Influence of inflammation in the process of T lymphocyte differentiation: Proliferative, metabolic, and oxidative changes

T lymphocytes, from their first encounter with their specific antigen as naïve cell until the last stages of their differentiation, in a replicative state of senescence, go through a series of phases. In several of these stages, T lymphocytes are subjected to exponential growth in successive encounters with the same antigen. This entire process occurs throughout the life of a human individual and, earlier, in patients with chronic infections/pathologies through inflammatory mediators, first acutely and later in a chronic form. This process plays a fundamental role in amplifying the activating signals on T lymphocytes and directing their clonal proliferation. The mechanisms that control cell growth are high levels of telomerase activity and maintenance of telomeric length that are far superior to other cell types, as well as metabolic adaptation and redox control. Large numbers of highly differentiated memory cells are accumulated in the immunological niches where they will contribute in a significant way to increase the levels of inflammatory mediators that will perpetuate the new state at the systemic level. These levels of inflammation greatly influence the process of T lymphocyte differentiation from naïve T lymphocyte, even before, until the arrival of exhaustion or cell death. The changes observed during lymphocyte differentiation are correlated with changes in cellular metabolism and these in turn are influenced by the inflammatory state of the environment where the cell is located. Reactive oxygen species (ROS) exert a dual action in the population of T lymphocytes. Exposure to high levels of ROS decreases the capacity of activation and T lymphocyte proliferation; however, intermediate levels of oxidation are necessary for the lymphocyte activation, differentiation, and effector functions. In conclusion, we can affirm that the inflammatory levels in the environment greatly influence the differentiation and activity of T lymphocyte populations. However, little is known about the mechanisms involved in these processes. The elucidation of these mechanisms would be of great help in the advance of improvements in pathologies with a large inflammatory base such as rheumatoid arthritis, intestinal inflammatory diseases, several infectious diseases and even, cancerous processes

When aging reaches CD4+ T-cells: Phenotypic and functional changes

Beyond midlife, the immune system shows aging features and its defensive capability becomes impaired, by a process known as immunosenescence that involves many changes in the innate and adaptive responses. Innate immunity seems to be better preserved globally, while the adaptive immune response exhibits profound age-dependent modifications. Elderly people display a decline in numbers of naïve T-cells in peripheral blood and lymphoid tissues, while, in contrast, their proportion of highly differentiated effector and memory T-cells, such as the CD28(null) T-cells, increases markedly. Naïve and memory CD4+ T-cells constitute a highly dynamic system with constant homeostatic and antigen-driven proliferation, influx, and loss of T-cells. Thymic activity dwindles with age and essentially ceases in the later decades of life, severely constraining the generation of new T-cells. Homeostatic control mechanisms are very effective at maintaining a large and diverse subset of naïve CD4+ T-cells throughout life, but although later than in CD8 + T-cell compartment, these mechanisms ultimately fail with age

Recent Advances in Artificial Intelligence-Assisted Ultrasound Scanning

Funded by the Spanish Ministry of Economic Affairs and Digital Transformation (Project MIA.2021.M02.0005 TARTAGLIA, from the Recovery, Resilience, and Transformation Plan financed by the European Union through Next Generation EU funds). TARTAGLIA takes place under the R&D Missions in Artificial Intelligence program, which is part of the Spain Digital 2025 Agenda and the Spanish National Artificial Intelligence Strategy.Ultrasound (US) is a flexible imaging modality used globally as a first-line medical exam procedure in many different clinical cases. It benefits from the continued evolution of ultrasonic technologies and a well-established US-based digital health system. Nevertheless, its diagnostic performance still presents challenges due to the inherent characteristics of US imaging, such as manual operation and significant operator dependence. Artificial intelligence (AI) has proven to recognize complicated scan patterns and provide quantitative assessments for imaging data. Therefore, AI technology has the potential to help physicians get more accurate and repeatable outcomes in the US. In this article, we review the recent advances in AI-assisted US scanning. We have identified the main areas where AI is being used to facilitate US scanning, such as standard plane recognition and organ identification, the extraction of standard clinical planes from 3D US volumes, and the scanning guidance of US acquisitions performed by humans or robots. In general, the lack of standardization and reference datasets in this field makes it difficult to perform comparative studies among the different proposed methods. More open-access repositories of large US datasets with detailed information about the acquisition are needed to facilitate the development of this very active research field, which is expected to have a very positive impact on US imaging.Depto. de Estructura de la Materia, Física Térmica y ElectrónicaFac. de Ciencias FísicasTRUEMinistry of Economic Affairs and Digital Transformation from the Recovery, Resilience, and Transformation PlanNext Generation EU fundspu

