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1.
Molecules ; 26(7)2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33810495

RESUMO

L-aspartate (Asp) serves as a central building block, in addition to being a constituent of proteins, for many metabolic processes in most organisms, such as biosynthesis of other amino acids, nucleotides, nicotinamide adenine dinucleotide (NAD), the tricarboxylic acid (TCA) cycle and glycolysis pathway intermediates, and hormones, which are vital for growth and defense. In animals and humans, lines of data have proved that Asp is indispensable for cell proliferation. However, in plants, despite the extensive study of the Asp family amino acid pathway, little attention has been paid to the function of Asp through the other numerous pathways. This review aims to elucidate the most important aspects of Asp in plants, from biosynthesis to catabolism and the role of Asp and its metabolic derivatives in response to changing environmental conditions. It considers the distribution of Asp in various cell compartments and the change of Asp level, and its significance in the whole plant under various stresses. Moreover, it provides evidence of the interconnection between Asp and phytohormones, which have prominent functions in plant growth, development, and defense. The updated information will help improve our understanding of the physiological role of Asp and Asp-borne metabolic fluxes, supporting the modular operation of these networks.

2.
Oxid Med Cell Longev ; 2021: 5564884, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33859778

RESUMO

Vascular smooth muscle cell (VSMC) apoptosis is a major defining feature of abdominal aortic aneurysm (AAA) and mainly caused by inflammatory cell infiltration. Smooth muscle (SM) 22α prevents AAA formation through suppressing NF-κB activation. However, the role of SM22α in VSMC apoptosis is controversial. Here, we identified that SM22α loss contributed to apoptosis of VSMCs via activation of macrophages. Firstly, deficiency of SM22α enhanced the interaction of VSMCs with macrophages. Macrophages were retained and activated by Sm22α -/- VSMCs via upregulating VCAM-1 expression. The ratio of apoptosis was increased by 1.62-fold in VSMCs treated with the conditional media (CM) from activated RAW264.7 cells, compared to that of the control CM (P < 0.01), and apoptosis of Sm22α -/- VSMCs was higher than that of WT VSMCs (P < 0.001). Next, circRasGEF1B from activated macrophages was delivered into VSMCs promoting ZFP36 expression via stabilization of ZFP36 mRNA. Importantly, circRasGEF1B, as a scaffold, guided ZFP36 to preferentially bind to and decay Bcl-2 mRNA in a sequence-specific manner and triggered apoptosis of VSMCs, especially in Sm22α -/- VSMCs. These findings reveal a novel mechanism by which the circRasGEF1B-ZFP36 axis mediates macrophage-induced VSMC apoptosis via decay of Bcl-2 mRNA, whereas Sm22α -/- VSMCs have a higher sensitivity to apoptosis.

3.
Dalton Trans ; 50(14): 4944-4951, 2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33877192

RESUMO

Herein, a novel and fluorescent zinc-organic framework sensor [Zn3(µ3-Hbptc)2(µ2-4,4'-bpy)2(H2O)4]n·2nH2O (1) (H4bptc = 2,3,3',4'-biphenyl tetracarboxylic acid, 4,4'-bpy = 4,4'-bipyridine) is synthesized and characterized, demonstrating its excellent fluorescence performance for Cu2+ detection and the enrichment of Cu2+ in aqueous media. The fluorescence intensity of 1 can be selectively quenched by Cu2+ in a linear range of Cu2+ concentrations of 0-0.7 µM. The limit of detection (LOD) value is as low as 32.4 nM, which is superior to those of most of the fluorescent sensors based on metal-organic frameworks (MOFs). It is also far below the maximum allowable concentration of Cu2+ in drinking water as defined by the U.S. Environmental Protection Agency (EPA) and the World Health Organization (WHO), so it is employed for the detection of Cu2+ in actual water samples. More importantly, the nature of the interaction between the active coordination site (COO-) of 1 and Cu2+ determines the quenching mechanism, that is Cu2+ in the analyte is captured by MOF 1, which has been investigated by ICP, luminescence, UV-vis, XPS, and lifetime studies. Besides, the chemosensor shows regeneration performance without the loss of performance in five consecutive cycles. So MOF 1 is a simple and convenient probe used not only for the rapid detection but also for the enrichment of trace amounts of Cu2+ in aqueous media, and the application can be further extended to a variety of environmental and biological analysis processes.

