effective triazolo[1,5-a]pyrimidine-based ABCB1 inhibitor and shows promise in reversing ABCB1-mediated PTX resistance.

6.
Materials (Basel) ; 14(21)2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34771958

RESUMO

It has become one of the research directions of intelligent materials for self-healing asphalt pavements to use a bionic microvascular containing oily rejuvenator. The rejuvenator in a microvascular can carry out the healing of asphalt micro-cracks, thus reducing the damage to and prolonging the life of asphalt pavement. The aim of this work was to investigate the smart self-healing capability of an asphalt/microvascular material through its microstructure and mechanical properties. Microstructure observation indicated no interface separation between the microvasculars and bitumen matrix. Micro-CT images showed that microvasculars dispersed in asphalt samples without accumulation or tangles. The phenomenon of microcracks healing without intervention was observed, which proved that the fractured asphalt sample carried out the self-healing process with the help of rejuvenator diffusing out from the broken microvasculars. The self-healing efficiency of asphalt samples was also evaluated through a tensile test considering the factors of microvasculars content, healing time and healing temperature. It was found that the tensile strength of the asphalt samples was greatly enhanced by the addition of microvasculars under a set test condition. Self-healing efficiency was enhanced with more broken microvasculars in the rupture interface of the asphalt sample. During two self-healing cycles, the self-healing efficiency of the asphalt sample with three microvascular per 1 cm2 of a broken interface were able to reach 80% and 86%. This proves that microvasculars containing rejuvenator play a practical role in the self-healing process of asphalt. With an increase in temperature from 0 to 30 °C, the self-healing capability of the asphalt samples increased dramatically. An increase in time increased the self-healing capability of the bitumen samples. At last, a preliminary mathematical model also deduced that the self-healing efficiency was determined by the individual healing steps, including release, penetration and diffusion of the rejuvenator agent.

7.
RNA ; 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34759006

RESUMO

Replication of the RNA genome of flaviviruses without a primer involves RNA-protein interactions that have been shown to include the recognition of the stem-loop A (SLA) in the 5' untranslated region (UTR) by the non-structural protein 5 (NS5). We show that DENV2 NS5 arginine 888, located within the C-terminal 18 residues, is completely conserved in all flaviviruses and interacts specifically with the top-loop of 3'SL in the 3'UTR which contains the pentanucleotide 5'-CACAG-3' previously shown to be critical for flavivirus RNA replication. We present virological and biochemical data showing the importance of this Arg 888 in virus viability and de novo initiation of RNA polymerase activity in vitro. Based on our binding studies, we hypothesize that ternary complex formation of NS5 with 3'SL, followed by dimerization, leads to the formation of the de novo initiation complex that could be regulated by the reversible zipping and unzipping of cis-acting RNA elements.

8.
Microbiol Spectr ; 9(2): e0157121, 2021 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-34704802

RESUMO

Iron is an essential element for the growth and survival of pathogenic bacteria; however, it is not fully understood how bacteria sense and respond to iron deficiency or excess. In this study, we show that xfeA in Xanthomonas oryzae pv. oryzicola senses extracytoplasmic iron and changes the hydrogen bonding network of ligand channel domains by adenosine-to-inosine (A-to-I) RNA editing. The frequency of A-to-I RNA editing during iron-deficient conditions increased by 76.87%, which facilitated the passage of iron through the XfeA outer membrane channel. When bacteria were subjected to high iron concentrations, the percentage of A-to-I editing in xfeA decreased, which reduced iron transport via XfeA. Furthermore, A-to-I RNA editing increased expression of multiple genes in the chemotaxis pathway, including methyl-accepting chemotaxis proteins (MCPs) that sense concentrations of exogenous ferrienterobactin (Fe-Ent) at the cytoplasmic membrane. A-to-I RNA editing helps X. oryzae pv. oryzicola move toward an iron-rich environment and supports our contention that editing in xfeA facilitates entry of a ferric siderophore. Overall, our results reveal a new signaling mechanism that bacteria use to adjust to iron concentrations. IMPORTANCE Adenosine-to-inosine (A-to-I) RNA editing, which is catalyzed by the adenosine deaminase RNA-specific family of enzymes, is a frequent posttranscriptional modification in metazoans. Research on A-to-I editing in bacteria is limited, and the importance of this editing is underestimated. In this study, we show that bacteria may use A-to-I editing as an alternative strategy to promote uptake of metabolic iron, and this form of editing can quickly and precisely modify RNA and subsequent protein sequences similar to an "on/off" switch. Thus, bacteria have the capacity to use a rapid switch-like mechanism to facilitate iron uptake and improve their competitiveness.

