Tangeretin has anti-asthmatic effects via regulating PI3K and Notch signaling and modulating Th1/Th2/Th17 cytokine balance in neonatal asthmatic mice

Abstract

Asthma is a chronic allergic disease characterized by airway inflammation, airway hyper-responsiveness (AHR), and mucus hypersecretion. T-lymphocytes are involved in the pathogenesis of asthma, mediating airway inflammatory reactions by secreting cytokines. The phosphoinositide 3-kinase (PI3K) and Notch signaling pathways are associated with T cell signaling, proliferation, and differentiation, and are important in the progression of asthma. Thus, compounds that can modulate T cell proliferation and function may be of clinical value. Here, we assessed the effects of tangeretin, a plant-derived flavonoid, in experimental asthma. BALB/c mice at postnatal day (P) 12 were challenged with ovalbumin (OVA). Separate groups of mice (n=18/group) were administered tangeretin at 25 or 50 mg/kg body weight by oral gavage. Dexamethasone was used as a positive control. Tangeretin treatment reduced inflammatory cell infiltration in bronchoalveolar lavage fluid (BALF) and also restored the normal histology of lung tissues. OVA-specific IgE levels in serum and BALF were reduced. AHR, as determined by airway resistance and lung compliance, was normalized. Flow cytometry analyses revealed a reduced Th17 cell population. Tangeretin reduced the levels of Th2 and Th17 cytokines and raised IFN-γ levels. PI3K signaling was inhibited. The expressions of the Notch 1 receptor and its ligands Jagged 1 and 2 were downregulated by tangeretin. Our findings support the possible use of tangeretin for treating allergic asthma.

Integrative Bioinformatics Study Reveals Tangeretin Targets and Molecular Mechanisms Against Metastatic Breast Cancer

“…Another study showed that tangeretin poses a potent neuroprotective activity by triggering the PI3K/Akt signaling pathway in pilocarpine-induced seizures rats (26). Tangeretin also inhibits PI3K and Notch signaling in neonatal asthmatic mice (47).…”

In vivo and in vitro safety evaluation of fermented Citrus sunki peel extract: acute and 90-day repeated oral toxicity studies with genotoxicity assessment

“…Among the polymethoxy flavonoids in C. sunki peel, tangeretin is one of the most abundant components and has been associated with in vivo toxicity in mice; Although LD50 was > 3000 mg/kg BW, repeated administration of 50 mg/kg caused reduction of relative liver weight with hepatocellular alteration, and increased triglycerides and total cholesterol of female groups in a 28-day oral toxicity study [ 34 ]. Also, tangeretin was reported to be a mild immunotoxicant as demonstrated in a concurrent reduction of T cell-derived interleukins and Th17 cell population by oral administration of 50 mg/kg tangeretin [ 35 ] and reduction of circulating lymphocytes by 0.22 mg/day [ 36 ]. In our 90-day toxicity study, we did not observe such pathological changes in the SD rats fed with 2000 mg/kg FCPE (equivalent to 6.8 mg/kg/day tangeretin) except for mild reduction of circulating lymphocytes in the male 1000 mg/kg group.…”

Regulation of γδT17 cells by Mycobacterium vaccae through interference with Notch/Jagged1 signaling pathway

“…Notch ligand Jagged1 has been shown to be highly expressed in the proximal asthmatic airways, which may lead to enhanced Th2 cell development (18,19). Many previous findings indicate that it may be possible to treat allergic asthma by inhibiting the production of Th2 and Th17 cytokines and downregulating the expression of Jagged1 (20). Consequently, the mechanism of action of the Notch signaling pathway in asthma has been intensely studied in recent years.…”