4.
Cell Death Dis ; 12(5): 409, 2021 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-33866326

RESUMO

The levels of fibroblast growth factor 23 (FGF23) rapidly increases after acute kidney injury (AKI). However, the role of FGF23 in AKI is still unclear. Here, we observe that pretreatment with FGF23 protein into ischemia-reperfusion induced AKI mice ameliorates kidney injury by promoting renal tubular regeneration, proliferation, vascular repair, and attenuating tubular damage. In vitro assays demonstrate that SDF-1 induces upregulation of its receptor CXCR4 in endothelial progenitor cells (EPCs) via a non-canonical NF-κB signaling pathway. FGF23 crosstalks with the SDF-1/CXCR4 signaling and abrogates SDF-1-induced EPC senescence and migration, but not angiogenesis, in a Klotho-independent manner. The downregulated pro-angiogenic IL-6, IL-8, and VEGF-A expressions after SDF-1 infusion are rescued after adding FGF23. Diminished therapeutic ability of SDF-1-treated EPCs is counteracted by FGF23 in a SCID mouse in vivo AKI model. Together, these data highlight a revolutionary and important role that FGF23 plays in the nephroprotection of IR-AKI.

5.
ACS Nano ; 15(4): 7649-7658, 2021 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-33871962

RESUMO

Accurate and rapid blood typing plays a vital role in a variety of biomedical and forensic scenarios, but recognizing weak agglutination remains challenging. Herein, we demonstrated a flipping identification with a prompt error-discrimination (FLIPPED) platform for automatic blood group readouts. Bromocresol green dye was exploited as a characteristic chromatography indicator for the differentiation of plasma from whole blood by presenting a teal color against a brown color. After integrating these color changes into a quick-response (QR) code, prompt typing of ABO and Rhesus groups was automatically achieved and data could be uploaded wirelessly within 30 s using a commercially available smartphone to facilitate blood cross-matching. We further designed a color correction model and algorithm to remove potential errors from scanning angles and ambient light intensities, by which weak agglutination could be accurately recognized. With comparable accuracy and repeatability to classical column assay in grouping 450 blood samples, the proposed approach further demonstrates to be a versatile sample-to-result platform for clinical diagnostics, food safety, and environmental monitoring.

6.
J Biol Chem ; : 100507, 2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33675749

RESUMO

Cardiovascular disease (CVD) remains the most common cause of adult morbidity and mortality in developed nations. As a result, predisposition for CVD is increasingly important to understand. Ankyrins are intracellular proteins required for the maintenance of membrane domains. Canonical ankyrin-G (AnkG) has been shown to be vital for normal cardiac function, specifically cardiac excitability, via targeting and regulation of the cardiac voltage-gated sodium channel. Non-canonical (giant) AnkG isoforms play a key role in neuronal membrane biogenesis and excitability, with evidence for human neurologic disease when aberrant. However, the role of giant AnkG in cardiovascular tissue has yet to be explored. Here, we identify giant AnkG in the myocardium and identify that it is enriched in 1-week old mice. Using a new mouse model lacking giant AnkG expression in myocytes, we identify that young mice displayed a dilated cardiomyopathy phenotype with aberrant electrical conduction and enhanced arrhythmogenicity. Structural and electrical dysfunction occurred at 1-week of age, when giant AnkG was highly expressed, and did not appreciably change in adulthood until advanced age. At a cellular level, loss of giant AnkG results in delayed and early afterdepolarizations. However, surprisingly, giant AnkG cKO myocytes display normal INa, but abnormal myocyte contractility, suggesting unique roles of the large isoform in heart. Finally, transcript analysis provided evidence for unique pathways that may contribute to the structural and electrical findings shown in giant AnkG cKO animals. In summary, we identify a critical role for giant AnkG that adds to the diversity of ankyrin function in heart.

