Search

The metabolism of T-lymphocytes has recently emerged as a pivotal area of investigation, offering insights into the supra-genic modulations that can influence the genetic mechanisms underlying lymphocyte clustering processes. Furthermore, it has become a crucial aspect in understanding lymphocyte plasticity within the immune microenvironment, both in physiological and pathological contexts. T-lymphocyte metabolism has recently emerged as a pivotal factor in both targeted therapy and the genetic signature of the T-lymphocyte, as a result of its influence on gatekeeper processes. From this perspective, the interconnections between the metabolic processes traditionally associated with energy production and the capacity to influence the genetic fate of the T lymphocyte have identified purine metabolism and nuclear/cytoplasmic signaling as pivotal elements in comprehending the intricacies of these molecular phenomena. The two aspects of purine metabolism and metabolic/molecular control of the nuclear envelope have been the subject of a number of significant studies published in recent years. However, from a certain perspective, the existing evidence remains sparse and inconclusive, hindering a comprehensive understanding of the subject matter. In this review, we endeavor to establish a connection between these aspects for the first time and to present a review of the molecular, immunological and genetic events that determine how these aspects, which have hitherto received insufficient attention, may represent a new avenue for lymphocyte reprogramming in the therapeutic field. This will be achieved by understanding the connections between nuclear control and purine flux within and outside the cell. [ABSTRACT FROM AUTHOR]

The CD4+ T‐cell population plays a vital role in the adaptive immune system by coordinating the immune response against different pathogens. A significant transformation occurs in CD4+ cells during an immune response, as they shift from a dormant state to an active state. This transformation leads to extensive proliferation, differentiation, and cytokine production, which contribute to regulating and coordinating the immune response. Th17 and Treg cells are among the most intriguing CD4+ T‐cell subpopulations in terms of genetics and metabolism. Gene expression modulation processes rely on and are linked to metabolic changes in cells. Lactylation is a new model that combines metabolism and gene modulation to drive Th17/Treg differentiation and functional processes. The focus of this review is on the metabolic pathways that impact lymphocyte gene modulation in a functionally relevant manner. [ABSTRACT FROM AUTHOR]

The Th17+ arrangement is critical for orchestrating both innate and acquired immune responses. In this context, the serum and glucocorticoid regulated kinase 1 (SGK1) exerts a key role in the governance of IL-23R-dependent Th17+ maturation, through the phosphorylation-dependent control of FOXO1 localization. Our previous work has shown that some of the SGK1-key functions are dependent on RAN-binding protein 1 (RANBP1), a terminal gene in the nuclear transport regulation. Here, we show that RANBP1, similarly to SGK1, is modulated during Th17+ differentiation and that RANBP1 fluctuations mediate the SGK1-dependent effects on Th17+ maturation. RANBP1, as the final effector of the SGK1 pathway, affects FOXO1 transport from the nucleus to the cytoplasm, thus enabling RORgt activation. In this light, RANBP1 represents the missing piece, in an essential and rate-limiting manner, underlying the Th17+ immune asset. [ABSTRACT FROM AUTHOR]

Hot pepper (Capsicum annuum) represents one of the most widespread functional foods of the Mediterranean diet, and is associated with a reduced risk of developing cardiovascular disease, cancer, and mental disorders. In particular, its bioactive spicy molecules, named Capsaicinoids, exhibit polypharmacological properties. Among them, Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is the most studied and reported in variegated scientific contributions for its beneficial effects, often linked to mechanisms of action unrelated to the activation of Transient Receptor Potential Vanilloid 1 (TRPV1). In this study, we present the application of in silico methods to Capsaicin for evaluating its inhibitory activity against the tumor-associated human (h) expressed CA IX and XII. In vitro assays confirmed Capsaicin inhibitory activity towards the most relevant tumor-related hCA isoforms. In particular, the hCAs IX and XII showed an experimental KI value of 0.28 μM and 0.064 μM, respectively. Then, an A549 model of non-small cell lung cancer, typically characterized by an elevated expression of hCA IX and XII, was employed to test the inhibitory effects of Capsaicin in vitro under both normoxic and hypoxic conditions. Finally, the migration assay revealed that Capsaicin [10 µM] inhibits cells from moving in the A549 cells model. [ABSTRACT FROM AUTHOR]

