Genistein inhibits rotavirus replication and upregulates AQP4 expression in rotavirus-infected Caco-2 cells

Rotavirus (RV) is the primary cause of severe dehydrating gastroenteritis and acute diarrheal disease in infants and young children. Previous studies have revealed that genistein can inhibit the infectivity of enveloped or nonenveloped viruses. Although the biological properties of genistein are well studied, the mechanisms of action underlying their anti-rotavirus properties have not been fully elucidated. Here, we report that genistein significantly inhibits RV-Wa replication in vitro by repressing viral RNA transcripts, and possibly viral protein synthesis. Interestingly, we also found that aquaporin 4 (AQP4) mRNA and protein expression, which was downregulated in RV-infected Caco-2 cells, can be upregulated by genistein in a time- and dose-dependent manner. Further experiments confirmed that genistein triggers CREB phosphorylation through PKA activation and subsequently promotes AQP4 gene transcription. These findings suggest that the pathophysiological mechanism of RV infection involves decreased expression of AQP4 and that genistein may be a useful candidate for developing a new anti-RV strategy by inhibiting rotavirus replication and upregulating AQP4 expression via the cAMP/PKA/CREB signaling pathway. Further studies on the effect of genistein on RV-induced diarrhea are warranted.