7.
Clin Exp Immunol ; 2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33735518

RESUMO

High expression of the inhibitory receptor programmed death ligand 1 (PD-L1) on tumor cells and tumor stromal cells have been found play a key role in tumor immune evasion in several human malignancies. However, the expression of PD-L1 on bone marrow mesenchymal stem cells (BMSCs) and whether the PD-1/PD-L1 signal pathway is involved in the BMSCs versus T cell immune response in Multiple Myeloma (MM) remain poorly defined. In this study, we explored the expression of PD-L1 on BMSCs from newly diagnosed MM (NDMM) patients and the role of PD-1/PD-L1 pathway in BMSCs-mediated regulation of CD8+ T cells. The data showed that the expression of PD-L1 on BMSCs in NDMM patients was significantly increased than that in normal controls(NC)(18.81±1.61% vs. 2.78±0.70 %; P<0.001). Furthermore, the PD-1 expression on CD8+ T cells with NDMM patients was significantly higher than that in normal controls (43.22±2.98% vs. 20.71±1.08%; P<0.001). However, there was no significant difference in PD-1 expression of CD4+ T cells and NK cells between NDMM group and NC group. Additionally, the co-culture assays revealed that BMSCs significantly suppressed CD8+ T cells function. However, PD-L1 inhibitor effectively reversed BMSCs-mediated suppression in CD8+ T cells. We also found that the combination of PD-L1 inhibitor and pomalidomide can further enhance the killing effect of CD8+ T cells on MM cells. In summary, our findings demonstrated that BMSCs in patients with MM may induce apoptosis of CD8+ T cells through the PD-1/PD-L1 axis and inhibit the release of perforin and granzyme B from CD8+ T cells so as to promote the immune escape of MM.

8.
Sheng Li Xue Bao ; 73(1): 82-88, 2021 Feb 25.
Artigo em Chinês | MEDLINE | ID: mdl-33665663

RESUMO

The research on the molecular mechanism of vascular injury has been a hot topic in recent years since the mechanism can be targeted for the treatment of vascular injury diseases. A large number of studies have found that vascular injury, repair and pathological remodeling are closely related to phenotype switching, abnormal proliferation and migration, and apoptosis of vascular smooth muscle cells (VSMCs). Smooth muscle 22α (SM22α) is a shape change and transformation sensitive F-actin-binding protein. SM22α decorates the contractile filament bundles within cultured VSMCs exhibiting differentiated phenotypes. In addition, SM22α is involved in regulation of cell signaling pathways related to vascular homeostasis and vascular remodeling. Here, we reviewed the recent research progress of SM22α in vascular homeostasis and remodeling.


Assuntos
Músculo Liso Vascular , Remodelação Vascular , Proliferação de Células , Células Cultivadas , Homeostase , Humanos , Proteínas Musculares , Miócitos de Músculo Liso , Fenótipo
9.
JAMA Psychiatry ; 78(5): 510-518, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33656533

