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Triple-negative breast cancer (TNBC) remains one of the most challenging subtypes since it is initially characterized by the absence of specific biomarkers and corresponding targeted therapies. Advances in methodology, translational informatics, genomics, and proteomics have significantly contributed to the identification of therapeutic targets. The development of innovative treatments, such as antibody-drug conjugates and immune checkpoint inhibitors, alongside chemotherapy, has now become the standard of care. However, the quest for biomarkers defining therapy outcomes is still ongoing. Peroxiporins, which comprise a subgroup of aquaporins, which are membrane pores facilitating the transport of water, glycerol, and hydrogen peroxide, have emerged as potential biomarkers for therapy response. Research on peroxiporins reveals their involvement beyond traditional channeling activities, which is also reflected in their cellular localization and roles in cellular signaling pathways. This research on peroxiporins provides fresh insights into the mechanisms of therapy resistance in tumors, offering potential avenues for predicting treatment outcomes and tailoring successful TNBC therapies.

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Milk is an important source of nutrients and energy, but there are still many uncertainties regarding the health effects of milk and dairy products consumption. Milk from different species varies in physicochemical and nutritional properties. We previously showed that dietary supplements with different milks in rats trigger significant differences in metabolic and inflammatory states, modulating mitochondrial functions in metabolically active organs such as the liver and skeletal muscle. Here, we have deepened the effects of isoenergetic supplementation of milk (82 kJ) from cow (CM), donkey (DM) or human (HM) on hepatic metabolism to understand the interlink between mitochondrial metabolic flexibility, lipid storage and redox state and to highlight the possible role of two hepatocyte aquaporins (AQPs) of metabolic relevance, AQP8 and AQP9, in this crosstalk. Compared with rats with no milk supplementation, DM- and HM-fed rats had reduced hepatic lipid content with enhanced mitochondrial function and decreased oxidative stress. A marked reduction in AQP8, a hydrogen peroxide channel, was seen in the liver mitochondria of DM-fed rats compared with HM-fed, CM-fed and control animals. DM-fed or HM-fed rats also showed reduced hepatic inflammatory markers and less collagen and Kupffer cells. CM-fed rats showed higher hepatic fat content and increased AQP9 and glycerol permeability. A role of liver AQP8 and AQP9 is suggested in the different metabolic profiles resulting from milk supplementation.

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The altered expression of known brain Aquaporin (AQP) channels 1, 4 and 9 has been correlated with neuropathological AD progression, but possible roles of other AQP classes in neurological disease remain understudied. The levels of transcripts of all thirteen human AQP subtypes were compared in healthy and Alzheimer's disease (AD) brains by statistical analyses of microarray RNAseq expression data from the Allen Brain Atlas database. Previously unreported, AQPs 0, 6 and 10, are present in human brains at the transcript level. Three AD-affected brain regions, hippocampus (HIP), parietal cortex (PCx) and temporal cortex (TCx), were assessed in three subgroups: young controls (n = 6, aged 24-57); aged controls (n = 26, aged 78-99); and an AD cohort (n = 12, aged 79-99). A significant positive correlation (p < 10-10) was seen for AQP transcript levels as a function of the subject's age in years. Differential expressions correlated with brain region, age, and AD diagnosis, particularly between the HIP and cortical regions. Interestingly, three classes of AQPs (0, 6 and 8) upregulated in AD compared to young controls are permeable to H2O2. Of these, AQPs 0 and 8 were increased in TCx and AQP6 in HIP, suggesting a role of AQPs in AD-related oxidative stress. The outcomes here are the first to demonstrate that the expression profile of AQP channels in the human brain is more diverse than previously thought, and transcript levels are influenced by both age and AD status. Associations between reactive oxygen stress and neurodegenerative disease risk highlight AQPs 0, 6, 8 and 10 as potential therapeutic targets.

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Malignant pleural mesothelioma (MPM) is an aggressive cancer of the pleural surface and is associated with previous asbestos exposure. The chemotherapy drug is one of the main treatments, but the median survival ranges from 8 to 14 months from diagnosis. The redox homeostasis of tumor cells should be carefully considered since elevated levels of ROS favor cancer cell progression (proliferation and migration), while a further elevation leads to ferroptosis. This study aims to analyze the functioning/role of aquaporins (AQPs) as a hydrogen peroxide (H2O2) channel in epithelial and biphasic MPM cell lines, as well as their possible involvement in chemotherapy drug resistance. Results show that AQP-3, -5, -6, -9, and -11 were expressed at mRNA and protein levels. AQP-6 was localized in the plasma membrane and intracellular structures. Compared to normal mesothelial cells, the water permeability of mesothelioma cells is not reduced by exogenous oxidative stress, but it is considerably increased by heat stress, making these cells resistant to ferroptosis. Functional experiments performed in mesothelioma cells silenced for aquaporin-6 revealed that it is responsible, at least in part, for the increase in H2O2 efflux caused by heat stress. Moreover, mesothelioma cells knocked down for AQP-6 showed a reduced proliferation compared to mock cells. Current findings suggest the major role of AQP-6 in providing mesothelioma cells with the ability to resist oxidative stress that underlies their resistance to chemotherapy drugs.

