Energetic metabolism supports rapid cell growth and proliferation, differentiation, polarization, and effector functions of T cells. T lymphocytes have the remarkable plasticity that allows them to ...shape their metabolism to adapt to extracellular and intracellular cues, a process that involves molecular modules referred to as "metabolic checkpoints" that sense metabolic signals and transduce effector messages. These metabolic checkpoints may represent a novel therapeutic strategy for immune modulation. Chemical immunosuppressive drugs including mammalian target of rapamycin inhibitors (sirolimus and everolimus), calcineurin inhibitors (tacrolimus and cyclosporine), and purine and pyrimidine synthesis inhibitors (6-mercaptopurine, mycophenolic acid, and methotrexate) are widely prescribed for the treatment of autoimmune and inflammatory diseases and for controlling alloimmunity in interfering with the signals that activate and allow T cells to proliferate. Emerging evidence indicates that these drugs also target T-cell metabolism and metabolic checkpoints, which, as a consequence, could contribute to their immunosuppressive effects. These examples raise the issue of how the modulation of these metabolic checkpoints can regulate T-cell activation, differentiation, and function. In this review we highlight emerging concepts about the modulation of metabolic reprogramming in T-cell responses by immunosuppressive drugs and how potential therapeutic interventions influence T-cell fate and effector function.
T lymphocytes undergo metabolic reprogramming to adapt to extracellular and intracellular cues. Specifically, T-cell metabolism results into ATP production, anabolism and catabolism pathways that not ...only support rapid cell growth and proliferation, but also differentiation and effector functions, recently referred as “immunometabolism”. Quiescent naïve T cells rely on oxidative phosphorylation whereas aerobic glycolysis (Warburg effect) occurs in activated T cells (effector CD4+ and CD8+). The molecular mechanisms that sense metabolic status and influence T-cell function require metabolic checkpoints including sensors of metabolic signals and transducers (Myc, HIF-1α, AMPK and mTOR). These metabolic checkpoints represent a novel therapeutic strategy for immune modulation. Interestingly, many immunosuppressive drugs including mTOR inhibitors (rapamycin), calcineurin inhibitors (tacrolimus, cyclosporine A) and inhibitors of de novo purine synthesis (6-mercaptopurine, mycophenolic acid and methotrexate) provide examples into how modulating these metabolic checkpoints can regulate T-cell activation, differentiation and function.
In this Review we highlight emerging concepts about metabolic reprogramming in T-cell responses and we discuss the potential therapeutic interventions to influence T-cell fate and effector function.
Display omitted
•Metabolic reprogramming allows for rapid cell adaptation to environmental cues.•Cancer and T cells undergo metabolic reprogramming to adapt to changing situations.•Changes in metabolism are critical for T-lymphocyte fate and effector functions.•Key regulators of cellular metabolism have a fundamental role in immune responses.•Immunosuppressive drugs affect T-cell metabolism by targeting metabolic checkpoints.
Phytophthora capsici is a highly destructive pathogen of crops. Although chemical pesticides are the most widely used strategy to counter phytopathogens, they have been inefficient to combat P. ...capsici and have produced significant environmental and health problems. Therefore, sustainable alternatives to control soilborne pathogens, such as the inhibitory effect of self‐extracellular DNA (eDNA), have been proposed. This inhibition phenomenon has been attributed to the action of self‐eDNA as a damage‐associated molecular pattern (DAMP). Here, we describe the effect of self‐eDNA on P. capsici zoospore germination rate, antioxidant enzymes activity and MAPK gene expression. Also, the effect of P. capsici eDNA on the protection of chilli pepper (Capsicum annuum) plants against P. capsici was investigated. The results highlight that P. capsici can sense 2–500 µg/ml self‐eDNA and induce stress‐related responses like SAK1 gene expression, and superoxide dismutase and catalase activities. Moreover, in vitro zoospore germination rate was suppressed with self‐eDNA concentrations ranging from 50 to 500 µg/ml. Interestingly, drench applications of P. capsici eDNA at 60 and 100 µg/ml on chilli pepper plants did not show any protective effect against the phytopathogen, whereas 2 µg/ml of P. capsici eDNA drench application showed a lower percentage of plants with symptoms and lower disease severity. Moreover, phenols and total flavonoids were increased in chilli pepper plants, therefore inducing plant immunity. This study showed that self‐eDNA acts as a DAMP in P. capsici and provides insight into the use of eDNA for the protection of crops of agronomic interest.
This study showed that self‐eDNA acts as a DAMP in P. capsici inducing stress‐related responses, giving an insight into the use of self‐eDNA in field‐like conditions against the phytopathogen.