RESUMO

Importance: Schizophrenia is associated with cognitive dysfunction and cardiovascular risk factors, including metabolic syndrome (MetS) and its constituent criteria. Cognitive dysfunction and cardiovascular risk factors can worsen cognition in the general population and may contribute to cognitive impairment in schizophrenia. Objective: To study the association between cognitive dysfunction and cardiovascular risk factors and cognitive impairment in individuals with schizophrenia. Data Sources: A search was conducted of Embase, Scopus, MEDLINE, PubMed, and Cochrane databases from inception to February 25, 2020, using terms that included synonyms of schizophrenia AND metabolic adversities AND cognitive function. Conference proceedings, clinical trial registries, and reference lists of relevant publications were also searched. Study Selection: Studies were included that (1) examined cognitive functioning in patients with schizophrenia or schizoaffective disorder; (2) investigated the association of cardiovascular disease risk factors, including MetS, diabetes, obesity, overweight, obesity or overweight, hypertension, dyslipidemia, and insulin resistance with outcomes; and (3) compared cognitive performance of patients with schizophrenia/schizoaffective disorder between those with vs without cardiovascular disease risk factors. Data Extraction and Synthesis: Extraction of data was conducted by 2 to 3 independent reviewers per article. Data were meta-analyzed using a random-effects model. Main Outcomes and Measures: The primary outcome was global cognition, defined as a test score using clinically validated measures of overall cognitive functioning. Results: Twenty-seven studies involving 10 174 individuals with schizophrenia were included. Significantly greater global cognitive deficits were present in patients with schizophrenia who had MetS (13 studies; n = 2800; effect size [ES] = 0.31; 95% CI, 0.13-0.50; P = .001), diabetes (8 studies; n = 2976; ES = 0.32; 95% CI, 0.23-0.42; P < .001), or hypertension (5 studies; n = 1899; ES = 0.21; 95% CI, 0.11-0.31; P < .001); nonsignificantly greater deficits were present in patients with obesity (8 studies; n = 2779; P = .20), overweight (8 studies; n = 2825; P = .41), and insulin resistance (1 study; n = 193; P = .18). Worse performance in specific cognitive domains was associated with cognitive dysfunction and cardiovascular risk factors regarding 5 domains in patients with diabetes (ES range, 0.23 [95% CI, 0.12-0.33] to 0.40 [95% CI, 0.20-0.61]) and 4 domains with MetS (ES range, 0.15 [95% CI, 0.03-0.28] to 0.40 [95% CI, 0.20-0.61]) and hypertension (ES range, 0.15 [95% CI, 0.04-0.26] to 0.27 [95% CI, 0.15-0.39]). Conclusions and Relevance: In this systematic review and meta-analysis, MetS, diabetes, and hypertension were significantly associated with global cognitive impairment in people with schizophrenia.

10.
Planta ; 253(4): 79, 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33740147

RESUMO

MAIN CONCLUSION: Short-term cold stress can induce the increased expression of key enzyme-encoding genes involved in secondary metabolite synthesis, thereby increasing secondary metabolite concentration. Cold stress is an ecologically limiting factor that strongly affects the physiological and biochemical properties of medicinal plants often resulting in changes of the secondary metabolic process. Ginsenosides are the main active ingredients in medicinal ginseng yet few studies exist on the effect of cold stress on the expression of ginsenosides or the molecular mechanism underlying its regulation. Here, we evaluated the effects of cold stress on the physiological characteristics and secondary metabolism of P. ginseng embryogenic calli. Physiological measurements and RNA-Seq analysis were used to dissect the metabolic and molecular responses of P. ginseng to cold conditions. We found that the dynamic accumulation of ginsenoside and various physiological indicators leads to homogenous adaptation to cold stress. Secondary metabolism of ginseng could be a compensation mechanism to facilitate its adaptation to cold stress. Combined with the changes in the endogenous hormone content, 9-cis-epoxycarotenoid dioxygenase (NCED), zeaxanthin epoxidase (ZEP), and short chain dehydrogenase (SDR) from the abscisic acid (ABA) synthesis pathway were identified as key mediators of this response. Thus, an appropriate degree of cold stress may promote accumulation of ginsenosides. Moreover, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR2), squalene epoxidase (SE1), squalene synthase (SS), dammarenediol synthase (DS-II), and ß-alanine C-28 hydroxylase (CYP716A52v2) should be considered key mediators of the cold stress response and ginsenoside biosynthesis. During industrial production, short-term cold stress should be carried out on ginseng calli to improve the quality of its medicinal materials.


