Pflügers Archiv - European Journal of Physiology最新文献

Sphingosine-1-phosphate (S1P) is a bioactive lipid signaling molecule with pleiotropic implications by both auto- and paracrine signaling. Signaling occurs by engaging five G protein-coupled receptors (S1P_1-5) or intracellular pathways. While the extensively studied S1P with a chain length of 18 carbon atoms (d18:1 S1P) affects lymphocyte trafficking, immune cell survival and inflammatory responses, the biological implication of atypical S1Ps such as d16:1 or d20:1 remains elusive. As S1P lipids have far-reaching implications in health and disease states in mammalian organisms, the previous contrasting results may be attributed to differences in S1P’s alkyl chain length. Current research is beginning to appreciate these less abundant atypical S1P moieties. This review provides an up-to-date foundation of recent findings on the biological implications of atypical S1P chain lengths and offers a perspective on future research endeavors on S1P alkyl chain length–influenced signaling and its implications for drug discovery.

Research on sphingolipids has proliferated exponentially over the past couple of decades, as exemplified in the findings reported at the International Leopoldina Symposium on Lipid Signaling held in Frankfurt in late 2023. Most researchers in the field study how sphingolipids function in regulating a variety of cellular processes and, in particular, how they are dysregulated in numerous human diseases; however, I now propose that we implement a more holistic research program in our study of sphingolipids, which embraces a sense of awe and wonder at the complexities and beauty of sphingolipids and of sphingolipid metabolism. I will outline the chemical complexity of sphingolipids, their modes of interaction within the lipid bilayer, and their biosynthetic pathways. I will then briefly touch upon the ability of current neo-Darwinian mechanisms to explain the emergence of both sphingolipids and of the complex pathways that generate them. Although such discussion is normally considered taboo in biological circles, I nevertheless submit that in-depth analysis of the minutiae of metabolic pathways, such as those of the sphingolipid biosynthetic pathway, raises challenges to current neo-Darwinian mechanisms that should not be shunned or ignored.

The transient receptor potential melastatin type 6 (TRPM6) is a divalent cation channel pivotal for gatekeeping Mg²⁺ balance. Disturbance in Mg²⁺ balance has been associated with the chronic use of proton pump inhibitors (PPIs) such as omeprazole. In this study, we investigated if TRPM6 plays a role in mediating the effects of short-term (4 days) omeprazole treatment on intestinal Mg²⁺ malabsorption using intestine-specific TRPM6 knockout (Vill1-TRPM6^−/−) mice. To do this, forty-eight adult male C57BL/6 J mice (50% TRPM6^fl/fl and 50% Vill1-TRPM6^−/−) were characterized, and the distal colon of these mice was subjected to RNA sequencing. Moreover, these mice were exposed to 20 mg/kg bodyweight omeprazole or placebo for 4 days. Vill1-TRPM6^−/− mice had a significantly lower ²⁵Mg²⁺ absorption compared to control TRPM6^fl/fl mice, accompanied by lower Mg²⁺ serum levels, and urinary Mg²⁺ excretion. Furthermore, renal Slc41a3, Trpm6, and Trpm7 gene expressions were higher in these animals, indicating a compensatory mechanism via the kidney. RNA sequencing of the distal colon revealed a downregulation of the Mn²⁺ transporter Slc30a10. However, no changes in Mn²⁺ serum, urine, and feces levels were observed. Moreover, 4 days omeprazole treatment did not affect Mg²⁺ homeostasis as no changes in serum ²⁵Mg²⁺ and total Mg²⁺ were seen. In conclusion, we demonstrate here for the first time that Vill1-TRPM6^−/− mice have a lower Mg²⁺ absorption in the intestines. Moreover, short-term omeprazole treatment does not alter Mg²⁺ absorption in both Vill1-TRPM6^−/− and TRPM6^fl/fl mice. This suggests that TRPM6-mediated Mg²⁺ absorption in the intestines is not affected by short-term PPI administration.

