AIMS: To investigate low molecular weight compounds produced in vitro by Lysobacter capsici AZ78 and their toxic activity against sporangia of plant pathogenic oomycetes. METHODS AND RESULTS: Assays ...carried out in vitro showed that L. capsici AZ78 drastically inhibits the growth of plant pathogenic oomycetes. Accordingly, the preventive application of culture filtrates of L. capsici AZ78 on grapevine and tomato plants reduced the infections, respectively, caused by Plasmopara (Pl.) viticola and Phytophthora infestans. The subsequent chemical analysis of the culture filtrates of L. capsici AZ78 by spectroscopic (essentially 1D and 2D¹H NMR and¹³C NMR and ESI MS spectra) and optical methods led to the identification of the 2,5‐diketopiperazine cyclo(l‐Pro‐l‐Tyr) that inhibited the development of P. infestans sporangia in vitro and on tomato leaves. Furthermore, a genomic region with high sequence identity with genes coding for a hybrid polyketide synthase and nonribosomal peptide synthetase was detected in L. capsici AZ78. CONCLUSIONS: Lysobacter capsici AZ78 produces cyclo(l‐Pro‐l‐Tyr) in vitro that was effective in killing the sporangia of P. infestans and Pl. viticola in vitro. Moreover, this low molecular weight compound prevents the occurrence of late blight lesions when applied on tomato leaves. SIGNIFICANCE AND IMPACT OF THE STUDY: The application of L. capsici AZ78 cells or its own culture filtrates effectively controls both P. infestans and Pl. viticola. Cyclo(l‐Pro‐l‐Tyr) produced by L. capsici AZ78 is toxic against sporangia of both these oomycetes. These data enforce the potential in the use of Lysobacter members for the control of plant pathogenic oomycetes and provide the basis for the development of new low‐impact fungicides based on cyclo(l‐Pro‐l‐Tyr).
Background:
Quadriceps strength deficits are observed clinically after anterior cruciate ligament (ACL) injury and reconstruction and are often not overcome despite rehabilitation. Given that ...quadriceps strength may be important for achieving symmetrical joint biomechanics and promoting long-term joint health, determining the magnitude of strength deficits that lead to altered mechanics is critical.
Purpose:
To determine if the magnitude of quadriceps strength asymmetry alters knee and hip biomechanical symmetry as well as functional performance and self-reported function.
Study Design:
Cross-sectional study; Level of evidence, 3.
Methods:
A total of 73 patients were tested at the time they were cleared for return to activity after ACL reconstruction. Quadriceps strength and activation, scores on the International Knee Documentation Committee form, the hop for distance test, and sagittal plane lower extremity biomechanics were recorded while patients completed a single-legged hop.
Results:
Patients with high and moderate quadriceps strength symmetry had larger central activation ratios as well as greater limb symmetry indices on the hop for distance compared with patients with low quadriceps strength symmetry (P < .05). Similarly, knee flexion angle and external moment symmetry were higher in the patients with high and moderate quadriceps symmetry compared with those with low symmetry (P < .05). Quadriceps strength was found to be associated with sagittal plane knee angle and moment symmetry (P < .05).
Conclusion:
Patients with low quadriceps strength displayed greater movement asymmetries at the knee in the sagittal plane. Quadriceps strength was related to movement asymmetries and functional performance. Rehabilitation after ACL reconstruction needs to focus on maximizing quadriceps strength, which likely will lead to more symmetrical knee biomechanics.
Mitochondria play an essential role in nitric oxide (NO) signal transduction in plants. Using the biotin-switch method in conjunction with nano-liquid chromatography and mass spectrometry, we ...identified 11 candidate proteins that were S-nitrosylated and/or glutathionylated in mitochondria of Arabidopsis (Arabidopsis thaliana) leaves. These included glycine decarboxylase complex (GDC), a key enzyme of the photorespiratory C₂ cycle in C3 plants. GDC activity was inhibited by S-nitrosoglutathione due to S-nitrosylation/S-glutathionylation of several cysteine residues. Gas-exchange measurements demonstrated that the bacterial elicitor harpin, a strong inducer of reactive oxygen species and NO, inhibits GDC activity. Furthermore, an inhibitor of GDC, aminoacetonitrile, was able to mimic mitochondrial depolarization, hydrogen peroxide production, and cell death in response to stress or harpin treatment of cultured Arabidopsis cells. These findings indicate that the mitochondrial photorespiratory system is involved in the regulation of NO signal transduction in Arabidopsis.