Assuntos
Resposta ao Choque Frio , Ginsenosídeos/biossíntese , Panax/fisiologia , Metabolismo Secundário , Regulação da Expressão Gênica de Plantas
11.
Anal Chem ; 93(13): 5562-5569, 2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33764735

RESUMO

As the pharmaceutical industry places greater emphasis on pairing biological pathways with appropriate therapeutic intervention, an increase in the use of biologic drugs has emerged. With increasing complexity of biotherapeutics, absorption, distribution, metabolism, and excretion (ADME) studies have also become increasingly complex. The characterization of ADME properties is critical to tuning the pharmacokinetic profiles of next generation biologics (NGBs). The knowledge of the fate of a drug is essential for the enhancement of the design processes, elongation of exposure at the desired site of action, and achieving efficacy with minimum toxicity. In vivo proteolytic cleavage of biotherapeutics may lead to undesirable in vivo properties, such as rapid clearance, low bioavailability, and loss of pharmacodynamic effect. All of these may affect drug efficacy and/or generate safety concerns through increases in immunogenicity or off-target toxicity. The work herein describes the development of a robust, fully automated immunoaffinity purification (IA)-capillary electrophoresis-mass spectrometry (CE-MS) workflow. The reagents were carefully optimized to maximize isolation yields while minimizing the number of experimental steps to analytical results. The result is the development of a comprehensive integrated platform for the characterization of a wide range of biotherapeutics, including peptibodies, monoclonal antibodies, and bispecific antibodies. Empowered by this automated IA-CE-MS approach, implementing biotransformation studies at an early drug discovery stage can speed up the drug development process.

12.
Biol Chem ; 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33713590

RESUMO

Diabetic nephropathy (DN) is the major life-threatening complication of diabetes, and oxidative stress takes part in its initiation and development. This study was performed to evaluate the effects of carotenoids from Sporidiobolus pararoseus (CSP) on the renal function and oxidative stress status of mice with streptozotocin (STZ)-induced DN. The results indicated that CSP significantly attenuated symptoms of STZ-induced DN shown by decreased fasting blood glucose, reduced urine volume, urine albumin, serum creatinine and serum urea nitrogen, and improved kidney histological morphology. Furthermore, biochemical analysis of serum and kidney revealed a marked increase in oxidative stress of DN mice as evidenced by reduced total antioxidant capacity (T-AOC), decreased activity of antioxidant enzyme -superoxide dismutase (SOD) and increased level of malondialdehyde (MDA). However, treatment with CSP improved oxidative stress status in DN mice as compared with the mice in model group. Exploration of the potential mechanism validated that CSP ameliorated the oxidative stress status in DN mice by activating the expressions of Nrf2, NQO-1, HO-1, GST and CAT in kidney. These data revealed that CSP may retard the progression of DN by ameliorating renal function, improving the oxidative stress status and activating the Nrf2/ARE pathway.

13.
BMC Genomics ; 22(1): 127, 2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33602144

RESUMO

BACKGROUND: The quality and yield of wool determine the economic value of the fine-wool sheep. Therefore, discovering markers or genes relevant to wool traits is the cornerstone for the breeding of fine-wool sheep. In this study, we used the Illumina HiSeq X Ten platform to re-sequence 460 sheep belonging to four different fine-wool sheep breeds, namely, Alpine Merino sheep (AMS), Chinese Merino sheep (CMS), Aohan fine-wool sheep (AHS) and Qinghai fine-wool sheep (QHS). Eight wool traits, including fiber diameter (FD), fiber diameter coefficient of variance (FDCV), fiber diameter standard deviation (FDSD), staple length (SL), greasy fleece weight (GFW), clean wool rate (CWR), staple strength (SS) and staple elongation (SE) were examined. A genome-wide association study (GWAS) was performed to detect the candidate genes for the eight wool traits. RESULTS: A total of 8.222 Tb of raw data was generated, with an average of approximately 8.59X sequencing depth. After quality control, 12,561,225 SNPs were available for analysis. And a total of 57 genome-wide significant SNPs and 30 candidate genes were detected for the desired wool traits. Among them, 7 SNPs and 6 genes are related to wool fineness indicators (FD, FDCV and FDSD), 10 SNPs and 7 genes are related to staple length, 13 SNPs and 7 genes are related to wool production indicators (GFW and CWR), 27 SNPs and 10 genes associated with staple elongation. Among these candidate genes, UBE2E3 and RHPN2 associated with fiber diameter, were found to play an important role in keratinocyte differentiation and cell proliferation. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment results, revealed that multitude significant pathways are related to keratin and cell proliferation and differentiation, such as positive regulation of canonical Wnt signaling pathway (GO:0090263). CONCLUSION: This is the first GWAS on the wool traits by using re-sequencing data in Chinese fine-wool sheep. The newly detected significant SNPs in this study can be used in genome-selective breeding for the fine-wool sheep. And the new candidate genes would provide a good theoretical basis for the fine-wool sheep breeding.