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Sigma1 Receptor (S1R) is involved in oxidative stress, since its activation is triggered by oxidative or endoplasmic reticulum stress. Since specific aquaporins (AQP), called peroxiporins, play a relevant role in controlling H2O2 permeability and ensure reactive oxygen species wasted during oxidative stress, we studied the effect of S1R modulators on AQP-dependent water and hydrogen peroxide permeability in the presence and in the absence of oxidative stress. Applying stopped-flow light scattering and fluorescent probe methods, water and hydrogen peroxide permeability in HeLa cells have been studied. Results evidenced that S1R agonists can restore water permeability in heat-stressed cells and the co-administration with a S1R antagonist totally counteracted the ability to restore the water permeability. Moreover, compounds were able to counteract the oxidative stress of HeLa cells specifically knocked down for S1R. Taken together these results support the hypothesis that the antioxidant mechanism is mediated by both S1R and AQP-mediated H2O2 permeability. The finding that small molecules can act on both S1R and AQP-mediated H2O2 permeability opens a new direction toward the identification of innovative drugs able to regulate cell survival during oxidative stress in pathologic conditions, such as cancer and degenerative diseases.

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Septic shock is the most severe complication of sepsis, being characterized by a systemic inflammatory response following bacterial infection, leading to multiple organ failure and dramatically high mortality. Aquaporin-9 (AQP9), a membrane channel protein mainly expressed in hepatocytes and leukocytes, has been recently associated with inflammatory and infectious responses, thus triggering strong interest as a potential target for reducing septic shock-dependent mortality. Here, we evaluated whether AQP9 contributes to murine systemic inflammation during endotoxic shock. Wild type (Aqp9+/+; WT) and Aqp9 gene knockout (Aqp9-/-; KO) male mice were submitted to endotoxic shock by i.p. injection of lipopolysaccharide (LPS; 40 mg/kg) and the related survival times were followed during 72 h. The electronic paramagnetic resonance and confocal microscopy were employed to analyze the nitric oxide (NO) and superoxide anion (O2-) production, and the expression of inducible NO-synthase (iNOS) and cyclooxigenase-2 (COX-2), respectively, in the liver, kidney, aorta, heart and lung of the mouse specimens. LPS-treated KO mice survived significantly longer than corresponding WT mice, and 25% of the KO mice fully recovered from the endotoxin treatment. The LPS-injected KO mice showed lower inflammatory NO and O2- productions and reduced iNOS and COX-2 levels through impaired NF-κB p65 activation in the liver, kidney, aorta, and heart as compared to the LPS-treated WT mice. Consistent with these results, the treatment of FaO cells, a rodent hepatoma cell line, with the AQP9 blocker HTS13268 prevented the LPS-induced increase of inflammatory NO and O2-. A role for AQP9 is suggested in the early acute phase of LPS-induced endotoxic shock involving NF-κB signaling. The modulation of AQP9 expression/function may reveal to be useful in developing novel endotoxemia therapeutics.

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Hydrogen peroxide (H2O2) is an essential second intracellular messenger. To reach its targets in the cytosol, H2O2 must cross a membrane, a feat that requires aquaporins (AQP) endowed with 'peroxiporin' activity (AQP3, AQP8, AQP9). Here, we exploit different organelle-targeted H2O2-sensitive probes to show that also AQP11 efficiently conduits H2O2. Unlike other peroxiporins, AQP11 is localized in the endoplasmic reticulum (ER), accumulating partly in mitochondrial-associated ER membranes (MAM). Its downregulation severely perturbs the flux of H2O2 through the ER, but not through the mitochondrial or plasma membranes. These properties make AQP11 a potential regulator of ER redox homeostasis and signaling.

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The transport of H2O2 across membranes by specific aquaporins (AQPs) has been considered the last milestone in the timeline of hydrogen peroxide discoveries in biochemistry. According to its concentration and localization, H2O2 can be dangerous or acts as a signaling molecule in various cellular processes as either a paracrine (intercellular) and/or an autocrine (intracellular) signal. In this review, we investigate and critically examine the available information on AQP isoforms able to facilitate H2O2 across biological membranes ("peroxiporins"), focusing in particular on their role in cancer. Moreover, the ability of natural compounds to modulate expression and/or activity of peroxiporins is schematically reported and discussed.

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Hydrogen peroxide emerged as major redox metabolite operative in redox sensing, signaling and redox regulation. Generation, transport and capture of H2O2 in biological settings as well as their biological consequences can now be addressed. The present overview focuses on recent progress on metabolic sources and sinks of H2O2 and on the role of H2O2 in redox signaling under physiological conditions (1-10nM), denoted as oxidative eustress. Higher concentrations lead to adaptive stress responses via master switches such as Nrf2/Keap1 or NF-κB. Supraphysiological concentrations of H2O2 (>100nM) lead to damage of biomolecules, denoted as oxidative distress. Three questions are addressed: How can H2O2 be assayed in the biological setting? What are the metabolic sources and sinks of H2O2? What is the role of H2O2 in redox signaling and oxidative stress?

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