The extracellular proteins of Lactobacillus acidophilus DSM 20079T display anti-inflammatory effect in both in piglets, healthy human donors and Crohns Disease patients

Lactobacillus genus includes both probiotic and representative strains of the human gut microbiota. Independent studies have reported on the anti-inflammatory properties of different Lactobacillus strains, although we are far from understanding the underlying molecular interplay. In this work we show that a daily administration of Lactobacillus acidophilus DSM20079T (DSM20079) to healthy piglets resulted in plasmatic increases of the anti-inflammatory IL10, whilst IL12 and the pro-inflammatory ratio IL12+TNF/IL10 decreased. The extracellular protein fraction of DSM20079 was identified as the responsible for the crosstalk interaction that elicited these tolerogenic effects. This strain was able to activate innate immune pathways in dendritic cells and to decrease the production of pro-inflammatory cytokines in both CD4+/CD8+ T cell subsets in healthy donors and in Crohns Disease patients. The tolerogenic effect exerted by the extracellular proteins of this strain suggests their potential use as coadjutant for therapeutic applications targeting chronic inflammatory illnesses.Our work is supported by the Spanish “Programa Estatal de Investigación, Desarrollo e Inovación Orientada a los Retos de la Sociedad” (grant AGL2016-78311-R); the Asociación Española Contra el Cancer (“Obtención de péptidos bioactivos contra el Cáncer ColoRectal a partir de secuencias genéticas de microbiomas intestinales”, Grant PS-2016) and by the Asturias Regional Plan I+D+i for research groups (FYCYT-IDI/2018/000236). This study was also supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2013 unit and COMPETE 2020 (POCI-01-0145-FEDER006684). SING group thanks CITI (Centro de Investigación, Transferencia e Innovación) from University of Vigo for hosting its IT infrastructure. LJR was supported by the Principado de Asturias, PCTI 2018–2020 (GRUPIN: IDI2018-000237) and FEDER. This work was partially supported by the Consellería de Educación, Universidades e Formación Profesional (Xunta de Galicia) under the scope of the strategic funding of ED431C2018/55-GRC Competitive Reference Group.info:eu-repo/semantics/publishedVersio

In silico and functional analyses of immunomodulatory peptides encrypted in the human gut metaproteome

Supplementary data to this article can be found online at https:// doi.org/10.1016/j.jff.2020.103969.This work supports the massive presence of potential immunomodulatory peptides in the human gut metaproteome. These peptides were identified through the MAHMI database as potentially anti-inflammatory, and sixteen of them synthesized for characterize their mechanism of action. From them, peptide HM14 was encrypted in an extracellular protein produced by Bifidobacterium longum, a common member of the human microbiota, and displayed the highest anti-inflammatory capability. Molecular mechanism of action of HM14 pointed to a specific interaction between this immunomodulatory peptide and antigen presenting cells, which resulted in a higher formation of iTreg cells. Moreover, HM14 was effective in decreasing pro-inflammatory parameters in PBMCs isolated from a cohort of Crohns patients. Finally, non-targeted metabolomics confirmed the ability of HM14 to modulate the metabolic activity of PBMCs to fulfil its energy and biosynthetic requirements. Overall, our combined in silico/multiomics approach supports the human gut metaproteome as a source for immunomodulatory peptides.Our work is supported by the Spanish “Programa Estatal de Investigación. Desarrollo e Innovación Orientada a los Retos de la Sociedad” (grants AGL2013-44761-P and AGL2016-78311-R); the Asociación Española Contra el Cancer (“Obtención de péptidos bioactivos contra el Cáncer Colo-Rectal a partir de secuencias genéticas de microbiomas intestinales”, Grant PS-2016), by the Asturias Regional Plan I + D + i for research groups (FYCYT-IDI/2018/000236) and by the Autonomic “Investigadores Emerxentes do Sistema Universitario de Galicia” (Grant EM2014/046). This work was partially supported by the Consellería de Educación. Universidades e Formación Profesional (Xunta de Galicia) under the scope of the strategic funding of ED431C2018/55-GRC Competitive Reference Group. Finally, the authors wish to thank Jaume Morales and Rubén García form Agilent Technologies for technical support.info:eu-repo/semantics/publishedVersio

GLUT1 protects prostate cancer cells from glucose deprivation-induced oxidative stress