9.
Eur J Med Chem ; 226: 113896, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34624825

RESUMO

Targeting neddylation pathway has been recognized as an attractive anticancer therapeutic strategy, thus discovering potent and selective neddylation inhibitors is highly desirable. Our work reported the discovery of novel cinnamyl piperidine compounds and their antitumor activity in vitro and in vivo. Among these compounds, compound 4g was identified as a novel neddylation inhibitor and decreased the neddylation levels of cullin 1, cullin 3 and cullin 5. Mechanistic studies demonstrated that compound 4g could inhibit the migration ability of gastric cancer cells and induce apoptosis partly mediated by the Nrf2-Keap1 pathway. Furthermore, in vivo anti-tumor studies showed that 4g effectively inhibited tumor growth without obvious toxicity. Collectively, the cinnamyl piperidine derivatives could serve as new lead compounds for developing highly effective neddylation inhibitors for gastric cancer therapy.

10.
Adv Mater ; : e2105080, 2021 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-34693564

RESUMO

Circularly polarized thermally activated delayed fluorescence (CP-TADF) and multiple-resonance thermally activated delayed fluorescence (MR-TADF), which exhibit novel circularly polarized luminescence and excellent color fidelity, respectively, have gained immense popularity. In this study, integrated CP-TADF and MR-TADF (CPMR-TADF) are prepared by strategic design and synthesis of asymmetrical peripherally locked enantiomers, which are separated and denoted as (P,P″,P″)-/(M,M″,M″)-BN4 and (P,P″,P″)-/(M,M″,M″)-BN5 and exhibit TADF and circularly polarized light (CPL) properties. As the entire molecular frame participates in the frontier molecular orbitals, the resulting helical chirality of (+)/(-)-BN4- and (+)/(-)-BN5-based solution-processed organic light-emitting diodes (OLEDs) helps in achieving a narrow full width at half maximum (FWHM) of 49/49 and 48/48 nm and a high maximum external quantum efficiency (EQE) of 20.6%/19.0% and 22.0%/26.5%, respectively. Importantly, unambiguous circularly polarized electroluminescence signals with dissymmetry factors (gEL ) of +3.7 × 10-3 /-3.1 × 10-3 (BN4) and +1.9 × 10-3 /-1.6 × 10-3 (BN5) are obtained. The results indicate successful exploitation of CPMR-TADF-emitter-based OLEDs to exhibit three characteristics: high efficiency, color purity, and circularly polarized light.

11.
Front Immunol ; 12: 702244, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34484198

RESUMO

Primary intracerebral hemorrhage (ICH) is a significant cause of morbidity and mortality throughout the world. ICH is a multifactorial disease that emerges from interactions among multiple genetic and environmental factors. DNA methylation plays an important role in the etiology of complex traits and diseases. We used the Illumina Infinium Human Methylation 850k BeadChip to detect changes in DNA methylation in peripheral blood samples from patients with ICH and healthy controls to explore DNA methylation patterns in ICH. Here, we compared genomic DNA methylation patterns in whole blood from ICH patients (n = 30) and controls (n = 34). The ICH and control groups showed significantly different DNA methylation patterns at 1530 sites (p-value < 5.92E-08), with 1377 hypermethylated sites and 153 hypomethylated sites in ICH patients compared to the methylation status in healthy controls. A total of 371 hypermethylated sites and 35 hypomethylated sites were in promoters, while 738 hypermethylated sites and 67 hypomethylated sites were in coding regions. Furthermore, the differentially methylated genes between ICH patients and controls were largely related to inflammatory pathways. Abnormalities in the DNA methylation pattern identified in the peripheral blood of ICH patients may play an important role in the development of ICH and warranted further investigation.

12.
Thorac Cancer ; 12(19): 2544-2550, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34510768

RESUMO

BACKGROUND: To explore the genetic and immunophenotyping heterogeneities between patients with intrapulmonary metastasis (IPM) or multiple primary lung cancer (MPLC). METHODS: Whole exome sequencing (WES) and transcriptome sequencing (RNA-seq) were performed on the tissue and blood samples of IPM and MPLC patients to comprehensively analyze the clonal evolution, molecular typing and immunophenotyping. RESULTS: There was no significant difference in genetic mutation, tumor mutational burden (TMB) value and mutant allele tumor heterogeneity (MATH) value between IPM and MPLC patients. Notably, the loss of heterozygosity (LOH) of human leukocyte antigen (HLA) appeared in all IPM patients, while there was also no significant difference between the two groups. In addition, expression of immune checkpoint-related genes including CTLA-4, BTLA, TIGIT and HAVCR2 in the MPLC group was significantly higher than those in IPM group. At the same time, 86 differentially expressed genes (DEGs) were observed between IPM and MPLC patients with transcriptome sequencing, of which 56 DEGs were upregulated and 30 were downregulated in the IPM group compared with the MPLC group. The cluster analysis revealed that the 86 DEGs could be distinguished in IPM and MPLC samples. Moreover, only the infiltration levels of CD56dim natural killer cells in the IPM group was significantly higher than that in the MPLC group, and the infiltration levels of the remaining 27 immune cell subsets were similar in both groups. CONCLUSIONS: IPM and MPLC are roughly similar in genetic and immune characteristics indicating that genomics alone may not be able to effectively distinguish between IPM and MPLC, which still needs to be comprehensively evaluated with clinical manifestations, imaging, and pathological characteristics.