The dynamics of volatilomes emitted during the interaction between plant-growth-promoting bacteria (PGPB) and the phytopathogen
Fusarium solani
were evaluated for 5 days. The first screening was done ...to evaluate the antagonist activity of volatile compounds emitted by PGPB against
F. solani
. Volatilomes from 11 PGPB were determined individually and together with
F. solani
by using solid-phase microextraction coupled to gas-chromatography–mass spectrometry. Isolates of PGPB belonged to the
Bacillus
genus and inhibited from 18 to 24% the fungal mycelium growth. The isolates also induced morphological alterations of fungal hyphae, like small globular vesicles and the formation of chlamydospores, suggesting a stress mechanism response by the fungus. Volatilome profile showed 49 different compounds that appeared in the bacterial–fungal interaction, such as ketones, sesquiterpenes, monoterpenoids, alkanes, alkenes, carboxylic acids, and fatty acids. Some ketones and alcohols were detected in high abundance only in the interaction PGPB-fungus at 3 and 5 days.
Bacillus circulans
A19,
Bacillus amyloliquefaciens
A21, and
Bacillus wiedmannii
S18 shared a group of emitted alcohols and ketones when they were exposed to
F. solani
.
F. solani
produced its own volatilome profile, with the presence of sesquiterpenes, such as α-cubebene and caryophyllene, which increased significantly in co-incubation with the tested bacteria, suggesting chemical communication between them.
Graphic abstract
Ice ages within Europe forced many species to retreat to refugia, of which three major biogeographic basic types can be distinguished: "Mediterranean", "Continental" and "Alpine / Arctic" species. ...However, this classification often fails to explain the complex phylogeography of European species with a wide range of latitudinal and altitudinal distribution. Hence, we tested for the possibility that all three mentioned faunal elements are represented within one species. Our data was obtained by scoring 1,307 Euphydryas aurinia individuals (46 European locations) for 17 allozyme loci, and sequencing a subset of 492 individuals (21 sites) for a 626 base pairs COI fragment. Genetic diversity indices, F statistics, hierarchical analyses of molecular variance, individual-based clustering, and networks were used to explore the phylogeographic patterns. The COI fragment represented 18 haplotypes showing a strong geographic structure. All but one allozyme loci analysed were polymorphic with a mean FST of 0.20, supporting a pronounced among population structure. Interpretation of both genetic marker systems, using several analytical tools, calls for the recognition of twelve genetic groups. These analyses consistently distinguished different groups in Iberia (2), Italy, Provence, Alps (3), Slovenia, Carpathian Basin, the lowlands of West and Central Europe as well as Estonia, often with considerable additional substructures. The genetic data strongly support the hypothesis that E. aurinia survived the last glaciation in Mediterranean, extra-Mediterranean and perialpine refugia. It is thus a rare example of a model organism that combines attributes of faunal elements from all three of these sources. The observed differences between allozymes and mtDNA most likely result from recent introgression of mtDNA into nuclear allozyme groups. Our results indicate discrepancies with the morphologically-based subspecies models, underlining the need to revise the current taxonomy.
Background
Atherosclerosis represents a cardiovascular risk. Chronic inflammation is a key factor for atherogenic progression. Neutrophil‐to‐lymphocyte ratio (NLR) has been proposed as a novel ...biomarker for cardiovascular risks. We aimed to explore whether NLR was related to surrogate pro‐atherogenic promoters driving atherogenic progression, as measured by carotid intima‐media thickness (CIMT).
Study Design
Thirty‐one patients with obesity candidates for bariatric surgery were recruited from Centro Médico Nacional “20 de Noviembre”, ISSSTE, Mexico City. The results are part of the “CROP” study (NCT03561987). NLR was calculated from routine complete blood count, and its relation with plasma pro‐inflammatory mediators (hsCRP, TNF‐α and IL‐1β), adipokines (adiponectin and leptin), adiposity markers (visceral adipose tissue VAT determined from CT scan image and VAT individual adipocyte area at histological sample) and CIMT were determined.
Results
Neutrophil‐to‐lymphocyte ratio correlated with hsCRP (Spearman's r = 0.70 95% CI 0.46 to 0.85, P < 0.01), TNF‐α (r = 0.69 0.44 to 0.84, P < 0.0001) and adiponectin (r = −0.69 −0.84 to −0.45, P < 0.03), as well as with VAT individual adipocyte area (r = 0.64 0.37 to 0.81, P < 0.0001) and with VAT area (r = 0.43; 0.07 to 0.68, P < 0.01). Leptin and adiponectin showed further independent association with higher NLR (multivariate regression analysis OR 7.9 95% CI 1.1 to 56.2 P = 0.03 and 0.1 0.01 to 1.0 P = 0.05, respectively). Moreover, NLR distribution significantly varied between subgroups divided according to progressive CIMT (P = 0.05); whereas adiponectin and VAT adipocyte area associated with CIMT > 0.9 mm (univariate analysis OR 0.1 0.01 to 1.0 P = 0.05 and 13.1 1.4 to 126.3 P = 0.03, respectively).