Glucose, chief metabolic support for cancer cell survival and growth, is mainly imported into cells by facilitated glucose transporters (GLUTs). The increase in glucose uptake along with tumor progression is due to an increment of facilitative glucose transporters as GLUT1. GLUT1 prevents cell death of cancer cells caused by growth factors deprivation, but there is scarce information about its role on the damage caused by glucose deprivation, which usually occurs within the core of a growing tumor. In prostate cancer (PCa), GLUT1 is found in the most aggressive tumors, and it is regulated by androgens. To study the response of androgen-sensitive and insensitive PCa cells to glucose deprivation and the role of GLUT1 on survival mechanisms, androgen-sensitive LNCaP and castration-resistant LNCaP-R cells were employed. Results demonstrated that glucose deprivation induced a necrotic type of cell death which is prevented by antioxidants. Androgen-sensitive cells show a higher resistance to cell death triggered by glucose deprivation than castration-resistant cells. Glucose removal causes an increment of H2O2, an activation of androgen receptor (AR) and a stimulation of AMP-activated protein kinase activity. In addition, glucose removal increases GLUT1 production in androgen sensitive PCa cells. GLUT1 ectopic overexpression makes PCa cells more resistant to glucose deprivation and oxidative stress-induced cell death. Under glucose deprivation, GLUT1 overexpressing PCa cells sustains mitochondrial SOD2 activity, compromised after glucose removal, and significantly increases reduced glutathione (GSH). In conclusion, androgen-sensitive PCa cells are more resistant to glucose deprivation-induced cell death by a GLUT1 upregulation through an enhancement of reduced glutathione levels. Keywords: Glut1, Prostate cancer, Glucose deprivation, Androgen receptor, Glutathione, Oxidative stres

The extracellular proteins of Lactobacillus acidophilus DSM 20079T display anti-inflammatory effect in both in piglets, healthy human donors and Crohn’s Disease patients

Lactobacillus genus includes both probiotic and representative strains of the human gut microbiota. Independent studies have reported on the anti-inflammatory properties of different Lactobacillus strains, although we are far from understanding the underlying molecular interplay. In this work we show that a daily administration of Lactobacillus acidophilus DSM20079T (DSM20079) to healthy piglets resulted in plasmatic increases of the anti-inflammatory IL10, whilst IL12 and the pro-inflammatory ratio IL12+TNFα/IL10 decreased. The extracellular protein fraction of DSM20079 was identified as the responsible for the crosstalk interaction that elicited these tolerogenic effects. This strain was able to activate innate immune pathways in dendritic cells and to decrease the production of pro-inflammatory cytokines in both CD4+/CD8+ T cell subsets in healthy donors and in Crohn’s Disease patients. The tolerogenic effect exerted by the extracellular proteins of this strain suggests their potential use as coadjutant for therapeutic applications targeting chronic inflammatory illnesses.Asociación Española Contra el Cancer | Ref. PS-2016Fundação para a Ciência e a Tecnologia | | Ref. UID/BIO/04469/2013Agencia Estatal de Investigación | Ref. AGL2016-78311-RPrincipado de Asturias | Ref. PCTI 2018–2020Xunta de Galicia | Ref. ED431C2018/5

In silico and functional analyses of immunomodulatory peptides encrypted in the human gut metaproteome

This work supports the massive presence of potential immunomodulatory peptides in the human gut metaproteome. These peptides were identified through the MAHMI database as potentially anti-inflammatory, and sixteen of them synthesized for characterize their mechanism of action. From them, peptide HM14 was encrypted in an extracellular protein produced by Bifidobacterium longum, a common member of the human microbiota, and displayed the highest anti-inflammatory capability. Molecular mechanism of action of HM14 pointed to a specific interaction between this immunomodulatory peptide and antigen presenting cells, which resulted in a higher formation of iTreg cells. Moreover, HM14 was effective in decreasing pro-inflammatory parameters in PBMCs isolated from a cohort of Crohn's patients. Finally, non-targeted metabolomics confirmed the ability of HM14 to modulate the metabolic activity of PBMCs to fulfil its energy and biosynthetic requirements. Overall, our combined in silico/multiomics approach supports the human gut metaproteome as a source for immunomodulatory peptides.Ministerio de Economía y Competitividad | Ref. AGL2013-44761-PAgencia Estatal de Investigación | Ref. AGL2016-78311-

Las proteínas extracelulares de Lactobacillus acidophilus DSM 20079t como potenciales moduladores de la respuesta inmune en enfermedades inflamatorias crónicas