Simple Summary: In just less than 30 years since the cloning of RANBP1 (RAN binding protein 1), this review represents the first attempt for a comprehensive and analytical compilation of the main works that have characterized the history of this gene. Originally defined as an accessory element of not well-defined proteins involved in nuclear transport, RANBP1 has been demonstrated, over time, to play an essential role in maintaining both nuclear import/export machinery and spindle check-point formation. Since the first biochemical characterization, knowledge has accumulated that paints a very complex picture of how RANBP1 and its Small-GTPase-related complex plays a fine regulation of cellular homeostasis, with a differentially phase-cell-dependent role. From its molecular context, up to the role in neoplastic and other pathologies of complex traits, RANBP1 always embodies further the missing piece of a gene signature that recapitulates several aspects of mammalian cell biology. RANBP1 encoded by RANBP1 or HTF9A (Hpall Tiny Fragments Locus 9A), plays regulatory functions of the RAN-network, belonging to the RAS superfamily of small GTPases. Through this function, RANBP1 regulates the RANGAP1 activity and, thus, the fluctuations between GTP-RAN and GDP-RAN. In the light of this, RANBP1 take actions in maintaining the nucleus–cytoplasmic gradient, thus making nuclear import–export functional. RANBP1 has been implicated in the inter-nuclear transport of proteins, nucleic acids and microRNAs, fully contributing to cellular epigenomic signature. Recently, a RANBP1 diriment role in spindle checkpoint formation and nucleation has emerged, thus constituting an essential element in the control of mitotic stability. Over time, RANBP1 has been demonstrated to be variously involved in human cancers both for the role in controlling nuclear transport and RAN activity and for its ability to determine the efficiency of the mitotic process. RANBP1 also appears to be implicated in chemo-hormone and radio-resistance. A key role of this small-GTPases related protein has also been demonstrated in alterations of axonal flow and neuronal plasticity, as well as in viral and bacterial metabolism and in embryological maturation. In conclusion, RANBP1 appears not only to be an interesting factor in several pathological conditions but also a putative target of clinical interest. [ABSTRACT FROM AUTHOR]

Chronic venous disease is a condition globally widespread, resulting in a disabling pathological disorder. The CD4 + Th17+ (Cluster Differentiation 4) lymphocytes represent a regulative factor for innate immunity related to the development of complex diseases. Recently, these mechanisms have been associated with vascular disease. The aim of this work is to validate whether the Th17 response correlates with the development of CVI (Chronic venous insufficiency)and CVLUs (chronic venous limbs ulcers) and whether Th17 markers can be used, both as intrinsic risk factors and diagnostic markers, for disease development. PBL derived from peripheral blood samples of patients and controls were subjected to gene expression analysis for IL23R, IL17, SGK1, TGFβ, RORγ, FOXO1, and RANBP1 by qRT-PCR and immunoblot. A post hoc correlation, the diagnostic performance of the target genes, and multivariable analyses were properly conducted. The main expression markers of the CD4 + Th17+ switch were strongly activated in chronic venous insufficiency and in advanced ulceration. The correlation analysis demonstrated the inter-dependence on Th17's signature modulation. ROC (Receiver Operating Characteristic) analysis defined, for the examined genes, a clinical value as the potential diagnostic markers. Multi-logistic regression studies showed that Th17 markers behave as empirical risk factors for CVD (chronic venous disease) development. Taken together, the present data provide a new hypothesis for the TH17-dependent pathogenesis of CVD, favoring the possibility for the development of new diagnostic, preventive, and therapeutic approaches. [ABSTRACT FROM AUTHOR]