Conclusion
Neutrophil‐to‐lymphocyte ratio was related to pro‐inflammatory, adiposity biomarkers and progressive subclinical atherogenesis.
Introduction
People with chronic obstructive pulmonary disease (COPD) present high prevalence of physical inactivity that leads to a negative effect on health-related quality of life (HRQoL). The ...present study investigated COPD phenotypes according to their levels of physical activity and sedentary behaviour, as well as body composition and skeletal muscle strength.
Methods
This is an observational and cross-sectional study. Anthropometric data and COPD clinical control were collected and all participants underwent assessments of lung function, HRQoL, dyspnoea, levels of physical activity and sedentary behaviour, body composition and skeletal muscle strength. Participants were classified using hierarchical cluster analysis. Age, dyspnoea and obstruction (ADO) index was used to determine prognosis and calculated for each cluster.
Results
One hundred and fifty-two participants were included. Three distinct phenotypes were identified. Participants in phenotype 1 were more physically active, less sedentary and had better body composition and lower ADO index (
p
< 0.0001 for all variables). Overall, participants in phenotypes 2 and 3 were less physically active, more sedentary having a higher ADO index. However, participants in phenotype 2 were older, whereas participants in phenotype 3 had worse HRQoL, clinical control and body composition. Lung function did not differ across the three phenotypes.
Conclusions
Our results show that physical activity, sedentary behaviour and body composition should be considered to determine phenotypes in people with COPD and are involved in the prognosis of the disease. Less sedentary patients have better prognosis while age, body composition and clinical control seems to differentiate physically inactive patients.
There is not much information about breast health in transgender (transexual) persons given the historical stigma that this population suffers. This research aimed to describe breast imaging patterns ...in transgender (trans) women and men that had been using gender affirmation hormone treatment for at least 3 years.
In this observational, cross-sectional study, 67 transgender individuals (34 trans women and 33 trans men) had mammography and breast ultrasound performed. We also classified the findings by the American College of Radiology - Breast Imaging Reporting and Data System (ACR BI-RADS®).
We found that there was a higher frequency of dense breasts in trans women (75.8%) and in trans men (66,6%) than expected for cisgender (cis) women.
This study highlights the importance of a deeper understanding of the image patterns of transgender breasts because of hormonal effects that the gender transition entails so we can offer better health care and preventive services in the transgender (transexual) population.
The anticancer drug 6-mercaptopurine (6-MP) inhibits de novo purine synthesis and acts as an antiproliferative agent by interfering with protein, DNA and RNA synthesis and promoting apoptosis. ...Metabolic reprogramming is crucial for tumor progression to foster cancer cells growth and proliferation, and is regulated by mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) as well as the oncogenes Myc and hypoxia inducible factor 1α (HIF-1α). We hypothesized that 6-MP impacts metabolic remodeling through its action on nucleotide synthesis. The aim of our study is to provide a comprehensive characterization of the metabolic changes induced by 6-MP in leukemic T cells. Our results indicate that exposition to 6-MP rapidly reduces intracellular ATP concentration, leading to the activation of AMPK. In turn, mTOR, an AMPK target, was inhibited, and the expression of HIF-1α and Myc was reduced upon 6-MP incubation. As a consequence of these inhibitions, glucose and glutamine fluxes were strongly decreased. Notably, no difference was observed on glucose uptake upon exposition to 6-MP. In conclusion, our findings provide new insights into how 6-MP profoundly impacts cellular energetic metabolism by reducing ATP production and decreasing glycolytic and glutaminolytic fluxes, and how 6-MP modifies human leukemic T cells metabolism with potential antiproliferative effects.
Oxidative stress is one of the key phenomena behind the most common types of chronic diseases. Therefore, the modulation of oxidative stress is an interesting target for acting either through ...prevention or as a therapeutic approach. In this work, a Portuguese variety of cherry (Saco Cherry) was processed in order to obtain a potent in vitro antioxidant phenolic-rich extract (Ch-PRE), which was further explored to evaluate its potential application as nutraceutical agent against cellular oxidative stress damage. Ch-PRE was mainly composed of anthocyanins, particularly cyanidin-3-rutinoside, cyanidin-3-glucoside, peonidin-3-glucoside and neochlorogenic acid, and exhibited a potent chemical antioxidant activity expressed by its oxygen radical absorbance capacity (ORAC) and hydroxyl radical averting capacity (HORAC) values. Ch-PRE also displayed effective intracellular radical scavenging properties in intestinal epithelial and neuronal cells challenged with oxidative stress but showed a different order of effectiveness regarding the modulation of endogenous antioxidant system. Ch-PRE could be an attractive candidate to formulate an agent for the prevention of oxidative stress-induced disorders such as intestinal inflammation disorders or with an appropriated delivery system for neurodegenerative diseases.
PDF