14.
Artigo em Inglês | MEDLINE | ID: mdl-33395682

RESUMO

BACKGROUND/AIMS: Endoscopic vidian neurectomy (EVN) for allergic rhinitis (AR) has good clinical effects. However, the pathophysiological basis of the effect of EVN on AR is still poorly understood. This study aimed to investigate the efficacy of EVN on house dust mite (HDM)-sensitive AR and the dynamic changes of serum immunoglobulin E and some immune regulatory factors. METHODS: Twenty HDM-sensitive AR patients were treated with bilateral EVN (EVN group), 15 HDM-sensitive AR patients were treated with subcutaneous immunotherapy (SCIT group), and 15 healthy subjects served as healthy controls. Quality of daily life was assessed by the scores of the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQs). The visual analog scale was used to assess clinical efficacy. Serum molecules were measured by ELISA and the UNICAP system. RESULTS: Compared with the SCIT group, the RQLQs in the EVN group were lower 12 months after treatment (both p < 0.05). There was no significant difference in improving nasal itching and sneezing (both p > 0.05), but the clinical efficacy of bilateral EVN was greater than SCIT in improving nasal obstruction, rhinorrhea, eye itching, and lachrymation 12 months after treatment (all p < 0.05). Compared with before treatment, the serum levels of total immunoglobulin E (tIgE), Dermatophagoides pteronyssinus- and Dermatophagoides farinae-specific immunoglobulin E (sIgE), and tumor necrosis factor (TNF)-α in the EVN group and the serum levels of TNF-α and interleukin-4 in the SCIT group were lower 12 months after treatment (all p < 0.05). CONCLUSION: The short-term efficacy of bilateral EVN is more effective than SCIT in treating HDM-sensitive AR. This may be because the surgery reduced the tIgE and sIgE levels. TNF-α may be involved in the therapeutic mechanism.

15.
J Fungi (Basel) ; 7(2)2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33513923

RESUMO

Fusarium solani (Fs) is one of the notorious necrotrophic fungal pathogens that cause root rot and vascular wilt, accounting for the severe loss of Populus production worldwide. The plant-pathogen interactions have a strong molecular basis. As yet, the genomic information and transcriptomic profiling on the attempted infection of Fs remain unavailable in a woody model species, Populus trichocarpa. We used a full RNA-seq transcriptome to investigate the molecular interactions in the roots with a time-course infection at 0, 24, 48, and 72 h post-inoculation (hpi) of Fs. Concomitantly, the invertase and invertase inhibitor-like gene families were further analyzed, followed by the experimental evaluation of their expression patterns using quantitative PCR (qPCR) and enzyme assay. The magnitude profiles of the differentially expressed genes (DEGs) were observed at 72 hpi inoculation. Approximately 839 genes evidenced a reception and transduction of pathogen signals, a large transcriptional reprogramming, induction of hormone signaling, activation of pathogenesis-related genes, and secondary and carbohydrate metabolism changes. Among these, a total of 63 critical genes that consistently appear during the entire interactions of plant-pathogen had substantially altered transcript abundance and potentially constituted suitable candidates as resistant genes in genetic engineering. These data provide essential clues in the developing new strategies of broadening resistance to Fs through transcriptional or translational modifications of the critical responsive genes within various analyzed categories (e.g., carbohydrate metabolism) in Populus.

