Tocilizumab has been proposed as a means of opposing hyperinflammatory responses in intensive care patients with COVID-19. Here, we briefly discuss the potentially multiple, synergistic mechanisms ...whereby tocilizumab might exert therapeutic activity, mostly focusing on the production of tryptophan-derived catabolites that would result from blockade of IL-6 signaling, as contextualized to the cytokine storm occurring in COVID-19 patients.
Among the 20 amino acids needed for protein synthesis, Tryptophan (Trp) is an aromatic amino acid fundamental not only for the synthesis of the major components of living cells (namely, the ...proteins), but also for the maintenance of cellular homeostasis ....
Wolfram syndrome (WS), a rare genetic disorder, is considered the best prototype of endoplasmic reticulum (ER) diseases. Classical WS features are childhood-onset diabetes mellitus, optic atrophy, ...deafness, diabetes insipidus, neurological signs, and other abnormalities. Two causative genes (WFS1 and WFS2) have been identified. The transmission of the disease takes place in an autosomal recessive mode but autosomal dominant mutations responsible for WS-related disorders have been described. Prognosis is poor, death occurs at the median age of 39 years with a major cause represented by respiratory failure as a consequence of brain stem atrophy and neurodegeneration. The aim of this narrative review is to focus on etiology, pathogenesis and natural history of WS for an adequate patient management and for the discussion of future therapeutic interventions.
WS requires a multidisciplinary approach in order to be successfully treated. A prompt diagnosis decreases morbidity and mortality through prevention and treatment of complications. Being a monogenic pathology, WS represents a perfect model to study the mechanisms of ER stress and how this condition leads to cell death, in comparison with other prevalent diseases in which multiple factors interact to produce the disease manifestations. WS is also an important disease prototype to identify drugs and molecules associated with ER homeostasis. Evidence indicates that specific metabolic diseases (type 1 and type 2 diabetes), neurodegenerative diseases, atherosclerosis, inflammatory pathologies and also cancer are closely related to ER dysfunction.
Therapeutic strategies in WS are based on drug repurposing (i.e., investigation of approved drugs for novel therapeutic indications) with the aim to stop the progression of the disease by reducing the endoplasmic reticulum stress. An extensive understanding of WS from pathophysiology to therapy is fundamental and more studies are necessary to better manage this devastating disease and guarantee the patients a better quality of life and longer life expectancy.
Arginase 1 (Arg1) and indoleamine 2,3-dioxygenase 1 (IDO1) are immunoregulatory enzymes catalyzing the degradation of l-arginine and l-tryptophan, respectively, resulting in local amino acid ...deprivation. In addition, unlike Arg1, IDO1 is also endowed with non-enzymatic signaling activity in dendritic cells (DCs). Despite considerable knowledge of their individual biology, no integrated functions of Arg1 and IDO1 have been reported yet. We found that IDO1 phosphorylation and consequent activation of IDO1 signaling in DCs was strictly dependent on prior expression of Arg1 and Arg1-dependent production of polyamines. Polyamines, either produced by DCs or released by bystander Arg1+ myeloid-derived suppressor cells, conditioned DCs toward an IDO1-dependent, immunosuppressive phenotype via activation of the Src kinase, which has IDO1-phosphorylating activity. Thus our data indicate that Arg1 and IDO1 are linked by an entwined pathway in immunometabolism and that their joint modulation could represent an important target for effective immunotherapy in several disease settings.
•Dendritic cells (DCs) can co-express Arg1 and IDO1 immunosuppressive enzymes•Arg1 activity is required for IDO1 induction by TGF-β in DCs•Spermidine, a downstream Arg1 product, but not arginine starvation, induces IDO1 in DCs•Arg1+ myeloid derived suppressor cells (MDSCs) can render DCs immunosuppressive via IDO1
Arginase 1 (Arg1) and indoleamine 2,3-dioxygenase 1 (IDO1) are immunosuppressive enzymes known to operate in distinct immune cells. Mondanelli and colleagues demonstrate that Arg1 and IDO1 cooperate in conferring long-term, immunosuppressive effects to dendritic cells.
In recent years, attention has been given to the role potentially played by gut microbiota in the development of obesity. Several studies have shown that in individuals with obesity, the gut ...microbiota composition can be significantly different from that of lean individuals, that faecal bacteria can exert a fundamental role in modulating energy metabolism, and that modifications of gut microbiota composition can be associated with increases or reductions of body weight and body mass index. Based on this evidence, manipulation of the gut microbiota with probiotics has been considered a possible method to prevent and treat obesity. However, despite a great amount of data, the use of probiotics to prevent and treat obesity and related problems remains debated. Studies have found that the probiotic effect on body weight and metabolism is strain specific and that only some of the species included in the
and
genera are effective, whereas the use of other strains can be deleterious. However, the dosage, duration of administration, and long-term effects of probiotics administration to prevent overweight and obesity are not known. Further studies are needed before probiotics can be rationally prescribed for the prevention or treatment of obesity. Control of the diet and environmental and life-style factors that favour obesity development remain the best solution to problems related to weight gain.
