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Objective: This study was designed to investigate whether necroptosis is involved in the pathogenesis of chemoradiation‐induced oral mucositis in a murine model and whether 1‐palmitoyl‐2‐linoleoyl‐3‐acetyl‐rac‐glycerol (PLAG) ameliorates this disorder. Materials and Methods: A chemoradiation‐induced oral mucositis model was established by treating mice with concurrent 5‐fluorouracil (100 mg/kg, i.p.) and head and neck X‐irradiation (20 Gy). Phosphate‐buffered saline or PLAG (100 mg/kg or 250 mg/kg, p.o.) was administered daily. Body weights were recorded daily, and mice were sacrificed on Day 9 for tongue tissue analysis. Results: On Day 9, chemoradiotherapy‐treated (ChemoRT) mice had tongue ulcerations and experienced significant weight loss (Day 0:26.18 ± 1.41 g; Day 9:19.44 ± 3.26 g). They also had elevated serum macrophage inhibitory protein 2 (MIP‐2) (control: 5.57 ± 3.49 pg/ml; ChemoRT: 130.14 ± 114.54 pg/ml) and interleukin (IL)‐6 (control: 198.25 ± 16.91 pg/ml; ChemoRT: 467.25 ± 108.12 pg/ml) levels. ChemoRT‐treated mice who received PLAG exhibited no weight loss (Day 0:25.78 ± 1.04 g; Day 9:26.46 ± 1.68 g) and had lower serum MIP‐2 (4.42 ± 4.04 pg/ml) and IL‐6 (205.75 ± 30.41 pg/ml) levels than ChemoRT‐treated mice who did not receive PLAG. Tongue tissues of mice who received PLAG also displayed lower phosphorylation levels of necroptotic signalling proteins. Conclusion: 1‐Palmitoyl‐2‐linoleoyl‐3‐acetyl‐rac‐glycerol mitigated chemoradiation‐induced oral mucositis by modulating necroptosis. [ABSTRACT FROM AUTHOR]

Granulocyte colony-stimulating factor (G-CSF) is widely used for preventing neutropenia during chemotherapy. Polyethylene glycol-conjugated granulocyte colony-stimulating factor (PEG-G-CSF, pegfilgrastim) serves the same purpose but has a longer half-life and greater stability than G-CSF. In this study, we investigated whether 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol, acetylated diglyceride (PLAG), augments the therapeutic effect of pegfilgrastim on chemotherapy-induced neutropenia. We compared neutrophil counts in four groups of mice: control mice, gemcitabine-treated mice, gemcitabine/pegfilgrastim-treated mice, and gemcitabine/pegfilgrastim/PLAG-treated mice. PLAG (50 mg/kg) was orally administered every day during the treatment course. CBC analysis showed that the group treated with PLAG experienced a dramatically increased neutrophil counts on the third day following pegfilgrastim treatment. PLAG had no effect on blood cell apoptosis and neutrophil release from bone marrow. Additionally, pegfilgrastim-induced CXCR2 expression in neutrophils was markedly decreased in PLAG-treated animals. These results suggest that PLAG plays a role in inhibiting neutrophil extravasation, giving rise to an increased number of circulating neutrophils when used with pegfilgrastim during gemcitabine treatment. These data support the potential for PLAG to be used with pegfilgrastim to treat or prevent chemotherapy-induced neutropenia by modulating neutrophil transmigration. [ABSTRACT FROM AUTHOR]