13.
BMC Med Genomics ; 14(1): 198, 2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34348722

RESUMO

BACKGROUND: Gitelman syndrome (GS) is an autosomal recessive tubulopathy caused by mutations of the SLC12A3 gene. It is characterized by hypokalemic metabolic alkalosis, hypomagnesemia and hypocalciuria. It is universally known that both hypokalemia and hypomagnesemia can influence insulin secretion and insulin resistance, but the exact mechanisms require further study. We identified a novel deletion variant of the SLC12A3 gene and discussed the appropriate hypoglycemic drugs in Gitelman syndrome (GS) patients with type 2 diabetes. CASE PRESENTATION: A 55-year-old diabetic female patient was hospitalized for evaluation because of paroxysmal general weakness and numbness of extremities for one year. We suspected that she was suffering from GS by initial estimation. Direct Sanger sequencing was used to analyze the causative gene SLC12A3 of GS. Oral glucose tolerance test (OGTT) was carried out to assess the glucose metabolism and insulin resistance status. Genetic analysis revealed that she was a compound heterozygote for a recurrent missense mutation c.179C > T and a novel deletion c.1740delC in SLC12A3, thus her diagnosis of GS was confirmed. The patient was treated with potassium chloride (3.0 g/d) and magnesium chloride (element magnesium 350 mg/d) on the basis of initial treatment of diabetes with hypoglycemic drug (Repaglinide, 3.0 mg/day). However, she developed frequent hypoglycemia after one week. OGTT showed that her glucose metabolism and insulin resistance much improved after potassium and magnesium supplemental therapy. Then we changed the hypoglycemic agent to a dipeptidyl peptidase-4 (DPP-4) inhibitor (Trajenta 5 mg/d), since then her blood glucose level remained normal during two-year of follow-up. CONCLUSION: We have identified a novel deletion of the SLC12A3 gene and discussed the appropriate hypoglycemic drugs in Gitelman syndrome (GS) patients with type 2 diabetes. We suggested that attention need to be paid to blood glucose monitoring in GS patients, especially when hypokalemia and hypomagnesemia are corrected. Besides, the insufficient blood volume and serum electrolyte disturbance should also be taken into consideration in the selecting hypoglycemic drugs for GS patients.

14.
Phytopathology ; 2021 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-34420356

RESUMO

Emerging role of circular RNAs (circRNAs) in various biological processes have advanced our knowledge of transcriptional and post-transcriptional gene regulation. To date, no research has been conducted to explore their roles in the rice- Xanthomonas oryzae pv. oryzae (Xoo) interaction. Therefore, we identified 3517 circRNAs from the highly virulent Xoo strain PXO99A-infected rice leaves using the ribosomal RNA (rRNA) depleted RNA-sequencing technique coupled with the CIRI2 and CIRCexplorer2 pipeline. Characterization analyses showed that these circRNAs were distributed across the whole genome of rice, and most circRNAs arised from exons (85.13 %), ranged from 200 bp to 1000 bp and were with a non-canonical GT/AG (including CT/AC equivalent) splicing signal. Functional annotation and enrichment analysis of the host genes that produced the DEcircRNAs suggested that these identified circRNAs might play an important role in reprogramming rice responses to PXO99A invasion, mainly by mediating photorespiration, chloroplast, peroxisome and diterpenoid biosynthesis. Moreover, 31 differentially expressed circRNAs (DEcircRNAs) were predicted to act as miRNA decoys in rice. The expression profile of 4 DEcircRNAs were validated by RT-qPCR with divergent primers, and the back-splicing sites of seven DEcircRNAs were verified by PCR analysis and Sanger sequencing. Collectively, these results inferred a potential functional role of circRNAs in the regulation of rice immunity and provide novel clues for revealing the molecular mechanisms of rice-PXO99A interaction.