Neutrophils are a vital component of immune protection, yet in cancer they may promote tumour progression, partly by generating reactive oxygen species (ROS) that disrupts lymphocyte functions. ...Metabolically, neutrophils are often discounted as purely glycolytic. Here we show that immature, c-Kit
neutrophils subsets can engage in oxidative mitochondrial metabolism. With limited glucose supply, oxidative neutrophils use mitochondrial fatty acid oxidation to support NADPH oxidase-dependent ROS production. In 4T1 tumour-bearing mice, mitochondrial fitness is enhanced in splenic neutrophils and is driven by c-Kit signalling. Concordantly, tumour-elicited oxidative neutrophils are able to maintain ROS production and T cell suppression when glucose utilisation is restricted. Consistent with these findings, peripheral blood neutrophils from patients with cancer also display increased immaturity, mitochondrial content and oxidative phosphorylation. Together, our data suggest that the glucose-restricted tumour microenvironment induces metabolically adapted, oxidative neutrophils to maintain local immune suppression.
Epidemiology of Posttraumatic Osteoarthritis Thomas, Abbey C; Hubbard-Turner, Tricia; Wikstrom, Erik A ...
Journal of athletic training,
06/2017, Letnik:
52, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Osteoarthritis is a leading cause of disability whose prevalence and incidence continue to increase. History of joint injury represents an important risk factor for posttraumatic osteoarthritis and ...is a significant contributor to the rapidly growing percentage of the population with osteoarthritis. This review will present the epidemiology associated with posttraumatic osteoarthritis, with particular emphasis on the knee and ankle joints. It is important to understand the effect of posttraumatic osteoarthritis on the population so that sufficient resources can be devoted to countering the disease and promoting optimal long-term health for patients after joint injury.
Glutamine-synthetase (GS), the glutamine-synthesizing enzyme from glutamate, controls important events, including the release of inflammatory mediators, mammalian target of rapamycin (mTOR) ...activation, and autophagy. However, its role in macrophages remains elusive. We report that pharmacologic inhibition of GS skews M2-polarized macrophages toward the M1-like phenotype, characterized by reduced intracellular glutamine and increased succinate with enhanced glucose flux through glycolysis, which could be partly related to HIF1α activation. As a result of these metabolic changes and HIF1α accumulation, GS-inhibited macrophages display an increased capacity to induce T cell recruitment, reduced T cell suppressive potential, and an impaired ability to foster endothelial cell branching or cancer cell motility. Genetic deletion of macrophagic GS in tumor-bearing mice promotes tumor vessel pruning, vascular normalization, accumulation of cytotoxic T cells, and metastasis inhibition. These data identify GS activity as mediator of the proangiogenic, immunosuppressive, and pro-metastatic function of M2-like macrophages and highlight the possibility of targeting this enzyme in the treatment of cancer metastasis.
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•GS expression and activity are induced by M2 stimuli, especially under starvation•Inhibition of GS activity skews M2 macrophages toward an M1-like phenotype•Metabolic rewiring by GS loss favors immunostimulatory and antiangiogenic features•GS ablation in macrophages blocks vessels, immunosuppression, and metastasis
Palmieri et al. show that inhibiting glutamine synthetase activity in M2 macrophages skews their polarization toward an HIF1α-mediated M1 state, which impairs cytotoxic T cell recruitment and angiogenesis. As a consequence of a more pronounced immunostimulatory and antiangiogenic effect, GS ablation in macrophages translates into prevention of metastasis.
This work aimed to develop an efficient R1ρ dispersion imaging method for clinical studies of human knee cartilage at 3 T. Eight constant magnetizations (Mprep) were prepared by tailoring both the ...duration and amplitude (ω1) of a fully refocused spin‐lock preparation pulse. The limited Mprep dynamic range was expanded by the measure, equivalent to that with ω1 = ∞, from the magic angle location in the deep femoral cartilage. The developed protocol with Mprep = 60% was demonstrated on one subject's bilateral and two subjects' unilateral asymptomatic knees. The repeatability of the proposed protocol was estimated by two repeated scans with a three‐month gap for the last two subjects. The synthetic R1ρ and R2 derived from R1ρ dispersions were compared with the published references using state‐of‐the‐art R1ρ and R2 mapping (MAPSS). The proposed protocol demonstrated good (<5%) repeatability quantified by the intra‐ and intersubject coefficients of variation in the femoral and tibial cartilage. The synthetic R1ρ (1/s) and the references were comparable in the femoral (23.0 ± 5.3 versus 24.1 ± 3.8, P = 0.67) and the tibial (29.1 ± 8.8 versus 27.1 ± 5.1, P = 0.62), but not the patellar (16.5 ± 4.9 versus 22.7 ± 1.6, P < 0.01) cartilage. The same trends were also observed for the current and the previous R2. In conclusion, the developed R1ρ dispersion imaging scheme has been revealed to be not only efficient but also robust for clinical studies of human knee cartilage at 3 T.