16.
Biochem Pharmacol ; 184: 114400, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33387481

RESUMO

Multidrug-resistant (MDR) Acinetobacter baumannii presents a critical challenge to human health worldwide and polymyxins are increasingly used as a last-line therapy. Due to the rapid emergence of resistance during polymyxin monotherapy, synergistic combinations (e.g. with rifampicin) are recommended to treat A. baumannii infections. However, most combination therapies are empirical, owing to a dearth of understanding on the mechanism of synergistic antibacterial killing. In the present study, we employed metabolomics to investigate the synergy mechanism of polymyxin B-rifampicin against A. baumannii AB5075, an MDR clinical isolate. The metabolomes of A. baumannii AB5075 were compared at 1 and 4 h following treatments with polymyxin B alone (0.75 mg/L, i.e. 3 × MIC), rifampicin alone (1 mg/L, i.e. 0.25 × MIC) and their combination. Polymyxin B monotherapy significantly perturbed glycerophospholipid and fatty acid metabolism at 1 h, reflecting its activity on bacterial outer membrane. Rifampicin monotherapy significantly perturbed glycerophospholipid, nucleotide and amino acid metabolism, which are related to the inhibition of RNA synthesis. The combination treatment significantly perturbed the metabolism of nucleotides, amino acids, fatty acids and glycerophospholipids at 1 and 4 h. Notably, the intermediate metabolite pools from pentose phosphate pathway were exclusively enhanced by the combination, while most metabolites from the nucleotide and amino acid biosynthesis pathways were significantly decreased. Overall, the synergistic activity of the combination was initially driven by polymyxin B which impacted pathways associated with outer membrane biogenesis; and subsequent effects were mainly attributed to rifampicin via the inhibition of RNA synthesis. This study is the first to reveal the synergistic killing mechanism of polymyxin-rifampicin combination against polymyxin-susceptible MDR A. baumannii at the network level. Our findings provide new mechanistic insights for optimizing this synergistic combination in patients.


Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/metabolismo , Antibacterianos/farmacologia , Polimixina B/farmacologia , Rifampina/farmacologia , Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/isolamento & purificação , Parede Celular/efeitos dos fármacos , Parede Celular/metabolismo , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Sinergismo Farmacológico , Quimioterapia Combinada , Glicerofosfolipídeos/metabolismo , Humanos , Metabolômica/métodos , Nucleotídeos/metabolismo , Fosfolipídeos/metabolismo
17.
Transl Psychiatry ; 11(1): 65, 2021 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-33462194

RESUMO

Novelty-seeking behaviors and impulsivity are personality traits associated with several psychiatric illnesses including attention deficits hyperactivity disorders. The underlying neural mechanisms remain poorly understood. We produced and characterized a line of knockout mice for zdhhc15, which encodes a neural palmitoyltransferase. Genetic defects of zdhhc15 were implicated in intellectual disability and behavioral anomalies in humans. Zdhhc15-KO mice showed normal spatial learning and working memory but exhibited a significant increase in novelty-induced locomotion in open field. Striatal dopamine content was reduced but extracellular dopamine levels were increased during the habituation phase to a novel environment. Administration of amphetamine and methylphenidate resulted in a significant increase in locomotion and extracellular dopamine levels in the ventral striatum of mutant mice compared to controls. Number and projections of dopaminergic neurons in the nigrostriatal and mesolimbic pathways were normal. No significant change in the basal palmitoylation of known ZDHHC15 substrates including DAT was detected in striatum of zdhhc15 KO mice using an acyl-biotin exchange assay. These results support that a transient, reversible, and novelty-induced elevation of extracellular dopamine in ventral striatum contributes to novelty-seeking behaviors in rodents and implicate ZDHHC15-mediated palmitoylation as a novel regulatory mechanism of dopamine in the striatum.