15.
Front Mol Biosci ; 8: 689139, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34422902

RESUMO

Gastric cancer is the fifth most common cancer and the third most common cause of cancer death all over the world. E-cadherin encoded by human CDH1 gene plays important roles in tumorigenesis as well as in tumor progression, invasion and metastasis. Full-length E-cadhrin tethered on the cell membrane mainly mediates adherens junctions between cells and is involved in maintaining the normal structure of epithelial tissues. After proteolysis, the extracellular fragment of the full-length E-cadhein is released into the extracellular environment and the blood, which is called soluble E-cadherin (sE-cadherin). sE-cadherin promots invasion and metastasis as a paracrine/autocrine signaling molecule in the progression of various types of cancer including gastric cancer. This review mainly summarizes the dysregulation of E-cadherin and the regulatory roles in the progression, invasion, metastasis, and drug-resistance, as well as its clinical applications in diagnosis, prognosis, and therapeutics of gastric cancer.

16.
Sheng Li Xue Bao ; 73(4): 597-605, 2021 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-34405216

RESUMO

Prostaglandin E2 (PGE2) plays an important role in cardiovascular system. PGE2 regulates blood pressure through its 4 G protein coupled receptors, i.e., EP1, EP2, EP3, and EP4. The aim of this study was to investigate the role of EP4 receptors in vascular smooth muscle cells (VSMC) in blood pressure regulation. VSMC-specific human EP4 transgenic (VSMC-hEP4 Tg) mice were generated and genotyped. The systolic blood pressure (SBP) of the VSMC-hEP4 Tg mice and the wild-type (WT) littermates was measured under normal, low-salt (LSD) and high-salt diet (HSD) conditions using a tail-cuff method. Both WT and VSMC-hEP4 Tg mice were administered with a chronic infusion of angiotensin II (Ang II) with an osmotic pump and SBP levels were monitored every week. The mean arterial blood pressure (MAP) of WT and VSMC-hEP4 Tg mice upon Ang II intravenous infusion was measured via carotid arterial catheterization. Ang II-induced vasoconstriction of the mesenteric arterial rings from WT and VSMC-hEP4 Tg mice was measured using the multi myograph system. The effect of PGE1-OH (a selective EP4 agonist) on Ang II-induced phosphorylation of myosin phosphatase target subunit 1 (MYPT1) was detected by Western blot. The effect of two additional EP4 specific agonists (CAY10580 and CAY10598, 0.5 mg/kg) on blood pressure of WT mice was measured by carotid arterial catheterization. The results showed that the VSMC-hEP4 Tg mice were successfully generated and their basal SBP levels were lower than those of WT mice. Although blood pressure levels were significantly altered in WT mice under LSD and HSD, little change was observed in the VSMC-hEP4 Tg mice. After a chronic infusion and an acute intravenous injection of Ang II, SBP levels of VSMC-hEP4 Tg mice were significantly lower than those of WT mice. In addition, both CAY10580 and CAY10598 significantly reduced MAP levels of WT mice. Ex vivo study showed that treatment of isolated mesenteric arteries with PGE1-OH inhibited Ang II-induced phosphorylation of MYPT1. Collectively, these results demonstrate that specific overexpression of human EP4 gene in VSMCs significantly reduces basal blood pressure levels and attenuates Ang II-induced hypertension, possibly via inhibiting Ang II/AT1 signaling pathway. Our findings suggest that EP4 may represent an attractive target for the treatment of hypertension.


Assuntos
Angiotensina II , Hipertensão , Animais , Humanos , Hipertensão/induzido quimicamente , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular , Miócitos de Músculo Liso
17.
Hepatology ; 2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34435364

RESUMO

BACKGROUND & AIMS: In patients with acute liver failure (ALF) who suffer from massive hepatocyte loss, liver progenitor cells (LPC) take over key hepatocyte functions, which ultimately determines survival. This study investigated how the expression of HNF4α, its regulators and targets in LPC determines clinical outcome of ALF patients. APPROACH & RESULTS: Clinicopathological associations were scrutinized in 19 ALF patients (9 recovered and 10 receiving liver transplantation). Regulatory mechanisms between follistatin, activin, HNF4α and coagulation factor expression in LPC were investigated in vitro and in metronidazole-treated zebrafish. A prospective clinical study followed up 186 cirrhotic patients for 80 months to observe the relevance of follistatin levels in prevalence and mortality of acute-on-chronic liver failure (ACLF). Recovered ALF patients robustly express HNF4α in either LPC or remaining hepatocytes. As in hepatocytes, HNF4α controls the expression of coagulation factors by binding to their promoters in LPC. HNF4α expression in LPC requires the FOXH1-SMAD2/3/4 transcription factor complex, which is promoted by the TGF-ß superfamily member activin. Activin signaling in LPC is negatively regulated by follistatin, a hepatocyte-derived hormone controlled by insulin and glucagon. In contrast to patients requiring liver transplantation, recovered patients demonstrate a normal activin/follistatin ratio, robust abundance of the activin effectors phosphorylated SMAD2 and HNF4α in LPC, leading to significantly improved coagulation function. A follow-up study indicated that serum follistatin levels could predict the incidence and mortality of ACLF. CONCLUSIONS: These results highlight a crucial role of the follistatin-controlled activin-HNF4α-coagulation axis in determining the clinical outcome of massive hepatocyte loss-induced ALF. The effects of insulin and glucagon on follistatin suggests a key role of the systemic metabolic state in ALF.