We propose an efficient R1ρ dispersion imaging method for human knee cartilage studies. A constant magnetization was prepared by tailoring both duration and amplitude of a fully‐refocused spin‐lock preparation pulse, leading to not only an accessible clinical scan time but also less adverse k‐space filtering effect during image readout. The results from repeated scans and from comparisons with the literature suggest that the proposed method is a promising tool to further explore cartilage R1ρ dispersion in clinical settings.
The mitochondrial citrate–malate exchanger (CIC), a known target of acetylation, is up-regulated in activated immune cells and plays a key role in the production of inflammatory mediators. However, ...the role of acetylation in CIC activity is elusive. We show that CIC is acetylated in activated primary human macrophages and U937 cells and the level of acetylation is higher in glucose-deprived compared to normal glucose medium. Acetylation enhances CIC transport activity, leading to a higher citrate efflux from mitochondria in exchange with malate. Cytosolic citrate levels do not increase upon activation of cells grown in deprived compared to normal glucose media, indicating that citrate, transported from mitochondria at higher rates from acetylated CIC, is consumed at higher rates. Malate levels in the cytosol are lower in activated cells grown in glucose-deprived compared to normal glucose medium, indicating that this TCA intermediate is rapidly recycled back into the cytosol where it is used by the malic enzyme. Additionally, in activated cells CIC inhibition increases the NADP+/NADPH ratio in glucose-deprived cells; this ratio is unchanged in glucose-rich grown cells due to the activity of the pentose phosphate pathway. Consistently, the NADPH-producing isocitrate dehydrogenase level is higher in activated glucose-deprived as compared to glucose rich cells. These results demonstrate that, in the absence of glucose, activated macrophages increase CIC acetylation to enhance citrate efflux from mitochondria not only to produce inflammatory mediators but also to meet the NADPH demand through the actions of isocitrate dehydrogenase and malic enzyme.
•The mitochondrial citrate carrier, important for macrophage activation, is acetylated in human cells•CIC acetylation is higher in macrophages activated in low versus high glucose medium and increases CIC transport activity•Increased citrate efflux to the cytosol is necessary for NADPH production in the absence of glucose•Through CIC acetylation activated macrophages adjust metabolism to satisfy their demands in rapidly changing carbon sources
The importance of metabolism in macrophage function has been reported, but the in vivo relevance of the in vitro observations is still unclear. Here we show that macrophage metabolites are defined in ...a specific tissue context, and these metabolites are crucially linked to tissue-resident macrophage functions. We find the peritoneum to be rich in glutamate, a glutaminolysis-fuel that is exploited by peritoneal-resident macrophages to maintain respiratory burst during phagocytosis via enhancing mitochondrial complex-II metabolism. This niche-supported, inducible mitochondrial function is dependent on protein kinase C activity, and is required to fine-tune the cytokine responses that control inflammation. In addition, we find that peritoneal-resident macrophage mitochondria are recruited to phagosomes and produce mitochondrially derived reactive oxygen species, which are necessary for microbial killing. We propose that tissue-resident macrophages are metabolically poised in situ to protect and exploit their tissue-niche by utilising locally available fuels to implement specific metabolic programmes upon microbial sensing.
Nitric Oxide (NO) is a soluble endogenous gas with various biological functions like signaling, and working as an effector molecule or metabolic regulator. In response to inflammatory signals, immune ...myeloid cells, like macrophages, increase production of cytokines and NO, which is important for pathogen killing. Under these proinflammatory circumstances, called “M1”, macrophages undergo a series of metabolic changes including rewiring of their tricarboxylic acid (TCA) cycle. Here, we review findings indicating that NO, through its interaction with heme and non-heme metal containing proteins, together with components of the electron transport chain, functions not only as a regulator of cell respiration, but also a modulator of intracellular cell metabolism. Moreover, diverse effects of NO and NO-derived reactive nitrogen species (RNS) involve precise interactions with different targets depending on concentration, temporal, and spatial restrictions. Although the role of NO in macrophage reprogramming has been in evidence for some time, current models have largely minimized its importance. It has, therefore, been hiding in plain sight. A review of the chemical properties of NO, past biochemical studies, and recent publications, necessitates that mechanisms of macrophage TCA reprogramming during stimulation must be re-imagined and re-interpreted as mechanistic results of NO exposure. The revised model of metabolic rewiring we describe here incorporates many early findings regarding NO biochemistry and brings NO out of hiding and to the forefront of macrophages immunometabolism.
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