Src is a protein tyrosine kinase commonly activated downstream of transmembrane receptors and plays key roles in cell growth, migration, and survival signaling pathways. In conventional dendritic ...cells (cDCs), Src is involved in the activation of the non-enzymatic functions of indoleamine 2,3-dioxygenase 1 (IDO1), an immunoregulatory molecule endowed with both catalytic activity and signal transducing properties. Prompted by the discovery that the metabolite spermidine confers a tolerogenic phenotype on cDCs that is dependent on both the expression of IDO1 and the activity of Src kinase, we here investigated the spermidine mode of action. We found that spermidine directly binds Src in a previously unknown allosteric site located on the backside of the SH2 domain and thus acts as a positive allosteric modulator of the enzyme. Besides confirming that Src phosphorylates IDO1, here we showed that spermidine promotes the protein–protein interaction of Src with IDO1. Overall, this study may pave the way toward the design of allosteric modulators able to switch on/off the Src-mediated pathways, including those involving the immunoregulatory protein IDO1.
Indoleamine 2,3-dioxygenase (IDO), a metabolic enzyme that catalyzes tryptophan conversion into kynurenines, is a crucial regulator of immunity. Altered IDO activity is often associated with ...pathology, including neoplasia and autoimmunity. IDO is highly expressed in dendritic cells (DCs) that exploit the enzyme's activity and the production of tryptophan catabolites to regulate immune responses by acting on several cell types, including T lymphocytes, of which they promote a regulatory phenotype. IDO also contains immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that, once bound by distinct molecular partners, will either promote degradation or initiate signaling activity and self-maintenance of the enzyme. We here discuss how ITIM-dependent molecular events can affect the functional plasticity of IDO by modifying the protein half-life and its enzymic and nonenzymic functions.
The onion non-edible outside layers represent a widely available waste material deriving from its processing and consumption. As onion is a vegetable showing many beneficial properties for human ...health, a study aiming to evaluate the use of extract deriving from the non-edible outside layers was planned. An eco-friendly extraction method was optimized using a hydroalcoholic solution as solvent. The obtained extract was deeply characterized by in vitro methods and then formulated in autoadhesive, biocompatible and pain-free hydrogel polymeric films. The extract, very soluble in water, showed antioxidant, radical scavenging, antibacterial and anti-inflammatory activities, suggesting a potential dermal application for wounds treatment. In vitro studies showed a sustained release of the extract from the hydrogel polymeric film suitable to reach concentrations necessary for both antibacterial and anti-inflammatory activities. Test performed on human keratinocytes showed that the formulation is safe suggesting that the projected formulation could be a valuable tool for wound treatment.
The β-catenin signaling pathway has been demonstrated to promote the development of a tolerogenic dendritic cell (DC) population capable of driving regulatory T-cell (Treg) differentiation. Further ...studies have implicated tolerogenic DCs in promoting carcinogenesis in preclinical models. The molecular mechanisms underlying the establishment of immune tolerance by this DC population are poorly understood, and the methods by which developing cancers can co-opt this pathway to subvert immune surveillance are currently unknown. This work demonstrates that melanoma-derived Wnt5a ligand upregulates the durable expression and activity of the indoleamine 2,3-dioxygenase-1 (IDO) enzyme by local DCs in a manner that depends upon the β-catenin signaling pathway. These data indicate that Wnt5a-conditioned DCs promote the differentiation of Tregs in an IDO-dependent manner, and that this process serves to suppress melanoma immune surveillance. We further show that the genetic silencing of the PORCN membrane-bound O-acyl transferase, which is necessary for melanoma Wnt ligand secretion, enhances antitumor T-cell immunity, and that the pharmacologic inhibition of this enzyme synergistically suppresses melanoma progression when combined with anti-CTLA-4 antibody therapy. Finally, our data suggest that β-catenin signaling activity, based on a target gene expression profile that includes IDO in human sentinel lymph node-derived DCs, is associated with melanoma disease burden and diminished progression-free survival. This work implicates the Wnt-β-catenin signaling pathway as a novel therapeutic target in the melanoma immune microenvironment and demonstrates the potential impact of manipulating DC function as a strategy for optimizing tumor immunotherapy.
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