It is often the case that serious, end-stage manifestations of disease result from secondary complications in organs distinct from the initial site of injury or infection. This is particularly true of diseases of the heart–lung axis, given the tight anatomical connections of the two organs within a common cavity in which they collectively orchestrate the two major, intertwined circulatory pathways. Immune cells and the soluble mediators they secrete serve as effective, and targetable, messengers of signals between different regions of the body but can also contribute to the spread of pathology. In this review, we discuss the immunological basis of interorgan communication between the heart and lung in various common diseases, and in the context of organ crosstalk more generally. Gaining a greater understanding of how the heart and lung communicate in health and disease, and viewing disease progression generally from a more holistic, whole-body viewpoint have the potential to inform new diagnostic approaches and strategies for better prevention and treatment of comorbidities.

In humans, glucocorticoid resistance is attributed to mutations in the glucocorticoid receptor (GR). Most of these mutations result in decreased ligand binding, transactivation, and/or translocation, albeit with normal protein abundances. However, there is no clear genotype‒phenotype relationship between the severity or age at disease presentation and the degree of functional loss of the receptor. Previously, we documented that a GR^+/− rat line developed clinical features of glucocorticoid resistance, namely, hypercortisolemia, adrenal hyperplasia, and salt-sensitive hypertension. In this study, we analyzed the GR^+/em4 rat model heterozygously mutant for the deletion of exon 3, which encompasses the second zinc finger, including the domains of DNA binding, dimerization, and nuclear localization signals. On a standard diet, mutant rats exhibited a trend toward increased corticosterone levels and a normal systolic blood pressure and heart rate but presented with adrenal hyperplasia. They exhibited increased adrenal soluble epoxide hydroxylase (sEH), favoring an increase in less active polyunsaturated fatty acids. Indeed, a significant increase in nonactive omega-3 and omega-6 polyunsaturated fatty acids, such as 5(6)-DiHETrE or 9(10)-DiHOME, was observed with advanced age (10 versus 5 weeks old) and following a switch to a high-salt diet accompanied by salt-sensitive hypertension. In thoracic aortas, a reduced soluble epoxide hydrolase (sEH) protein abundance resulted in altered vascular reactivity upon a standard diet, which was blunted upon a high-salt diet. In conclusion, mutations in the GR affecting the ligand-binding domain as well as the dimerization domain resulted in deregulated GR signaling, favoring salt-sensitive hypertension in the absence of obvious mineralocorticoid excess.

Cardiac hypertrophy (CH) is an adaptive response to maintain cardiac function; however, persistent stress responses lead to contractile dysfunction and heart failure. Although inflammation is involved in these processes, the mechanisms that control cardiac inflammation and hypertrophy still need to be clarified. The NLRP3 inflammasome is a cytosolic multiprotein complex that mediates IL-1β production. The priming step of NLRP3 is essential for increasing the expression of its components and occurs following NF-κB activation. Hyperthyroidism triggers CH, which can progress to maladaptive CH and even heart failure. We have shown in a previous study that thyroid hormone (TH)-induced CH is linked to the upregulation of S100A8, leading to NF-κB activation. Therefore, we aimed to investigate whether the NLRP3 inflammasome is involved in TH-induced CH and its potential role in CH pathophysiology. Hyperthyroidism was induced in NLRP3 knockout (NLRP3-KO), Caspase-1-KO and Wild Type (WT) male mice of the C57Bl/6J strain, aged 8–12 weeks, by triiodothyronine (7 μg/100 g BW, i.p.) administered daily for 14 days. Morphological and cardiac functional analysis besides molecular assays showed, for the first time, that TH-induced CH is accompanied by reduced NLRP3 expression in the heart and that it occurs independently of the NLRP3 inflammasome and caspase 1-related pathways. However, NLRP3 is important for the maintenance of basal cardiac function since NLRP3-KO mice had impaired diastolic function and reduced heart rate, ejection fraction, and fractional shortening compared with WT mice.

Human arachidonate 15-lipoxygenase type B is a lipoxygenase that catalyzes the peroxidation of arachidonic acid at carbon-15. The corresponding murine ortholog however has 8-lipoxygenase activity. Both enzymes oxygenate polyunsaturated fatty acids in S-chirality with singular reaction specificity, although they generate a different product pattern. Furthermore, while both enzymes utilize both esterified fatty acids and fatty acid hydro(pero)xides as substrates, they differ with respect to the orientation of the fatty acid in their substrate-binding pocket. While ALOX15B accepts the fatty acid “tail-first,” Alox8 oxygenates the free fatty acid with its “head-first.” These differences in substrate orientation and thus in regio- and stereospecificity are thought to be determined by distinct amino acid residues. Towards their biological function, both enzymes share a commonality in regulating cholesterol homeostasis in macrophages, and Alox8 knockdown is associated with reduced atherosclerosis in mice. Additional roles have been linked to lung inflammation along with tumor suppressor activity. This review focuses on the current knowledge of the enzymatic activity of human ALOX15B and murine Alox8, along with their association with diseases.

