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Dexamethasone has a high anti-inflammatory efficacy in treating skin inflammation. However, its use is related to the rebound effect, rosacea, purple, and increased blood glucose levels. Nanotechnology approaches have emerged as strategies for drug delivery due to their advantages in improving therapeutic effects. To reduce dexamethasone-related adverse effects and improve the anti-inflammatory efficacy of treatments, we developed nanocarriers containing this corticosteroid and oleic acid. Nanocapsules and nanoemulsion presented dexamethasone content close to the theoretical value and controlled dexamethasone release in an in vitro assay. Gellan gum-based hydrogels were successfully prepared to employ the nanostructured systems. A permeation study employing porcine skin showed that hydrogels containing non-nanoencapsulated dexamethasone (0.025%) plus oleic acid (3%) or oleic acid (3%) plus dexamethasone (0.025%)-loaded nanocapsules provided a higher amount of dexamethasone in the epidermis compared to non-nanoencapsulated dexamethasone (0.5%). Hydrogels containing oleic acid plus dexamethasone-loaded nanocapsules effectively inhibited mice ear edema (with inhibitions of 89.26 ± 3.77% and 85.11 ± 2.88%, respectively) and inflammatory cell infiltration (with inhibitions of 49.58 ± 4.29% and 27.60 ± 11.70%, respectively). Importantly, the dexamethasone dose employed in hydrogels containing the nanocapsules that effectively inhibited ear edema and cell infiltration was 20-fold lower (0.025%) than that of non-nanoencapsulated dexamethasone (0.5%). Additionally, no adverse effects were observed in preliminary toxicity tests. Our study suggests that nanostructured hydrogel containing a reduced effective dose of dexamethasone could be a promising therapeutic alternative to treat inflammatory disorders with reduced or absent adverse effects. Additionally, testing our formulation in a clinical study on patients with skin inflammatory diseases would be very important to validate our study.

Aromatase inhibitors (AIs) cause symptoms of musculoskeletal pain, and some mechanisms have been proposed to explain them. However, signaling pathways downstream from kinin B 2 (B 2 R) and B 1 (B 1 R) receptor activation and their possible sensitizing of the Transient Receptor Potential Ankyrin 1 (TRPA1) remain unknown. The interaction between the kinin receptor and the TRPA1 channel in male C57BL/6 mice treated with anastrozole (an AI) was evaluated. PLC/PKC and PKA inhibitors were used to evaluate the signaling pathways downstream from B 2 R and B 1 R activation and their effect on TRPA1 sensitization. Anastrozole caused mechanical allodynia and muscle strength loss in mice. B 2 R (Bradykinin), B 1 R (DABk), or TRPA1 (AITC) agonists induced overt nociceptive behavior and enhanced and prolonged the painful parameters in anastrozole-treated mice. All painful symptoms were reduced by B 2 R (Icatibant), B 1 R (DALBk), or TRPA1 (A967079) antagonists. We observed the interaction between B 2 R, B 1 R, and the TRPA1 channel in anastrozole-induced musculoskeletal pain, which was dependent on the activation of the PLC/PKC and PKA signaling pathways. TRPA1 seems to be sensitized by mechanisms dependent on the activation of PLC/PKC, and PKA due to kinin receptors stimulation in anastrozole-treated animals. Thus, regulating this signaling pathway could contribute to alleviating AIs-related pain symptoms, patients' adherence to therapy, and disease control.

Cisplatin is the preferential chemotherapeutic drug for highly prevalent solid tumours. However, its clinical efficacy is frequently limited due to neurotoxic effects such as peripheral neuropathy. Chemotherapy-induced peripheral neuropathy is a dose-dependent adverse condition that negatively impacts quality of life, and it may determine dosage limitations or even cancer treatment cessation. Thus, it is urgently necessary to identify pathophysiological mechanisms underlying these painful symptoms. As kinins and their B 1 and B 2 receptors contribute to the development of chronic painful conditions, including those induced by chemotherapy, the contribution of these receptors to cisplatin-induced peripheral neuropathy was evaluated via pharmacological antagonism and genetic manipulation in male Swiss mice. Cisplatin causes painful symptoms and impaired working and spatial memory. Kinin B 1 (DALBK) and B 2 (Icatibant) receptor antagonists attenuated some painful parameters. Local administration of kinin B 1 and B 2 receptor agonists (in sub-nociceptive doses) intensified the cisplatin-induced mechanical nociception attenuated by DALBK and Icatibant, respectively. In addition, antisense oligonucleotides to kinin B 1 and B 2 receptors reduced cisplatin-induced mechanical allodynia. Thus, kinin B 1 and B 2 receptors appear to be potential targets for the treatment of cisplatin-induced painful symptoms and may improve patients' adherence to treatment and their quality of life.