Impact of protocatechuic acid on alleviation of pulmonary damage induced by cyclophosphamide targeting peroxisome proliferator activator receptor, silent information regulator type-1, and fork head box protein in rats.

Cyclophosphamide (CP) is a chemotherapeutic agent that causes pulmonary damage by generating free radicals and pro-inflammatory cytokines. Pulmonary damage has a high mortality rate due to the severe inflammation and edema occurred in lung. PPARγ/Sirt 1 signaling has been shown to be cytoprotective effect against cellular inflammatory stress and oxidative injury. Protocatechuic acid (PCA) is a potent Sirt1 activator and exhibits antioxidant as well as anti-inflammatory properties. The current study aims to investigate the therapeutic impacts of PCA against CP-induced pulmonary damage in rats. Rats were assigned randomly into 4 experimental groups. The control group was injected with a single i.p injection of saline. CP group was injected with a single i.p injection of CP (200 mg/kg). PCA groups were administered orally with PCA (50 and 100 mg/kg; p.o.) once daily for 10 consecutive days after CP injection. PCA treatment resulted in a significant decrease in the protein levels of MDA, a marker of lipid peroxidation, NO and MPO along with a significant increase in GSH and catalase protein levels. Moreover, PCA downregulated anti-inflammatory markers as IL-17, NF-κB, IKBKB, COX-2, TNF-α, and PKC and upregulated cytoprotective defenses as PPARγ, and SIRT1. In addition, PCA administration ameliorated FoxO-1 elevation, increased Nrf2 gene expression, and reduced air alveoli emphysema, bronchiolar epithelium hyperplasia and inflammatory cell infiltration induced by CP. PCA might represent a promising adjuvant to prevent pulmonary damage in patients receiving CP due to its antioxidant and anti-inflammatory effects with cytoprotective defenses.

Immunomodulatory effect of protocatechuic acid on cyclophosphamide induced brain injury in rat: Modulation of inflammosomes NLRP3 and SIRT1.

Modulation of the inflammasome NLRP3 and SIRT1 are new combat strategy for brain injury protection. The inflammasome activates proinflammatory cytokines releasing interleukin-1ß and interleukin-18 which in turn affect the toxins release from immune cells. In addition, SIRT1 controls many biological functions, such as immune response and oxidative stress. Protocatechuic has versatile biological activities and possesses antioxidant, anti-inflammatory and neuroprotective effects. So this work aims to study immunomodulatory effect of protocatechuic acid on cyclophosphamide chemotherapy drug-induced brain injury via modulation of inflammosomes NLRP3 and SIRT1. Rats were randomly assigned to four experimental groups. Normal control group was injected with a single i.p injection of saline. Cyclophosphamide group was injected with a single i.p injection of cyclophosphamide (200 mg/kg). Protocatechuic acid groups were orally administered (50 &100 mg/kg) once daily for 10 consecutive days after cyclophosphamide injection. Protocatechuic acid administration exhibited improvements of the cognition function and memory, a reduction in brain contents of MDA, NLRP3, IL-1 ß, NF-κB, IKBKB and Galectin 3 and an elevation of GSH and SIRT1 compared to cyclophosphamide group. In addition, protocatechuic acid administration ameliorated the elevation of caspase 3 and iNOS gene expression and alleviated the neuron degeneration caused by cyclophosphamide. In conclusion, the therapeutic action of protocatechuic acid and its cellular and molecular mechanisms are new insights against various human ailments, especially, neurodegenerative disease as brain injury induced by cyclophosphamide chemotherapy drug in rats through modulation of inflammosomes NLRP3 and SIRT1.