A metabolic constraint in the kynurenine pathway drives mucosal inflammation in IBD.

Inflammatory bowel disease (IBD) is associated with perturbed metabolism of the essential amino acid tryptophan (Trp). Whether increased degradation of Trp directly fuels mucosal inflammation or acts as a compensatory attempt to restore cellular energy levels via nicotinamide adenine dinucleotide (NAD ) synthesis is not understood. Employing a systems medicine approach on longitudinal IBD therapy intervention cohorts and targeted screening in preclinical IBD models, we discover that steady increases in Trp levels upon therapy success coincide with a rewiring of metabolic processes within the kynurenine pathway (KP).

A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation.

The intestinal tract generates significant reactive oxygen species (ROS), but the role of T cell antioxidant mechanisms in maintaining intestinal homeostasis is poorly understood. We used T cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), which impaired glutathione (GSH) production, crucially reducing IL-22 production by Th17 cells in the lamina propria, which is critical for gut protection. Under steady-state conditions, Gclc deficiency did not alter cytokine secretion; however, C.

A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation.

Although the intestinal tract is a major site of reactive oxygen species (ROS) generation, the mechanisms by which antioxidant defense in gut T cells contribute to intestinal homeostasis are currently unknown. Here we show, using T cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (), that the ensuing loss of glutathione (GSH) impairs the production of gut-protective IL-22 by Th17 cells within the lamina propria. Although ablation does not affect T cell cytokine secretion in the gut of mice at steady-state, infection with increases ROS, inhibits mitochondrial gene expression and mitochondrial function in -deficient Th17 cells.

Quantification of 782 Plasma Peptides by Multiplexed Targeted Proteomics.

Blood analysis is one of the foundations of clinical diagnostics. In recent years, the analysis of proteins in blood samples by mass spectrometry has taken a jump forward in terms of sensitivity and the number of identified proteins. The recent development of parallel reaction monitoring with parallel accumulation and serial fragmentation (prm-PASEF) combines ion mobility as an additional separation dimension.

Mitochondria preserve an autarkic one-carbon cycle to confer growth-independent cancer cell migration and metastasis.

Metastasis is the most common cause of death in cancer patients. Canonical drugs target mainly the proliferative capacity of cancer cells, which leaves slow-proliferating, persistent cancer cells unaffected. Metabolic determinants that contribute to growth-independent functions are still poorly understood.

The gut microbial metabolite formate exacerbates colorectal cancer progression.

The gut microbiome is a key player in the immunomodulatory and protumorigenic microenvironment during colorectal cancer (CRC), as different gut-derived bacteria can induce tumour growth. However, the crosstalk between the gut microbiome and the host in relation to tumour cell metabolism remains largely unexplored. Here we show that formate, a metabolite produced by the CRC-associated bacterium Fusobacterium nucleatum, promotes CRC development.

Neurodegeneration and neuroinflammation are linked, but independent of alpha-synuclein inclusions, in a seeding/spreading mouse model of Parkinson's disease.

A key pathological process in Parkinson's disease (PD) is the transneuronal spreading of α-synuclein. Alpha-synuclein (α-syn) is a presynaptic protein that, in PD, forms pathological inclusions. Other hallmarks of PD include neurodegeneration and microgliosis in susceptible brain regions.

Apomorphine Reduces A53T α-Synuclein-Induced Microglial Reactivity Through Activation of NRF2 Signalling Pathway.

The chiral molecule, apomorphine, is currently used for the treatment of Parkinson's disease (PD). As a potent dopamine receptor agonist, this lipophilic compound is especially effective for treating motor fluctuations in advanced PD patients. In addition to its receptor-mediated actions, apomorphine has also antioxidant and free radical scavenger activities.

Myosins: Driving us towards novel targets and biomarkers in cancer.

The view that myosins, which are actin based molecular motors, are only driving muscle contraction evolved a lot during the last decades. Nowadays, it is known that they reshape the actin skeleton, anchor or transport vesicles, organelles as well as protein complexes. Here, we review how their role in cell division, polarization, migration and death is related to the cancer phenotype.

Prognostic and Predictive Molecular Biomarkers for Colorectal Cancer: Updates and Challenges.

Colorectal cancer (CRC) is a leading cause of death among cancer patients. This heterogeneous disease is characterized by alterations in multiple molecular pathways throughout its development. Mutations in , along with the mismatch repair gene deficiency, are currently routinely tested in clinics.

Hypoxia-induced autophagy drives colorectal cancer initiation and progression by activating the PRKC/PKC-EZR (ezrin) pathway.

Unlabelled: In solid tumors, cancer stem cells (CSCs) or tumor-initiating cells (TICs) are often found in hypoxic niches. Nevertheless, the influence of hypoxia on TICs is poorly understood. Using previously established, TIC-enrichedpatient-derived colorectal cancer (CRC) cultures, we show that hypoxia increases the self-renewal capacity of TICs while inducing proliferation arrest in their more differentiated counterpart cultures.

Transcriptomic analyses of primary astrocytes under TNFα treatment.

Astrocytes, the most abundant glial cell population in the central nervous system, have important functional roles in the brain as blood brain barrier maintenance, synaptic transmission or intercellular communications [1], [2]. Numerous studies suggested that astrocytes exhibit a functional and morphological high degree of plasticity. For example, following any brain injury, astrocytes become reactive and hypertrophic.

Inflammation Promotes a Conversion of Astrocytes into Neural Progenitor Cells via NF-κB Activation.

Brain inflammation, a common feature in neurodegenerative diseases, is a complex series of events, which can be detrimental and even lead to neuronal death. Nonetheless, several studies suggest that inflammatory signals are also positively influencing neural cell proliferation, survival, migration, and differentiation. Recently, correlative studies suggested that astrocytes are able to dedifferentiate upon injury and may thereby re-acquire neural stem cell (NSC) potential.

NLRP3 Inflammasome Is Expressed and Functional in Mouse Brain Microglia but Not in Astrocytes.

Neuroinflammation is the local reaction of the brain to infection, trauma, toxic molecules or protein aggregates. The brain resident macrophages, microglia, are able to trigger an appropriate response involving secretion of cytokines and chemokines, resulting in the activation of astrocytes and recruitment of peripheral immune cells. IL-1β plays an important role in this response; yet its production and mode of action in the brain are not fully understood and its precise implication in neurodegenerative diseases needs further characterization.

Neuropilin-2 acts as a modulator of Sema3A-dependent glioma cell migration.

Semaphorin 3A (Sema3A) is a secreted guidance molecule initially described in the nervous system. This protein is able to control axon growth but also effects on endothelial cells migration. Here, we report that Sema3A acts as a chemorepellent factor for the rat C6 glioma cells and three different human glioma cell lines.

A PKC-dependent recruitment of MMP-2 controls semaphorin-3A growth-promoting effect in cortical dendrites.

There is increasing evidence for a crucial role of proteases and metalloproteinases during axon growth and guidance. In this context, we recently described a functional link between the chemoattractive Sema3C and Matrix metalloproteinase 3 (MMP3). Here, we provide data demonstrating the involvement of MMP-2 to trigger the growth-promoting effect of Sema3A in cortical dendrites.