The mammalian immune system senses foreign antigens by mechanisms that involve the interplay of various kinds of immune cells, culminating in inflammation resolution and tissue clearance. The ability of the immune cells to communicate (via chemokines) and to shift shape for migration, phagocytosis or antigen uptake is mainly supported by critical proteins such as aquaporins (AQPs) that regulate water fluid homeostasis and volume changes. AQPs are protein channels that facilitate water and small uncharged molecules’ (such as glycerol or hydrogen peroxide) diffusion through membranes. A number of AQP isoforms were found upregulated in inflammatory conditions and are considered essential for the migration and survival of immune cells. The present review updates information on AQPs’ involvement in immunity and inflammatory processes, highlighting their role as crucial players and promising targets for drug discovery.

Polyoxometalates (POMs) are of increasing interest due to their proven anticancer activities. Aquaporins (AQPs) were found to be overexpressed in tumors bringing particular attention to their inhibitors as anticancer drugs. Herein, we report for the first time the ability of polyoxotungstates (POTs), such as of Wells–Dawson P2W18, P2W12, and P2W15, and Preyssler P5W30 structures, to affect aquaporin-3 (AQP3) activity and impair melanoma cell migration. The tested POTs were revealed to inhibit AQP3 function with different effects, with P2W18, P2W12, and P5W30 being the most potent (50% inhibitory concentration (IC50) = 0.8, 2.8, and 3.2 µM), and P2W15 being the weakest (IC50 > 100 µM). The selectivity of P2W18 toward AQP3 was confirmed in yeast cells transformed with human aquaglyceroporins. The effect of P2W12 and P2W18 on melanoma cells that highly express AQP3 revealed an impairment of cell migration between 55% and 65% after 24 h, indicating that the anticancer properties of these compounds may in part be due to the blockage of AQP3-mediated permeability. Altogether, our data revealed that P2W18 strongly affects AQP3 activity and cancer cell growth, unveiling its potential as an anticancer drug against tumors where AQP3 is highly expressed.

Background: Lipopolysaccharide (LPS), an effective stimulator of the immune system, has been widely applied in an experimental pig model for human sepsis. Aquaporins (AQPs), a family of small integral membrane proteins responsible for facilitating water fluxes through the cell membrane, offer potential promising drug targets for sepsis treatment due to their role in water balance and inflammation. Methods: In order to investigate the potential effect of a dietary amino acid mixture supplementation on LPS-challenged weaned piglets, a total of 30, 28-day-old, males were randomly allocated to 1 of 3 dietary treatments for a 5-week period, with 10 animals in each: diet 1 was a control (CTL) treatment; diet 2 was LPS treatment, where the piglets were intraperitoneally administered LPS (at 25 µg/kg body weight); diet 3 was LPS + cocktail treatment, where the piglets were intraperitoneally administered LPS and fed a diet supplemented with a mixture of arginine, branched-chain amino acids (BCAA, leucine, valine, and isoleucine), and cystine. Key organs that control sepsis were collected and processed by real time quantitative PCR (RT-qPCR) for the AQPs and cytokines transcriptional profiles. Results: Minor variations were detected for AQPs and inflammatory markers mRNA levels, upon the dependence of LPS or the amino acid cocktail suggesting the piglets' immune recovery. Using a discriminant analysis tool, we report for the first time, a tissue-specific variation in AQPs and cytokines transcriptional profiles that clearly distinguish the small intestine and the kidney from the liver and the spleen. Conclusions: This study provides a novel insight into the gene expression signature of AQPs and cytokines in the functional physiology of each organ in piglets.

Objectives Ketogenic diets (KDs), promoting nutritional ketosis, profoundly impact energetic metabolism, and are being widely used for weight loss purposes. Aquaporins (AQPs) are transmembrane channels that facilitate water and glycerol transport across cell membranes and are critical players in energy homeostasis. The axis of adipose AQP7/hepatic AQP9 assures the body's glycerol homeostasis. Studies investigating the relation between KD, aquaporins, and energy homeostasis are scarce. Methods ApoE−/− mice were fed ad libitum a KD (Kcal%: 1/81/18, carbohydrate/fat/protein; n = 8) or a control diet (Kcal%: 70/11/18, carbohydrate/fat/protein; n = 7) for 12 weeks. Food consumption and body weight were determined weekly, and plasma was collected every 4 weeks for biochemical analyses. Upon euthanasia, the tissues involved in energy homeostasis, the liver, white adipose tissue (WAT), and brown adipose tissue (BAT), were collected for gene expression analysis. Results Bodyweight gain (% to the initial weight) was similar in both groups (4.0 ± 1.1, KD-mice vs. 3.3 ± 1.3, controls), in spite of the profoundly different diet fat content, thus confirming the anti-obesogenic effect of the diet. The plasma concentration of the major ketone body, ß-hydroxybutyrate, was significantly elevated in KD (2,019 ± 87 vs. control, 418 ± 72 nM, mean ± SEM), confirming the presence of nutritional ketosis under this dietary condition. The transcript level for uncoupling protein 1 (Ucp1) gene in BAT of KD-fed mice was upregulated by 400%, compared to control-fed mice, unveiling a thermogenic effect of KD. Lastly, mice subjected to KD exhibited: in BAT, a significant KD-induced upregulation of Aqp9 transcripts suggesting the participation in the influx of excess plasma glycerol to fuel thermogenesis; in WAT, a downregulation of Aqp7, suggesting the non-utilization of adipocyte lipid droplets as fuel; in the liver, an Aqp7 up-regulation suggesting its participation in glycerol influx into hepatocytes. Conclusions The anti-obesogenic effect of KD was associated with the upregulation of thermogenic genes in BAT and with the modulation of AQPs expression patterns in BAT, WAT, and the liver Funding Sources Magnetic Resonance Imaging Facility, The Huck Institutes of the Life Sciences, Penn State, USA Fundação para a Ciência e Tecnologia (FCT), Portugal.