Advances in biological regulation最新文献

Olfactory receptors (ORs) are seven transmembrane domains G protein-coupled receptors (GPCRs) located in the olfactory sensory neurons (OSNs) of the nasal olfactory epithelium. Although OR expression was initially hypothesized to be restricted to the OSNs, an ecnomotopic expression has been identified and associated with the modulation of different physiological functions, such as glucose and lipid metabolism, hypoxia sensing, wound healing and sperm chemiotaxis. However, the role of most ORs in non-olfactory tissues is still a matter of debate, as well as their specific ligands and mechanisms of action. High-density lipoproteins (HDL) are heterogenous, and multifunctional nanoparticles constituted primarily of proteins and lipids. Their main structural protein, namely, apolipoprotein A-I (A-I) has been recognized as the major determinant of the biological activities of HDL. Recently, our group, by using unique mouse models and microarray methodology, has demonstrated that human A-II (hA-II) and A-I_Milano (A-I_M), a molecular variant of A-I, strongly modulate the hepatic expression of different genes involved in lipid metabolism and immune/inflammatory pathways. Therefore, aiming at investigating the impact of these apolipoproteins on the hepatic expression of mouse ORs (Olfrs), we have performed a new bioinformatic analysis of the differentially expressed genes (DEGs) found in the liver of hA-II/A-I k-in versus hA-II/A-I_M k-in; A-I_M k-in versus hA-II/A-I_M k-in; A-I k-in versus A-I_M k-in; A-I k-in versus hA-II/A-I k-in mice. Our results suggest that the presence of A-I_M, either alone or in combination with hA-II, is critical for the efficient trafficking and functional expression of Olfrs at the cell surface. Moreover, co-expression of hA-II with A-I resulted in down-regulation of previously uncharacterized Olfrs genes an up-regulation of several known Olfrs, which are likely responsive to short-chain fatty acids and signal through the cAMP/CREB pathway.

Circadian rhythms are physiological, biochemical and behavioural processes with a 24-h period molecularly regulated by clock genes. Cardiovascular physiology is subject to circadian variations in heart rate, blood pressure and contractility to optimize its function according to the rest-activity phases. Adrenergic receptors (ARs), activated by endogenous catecholamine hormones, are crucial in the regulation of cardiac functions; however, controllable in vitro models to study the intrinsic cardiomyocyte circadian clock with minimal systemic timing cues remain limited. Here, we use HL-1 cardiomyocyte cell line (HL-1 cells), in which serum shock induces synchronized oscillations of core clock gene transcripts compared with unsynchronized cultures. Different ARs activators onto HL-1 cells were applied under non-synchronized or synchronized conditions and circadian oscillation of representative clock genes was determined. We show that alpha- and beta-AR activation differentially modulates clock gene mesor, amplitude and phase. These findings support HL-1 cells as a convenient in vitro platform to investigate interactions between adrenergic signaling and cardiomyocyte clock gene oscillations.

The presence of inositol lipids in the nucleus has been shown in the late 1980s and since then a considerable amount of interest has been raised about the role of these molecules in an autonomous nuclear signalling system different from that at both the plasma membrane and the cytoplasm. Here we review the main issues of nuclear structure and of nuclear inositol lipids and their related enzymes in cellular signaling, taking into account also the possible role in some human pathologies.

The immune system is central to the prevention and control of cancer, yet tumors evolve multiple strategies to subvert immune surveillance. Checkpoint inhibitors targeting CTLA-4, PD-1, and PD-L1 have revolutionized oncology by demonstrating that therapeutic restoration of T cell activity can yield durable remissions. However, their efficacy remains limited by the profoundly immunosuppressive tumor microenvironment (TME), where regulatory immune cells, suppressive cytokines, and metabolic stressors converge to dampen effector function. As interest in integrative and complementary approaches grows, plant-derived compounds - long used in traditional medicine - have been identified as bioactive agents capable of modulating immune function. This review focuses on three key phytochemicals: piperlongumine, berberine, and epigallocatechin gallate (EGCG). Piperlongumine, a pro-oxidative alkaloid from Piper longum, suppresses T cell activation and promotes regulatory T cell differentiation, suggesting potential for chronic inflammation but raising caution in oncology. Berberine, an isoquinoline alkaloid from Berberis vulgaris, reduces PD-L1 expression via CSN5 inhibition, thereby mimicking checkpoint blockade and enhancing cytotoxic T cell activity in preclinical models. EGCG, the major polyphenol in green tea, downregulates PD-L1 expression and augments anti-tumor immunity in murine melanoma. We critically assess the promise and pitfalls of these compounds in cancer immunotherapy, emphasizing mechanistic insights, pharmacokinetics, translational hurdles, and potential risks of interfering with established therapies. A precision immunology framework - integrating immune monitoring, patient stratification, and controlled clinical trials - will be essential to determine whether phytochemicals can be safely and effectively incorporated into oncology. Far from being benign, plant-derived agents exert potent immune effects that could either complement or compromise modern immunotherapy, underscoring the need for rigorous evaluation.

Nuclear receptors are lipid-regulated transcription factors that respond to the changing metabolic and signaling requirements of animal cells and tissues. Steroidogenic Factor 1 (SF-1, NR5A1) is a nuclear receptor and master regulator of steroidogenic gene expression. SF-1 is required for development and adult function of steroidogenic tissues, hyperactivation of SF-1 associates with adrenocortical carcinoma, while hypomorphic loss-of-function polymorphisms associate with disorders of sexual development. Many of these physiological functions of SF-1 are broadly understood, however the identity of the endogenous regulatory lipid ligands for SF-1 have yet to be well established, preventing progress on therapeutic development for human diseases, such as adrenocortical carcinoma. Several signaling lipids have been put forth as potential regulatory ligands of SF-1, including sphingosine, lyso-sphingomyelin, sphingomyelin, ceramide and several phosphoinositide species including PI(4,5)P2 and PI(3,4,5)P3. Here, we review the evidence linking the ability of these potential phospholipid ligands to regulate SF-1 mediated gene expression in metazoan cells, and discuss how lipid ligands regulate SF-1 from a structural perspective.

Diacylglycerol kinases (DGKs) are key enzymes that integrate lipid metabolism with multiple signaling pathways. DGKs regulate the conversion of diacylglycerol (DAG) into phosphatidic acid (PA), two essential bioactive lipids that promote the activation of distinctive proteins controlling cell growth, proliferation and differentiation. The variety of DGK isoforms enables them to perform specialized functions in different tissues, and dysregulation of DGK activity and expression contributes to diverse pathological conditions. DGKs exert potent inhibitory functions in T cells and are aberrantly expressed in a wide range of cancer types, which make DGKs attractive therapeutic targets for cancer immunotherapy. In recent years, the development of novel and highly isoform-specific inhibitors has opened exciting opportunities to further explore the fundamental functions of lipid metabolism in the maintenance of immune cell homeostasis and in the progression of several diseases. Besides T cells, DGKs play important roles in regulating inflammatory processes across distinct immune populations. The therapeutic potential of these drugs has been translated in several ongoing clinical trials. Therefore, it is crucial to delineate DGK-controlled signaling hubs to better understand their impact on immune signatures. In this work, we aimed to recapitulate the effects of modulating DAG/PA balance on immune cells that are relevant in the tumor microenvironment. By dissecting how DGK-mediated lipid signaling shapes immune cell behavior in the tumor microenvironment, we seek to provide mechanistic insights that may guide the rational use of drugs targeting DGKs to improve antitumor immunity.