Functional magnetic resonance imaging (fMRI) suggests that the hypoxic ventilatory response is facilitated by the AMP-activated protein kinase (AMPK), not at the carotid bodies, but within a subnucleus (Bregma -7.5 to -7.1 mm) of the nucleus tractus solitarius that exhibits right-sided bilateral asymmetry. Here, we map this subnucleus using cFos expression as a surrogate for neuronal activation and mice in which the genes encoding the AMPK-α1 (Prkaa1) and AMPK-α2 (Prkaa2) catalytic subunits were deleted in catecholaminergic cells by Cre expression via the tyrosine hydroxylase promoter. Comparative analysis of brainstem sections, relative to controls, revealed that AMPK-α1/α2 deletion inhibited, with right-sided bilateral asymmetry, cFos expression in and thus activation of a neuronal cluster that partially spanned three interconnected anatomical nuclei adjacent to the area postrema: SolDL (Bregma -7.44 mm to -7.48 mm), SolDM (Bregma -7.44 mm to -7.48 mm) and SubP (Bregma -7.48 mm to -7.56 mm). This approximates the volume identified by fMRI. Moreover, these nuclei are known to be in receipt of carotid body afferent inputs, and catecholaminergic neurons of SubP and SolDL innervate aspects of the ventrolateral medulla responsible for respiratory rhythmogenesis. Accordingly, AMPK-α1/α2 deletion attenuated hypoxia-evoked increases in minute ventilation (normalised to metabolism), reductions in expiration time, and increases sigh frequency, but increased apnoea frequency during hypoxia. The metabolic response to hypoxia in AMPK-α1/α2 knockout mice and the brainstem and spinal cord catecholamine levels were equivalent to controls. We conclude that within the brainstem an AMPK-dependent, hypoxia-responsive subnucleus partially spans SubP, SolDM and SolDL, namely SubSol-HIe, and is critical to coordination of active expiration, the hypoxic ventilatory response and defence against apnoea.

The integrity of the colon and the development of colon cancer depend on the sphingolipid balance in colon epithelial cells. In this review, we summarize the current knowledge on how ceramides and their complex derivatives influence normal colon development and colon cancer development. Ceramides, glucosylceramides and sphingomyelin are essential membrane components and, due to their biophysical properties, can influence the activation of membrane proteins, affecting protein–protein interactions and downstream signalling pathways. Here, we review the cellular mechanisms known to be affected by ceramides and their effects on colon development. We also describe which ceramides are deregulated during colorectal carcinogenesis, the molecular mechanisms involved in ceramide deregulation and how this affects carcinogenesis. Finally, we review new methods that are now state of the art for studying lipid-protein interactions in the physiological environment.

The myocardium is a highly oxidative tissue in which mitochondria are essential to supply the energy required to maintain pump function. When pathological hypertrophy develops, energy consumption augments and jeopardizes mitochondrial capacity. We explored the cardiac consequences of chronic swimming training, focusing on the mitochondrial network, in spontaneously hypertensive rats (SHR). Male adult SHR were randomized to sedentary or trained (T: 8-week swimming protocol). Blood pressure and echocardiograms were recorded, and hearts were removed at the end of the training period to perform molecular, imaging, or isolated mitochondria studies. Swimming improved cardiac midventricular shortening and decreased the pathological hypertrophic marker atrial natriuretic peptide. Oxidative stress was reduced, and even more interesting, mitochondrial spatial distribution, dynamics, function, and ATP were significantly improved in the myocardium of T rats. In the signaling pathway triggered by training, we detected an increase in the phosphorylation level of both AKT and glycogen synthase kinase-3 β, key downstream targets of insulin-like growth factor 1 signaling that are crucially involved in mitochondria biogenesis and integrity. Aerobic exercise training emerges as an effective approach to improve pathological cardiac hypertrophy and bioenergetics in hypertension-induced cardiac hypertrophy.