El uso de probióticos o compuestos bacterianos se ha propuesto como un mecanismo para modular la respuesta inmune del hospedador y remodelar el microbioma humano. Sin embargo, actualmente existe una falta de información sobre las vías moleculares inducidas por las bacterias probióticas, o sobre la interacción entre los probióticos y el sistema inmunológico. Lactobacillus es un género del filo Firmicutes que incluye cepas probióticas y representativas de la microbiota gastrointestinal humana. Estudios independientes han demostrado las propiedades antiinflamatorias de diferentes cepas de Lactobacillus, aunque estamos lejos de comprender la interacción molecular subyacente. En este trabajo, demostramos que una administración diaria de 5e10 células viables de Lactobacillus acidophilus DSM 20079T (DSM20079) a lechones sanos produjo un aumento plasmático de la interleucina antinflamatoria IL10, disminuyendo, a su vez, la interleucina IL12 y la ratio proinflamatorio IL12 + TNF / IL10. Además, las células mononucleares de sangre preriféricas (PBMCs) extraídas de estos lechones se volvieron menos reactivas contra el lipopolisacárido de Escherichia coli (LPS) y la fitohemaglutinina de Phaseolus vulgaris (PHA), cuando se ven afectadas por la cepa DSM20079. Se identificó la fracción proteica extracelular de DSM20079 como la responsable de esta modulación. El efecto tolerogénico ejercido por las proteínas extracelulares de esta cepa sugiere su uso potencial como coadyuvante para aplicaciones terapéuticas dirigidas a enfermedades inflamatorias crónicas.Este trabajo fue respaldado por el "Programa Estatal de Investigación, Desarrollo e Inovación Orientada a los Retos de la Sociedad" (AGL2016-78311-R); la Asociación Española Contra el Cáncer ("Obtención de péptidos bioactivos contra el Cáncer Colo-Rectal a partir de secuencias genéticas de microbiomas intestinales", PS-2016).info:eu-repo/semantics/publishedVersio

Metabolomic-Based Noninvasive Serum Test to Diagnose Nonalcoholic Steatohepatitis: Results From Discovery and Validation Cohorts

Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease worldwide and includes a broad spectrum of histologic phenotypes, ranging from simple hepatic steatosis or nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH). While liver biopsy is the reference gold standard for NAFLD diagnosis and staging, it has limitations due to its sampling variability, invasive nature, and high cost. Thus, there is a need for noninvasive biomarkers that are robust, reliable, and cost effective. In this study, we measured 540 lipids and amino acids in serum samples from biopsy-proven subjects with normal liver (NL), NAFL, and NASH. Using logistic regression analysis, we identified two panels of triglycerides that could first discriminate between NAFLD and NL and second between NASH and NAFL. These noninvasive tests were compared to blinded histology as a reference standard. We performed these tests in an original cohort of 467 patients with NAFLD (90 NL, 246 NAFL, and 131 NASH) that was subsequently validated in a separate cohort of 192 patients (7 NL, 109 NAFL, 76 NASH). The diagnostic performances of the validated tests showed an area under the receiver operating characteristic curve, sensitivity, and specificity of 0.88 +/- 0.05, 0.94, and 0.57, respectively, for the discrimination between NAFLD and NL and 0.79 +/- 0.04, 0.70, and 0.81, respectively, for the discrimination between NASH and NAFL. When the analysis was performed excluding patients with glucose levels >136 mg/dL, the area under the receiver operating characteristic curve for the discrimination between NASH and NAFL increased to 0.81 +/- 0.04 with sensitivity and specificity of 0.73 and 0.80, respectively. Conclusion: The assessed noninvasive lipidomic serum tests distinguish between NAFLD and NL and between NASH and NAFL with high accuracy.Supported by the National Institutes of Health Blueprint for Neuroscience Research (R01AT001576 to S.C.L., J.M.M.), Agencia Estatal de Investigacion of the Ministerio de Economia, Industria y Competitividad (SAF2014-52097R to J.M.M.), CIBER Hepatic and Digestive Diseases and Instituto de Salud Carlos III (PIE14/0003 to J.M.M.), Etorgai 2015-Gobierno Vasco (ER-2015/00015 to R.M., I.M.A., C.A., A.C.), Plan de Promocion de la Innovacion 2015-Diputacion Foral de Bizkaia (6/12/IN/2015/00131 to A.C., C.A.), National Institute of Diabetes and Digestive and Kidney Diseases (RO1DK81410 to A.J.S.), and Czech Ministry of Health (RVO VFN64165 to L.V.)