18.
Nat Commun ; 12(1): 456, 2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33469004

RESUMO

The semiclassical models of nonadiabatic transition were proposed first by Landau and Zener in 1932, and have been widely used in the study of electron transfer (ET); however, experimental demonstration of the Landau-Zener formula remains challenging to observe. Herein, employing the Hush-Marcus theory, thermal ET in mixed-valence complexes {[Mo2]-(ph)n-[Mo2]}+ (n = 1-3) has been investigated, spanning the nonadiabatic throughout the adiabatic limit, by analysis of the intervalence transition absorbances. Evidently, the Landau-Zener formula is valid in the adiabatic regime in a broader range of conditions than the theoretical limitation known as the narrow avoided-crossing. The intermediate system is identified with an overall transition probability (κel) of ∼0.5, which is contributed by the single and the first multiple passage. This study shows that in the intermediate regime, the ET kinetic results derived from the adiabatic and nonadiabatic formalisms are nearly identical, in accordance with the Landau-Zener model. The obtained insights help to understand and control the ET processes in biological and chemical systems.

19.
Plant J ; 105(6): 1689-1702, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33354819

RESUMO

Adventitious roots (ARs) are an important root type for plants and display a high phenotypic plasticity in response to different environmental stimuli. Previous studies found that dark-light transition can trigger AR formation from the hypocotyl of etiolated Arabidopsis thaliana, which was used as a model for the identification of regulators of AR biogenesis. However, the central regulatory machinery for darkness-induced hypocotyl AR (HAR) remains elusive. Here, we report that photoreceptors suppress HAR biogenesis through regulating the molecular module essential for lateral roots. We found that hypocotyls embedded in soil or in continuous darkness are able to develop HARs, wherein photoreceptors act as negative regulators. Distinct from wound-induced ARs that require WOX11 and WOX12, darkness-induced HARs are fully dependent on ARF7, ARF19, WOX5/7, and LBD16. Further studies established that PHYB interacts with IAA14, ARF7, and ARF9. The interactions stabilize IAA14 and inhibit the transcriptional activities of ARF7 and ARF19 and thus suppress biogenesis of darkness-induced HARs. This finding not only revealed the central machinery controlling HAR biogenesis but also illustrated that AR formation could be initiated by multiple pathways.

20.
Diabetes Res Clin Pract ; 172: 108629, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33347898

RESUMO

AIMS: The aim of this study was to develop a Diabetes Mellitus Treatment Adherence Scale (DMTAS) to fill the gap in the internationally accepted comprehensive scale. METHODS: An initial item pool for the Diabetes Mellitus Treatment Adherence Scale (DMTAS) was generated based on a review of the literature and an open-ended interview. An expert group screened this initial item pool using an item-level content validity index. Then, pilot testing with 116 participants was conducted. After removing redundant and cross-loading items by exploratory factor analysis, 630 subjects were recruited to evaluate the reliability and validity of DMTAS. Analyses included internal consistency, test-retest reliability, split-half reliability, construct validity, convergent validity, and discriminant validity analysis. RESULTS: The final DMTAS consisted of 19 items and six dimensions. The results of the exploratory factor analysis indicated that the variances of each factor explained were 23.07%, 12.28%, 9.50%, 8.25%, 7.85%, and 5.80%, and all six factors explained 66.75% of the variance in the 19 items. The items' factor loadings were all above 0.6. The results of the confirmatory factor analysis indicated that adequate fit indices (χ2 value to degrees of freedom = 3.62; root mean square error of approximation = 0.06; goodness-of-fit index = 0.92) were achieved. The Cronbach's alpha coefficient was 0.79, test-retest reliability was 0.73, and split-half reliability was 0.75. CONCLUSIONS: The DMTAS showed good validity and reliability to measure the out-of-hospital treatment adherence in patients with diabetes mellitus.


Assuntos
Diabetes Mellitus/terapia , Psicometria/métodos , Cooperação e Adesão ao Tratamento/estatística & dados numéricos , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , Inquéritos e Questionários , Estudos de Validação como Assunto
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