18.
Phytopathology ; 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34353121

RESUMO

Ancylobacter pratisalsi sp. nov. strain E130T is a Gram negative, non-motile, aerobic and rod-shaped bacterium, which was recently isolated from the rhizosphere of Plantago winteri Wirtg from a natural salt meadow. This strain was described as novel species in Ancylobacter genus, however information about its complete genome has yet not been reported. In this study, its genome was completely sequenced by PacBio SMRT cell platform, analyzed, and compared with other selected complete genome sequences of Ancylobacter and elucidated its potential plant growth promotion abilities. The genomic analysis revealed that the genome of strain E130T consists of one circular DNA chromosome of 4,618,530 bp with a GC content of 66% and one plasmid of 159,741 bp with a GC content of 64.13%. The entire genome contains 4,322 predicted coding genes, 49 tRNAs and 6 rRNA genes. Genome analysis identified a siderophore natural product biosynthesis cluster, which produces fuscachelin. Knockout of several key genes in this cluster, significantly reduces the plant growth-promotion ability of the strain E130T. Besides plant growth-promotion, the strain E130T can grow well on 5 % NaCl (w/v), conferring this strain as potential bio-resource for successful production of economic crops in alkaline soil.

19.
Eur J Med Chem ; 224: 113695, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34298282

RESUMO

The flavivirus genus of the Flaviviridae family comprises Dengue, Zika and West-Nile viruses which constitute unmet medical needs as neither appropriate antivirals nor safe vaccines are available. The dengue NS2BNS3 protease is one of the most promising validated targets for developing a dengue treatment however reported protease inhibitors suffer from toxicity and cellular inefficacy. Here we report SAR on our previously reported Zika-active carbazole scaffold, culminating prodrug compound SP-471P (EC50 1.10 µM, CC50 > 100 µM) that generates SP-471; one of the most potent, non-cytotoxic and cell-active protease inhibitors described in the dengue literature. In cell-based assays, SP-471P leads to inhibition of viral RNA replication and complete abolishment of infective viral particle production even when administered 6 h post-infection. Mechanistically, SP-471 appears to inhibit both normal intermolecular protease processes and intramolecular cleavage events at the NS2BNS3 junction, as well as at NS3 internal sites, all critical for virus replication. These render SP-471 a unique to date multimodal inhibitor of the dengue protease.

20.
PLoS Pathog ; 17(7): e1009762, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34297775

RESUMO

Pathogens integrate multiple environmental signals to navigate the host and control the expression of virulence genes. In this process, small regulatory noncoding RNAs (sRNAs) may function in gene expression as post-transcriptional regulators. In this study, the sRNA Xonc3711 functioned in the response of the rice pathogen, Xanthomonas oryzae pv. oryzicola (Xoc), to oxidative stress. Xonc3711 repressed production of the DNA-binding protein Xoc_3982 by binding to the xoc_3982 mRNA within the coding region. Mutational analysis showed that regulation required an antisense interaction between Xonc3711 and xoc_3982 mRNA, and RNase E was needed for degradation of the xoc_3982 transcript. Deletion of Xonc3711 resulted in a lower tolerance to oxidative stress due to the repression of flagella-associated genes and reduced biofilm formation. Furthermore, ChIP-seq and electrophoretic mobility shift assays showed that Xoc_3982 repressed the transcription of effector xopC2, which contributes to virulence in Xoc BLS256. This study describes how sRNA Xonc3711 modulates multiple traits in Xoc via signals perceived from the external environment.


Assuntos
Estresse Oxidativo/fisiologia , RNA Antissenso/metabolismo , Xanthomonas/patogenicidade , Oryza/parasitologia , Doenças das Plantas/genética , Pequeno RNA não Traduzido , Virulência/genética , Xanthomonas/genética , Xanthomonas/metabolismo
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