Luteolin Improves Cyclophosphamide-Induced Cystitis through TXNIP/NLRP3 and NF-κB Pathways

Abstract

Hemorrhagic cystitis is an important complication of cyclophosphamide chemotherapy, and current therapies for the disease are limited. The natural flavonoid luteolin (LUT) has significant anti-inflammatory and antioxidant properties, but its protective effect on cyclophosphamide (CYP)-induced bladder toxicity has yet to be evaluated. This study aims to explore the protective effect of LUT on CYP-induced acute cystitis in rats. Female Sprague-Dawley rats were randomly assigned to the control (CON) group, CON + LUT group, CYP group, and CYP + LUT group. A single intraperitoneal injection of CYP was administered to establish an acute hemorrhagic cystitis model. HE staining was performed to detect the degree of bladder tissue damage, and TUNEL staining was performed to count apoptotic cells. Oxidative stress indicators were measured using commercial kits, and bladder surgery was performed to assess urinary function. The levels of inflammatory cytokines, apoptosis-related indicators, TXNIP/NLRP3 pathway, and NF-κB pathway were detected by western blot. We found that LUT treatment reduced bladder bleeding, congestion, and edema caused by CYP. Compared with the CYP + LUT group, the level of apoptosis was more highly expressed in the CYP group. We also found that caspase-3, caspase-8, and Bax were significantly upregulated and Bcl-2 was downregulated after LUT treatment. In addition, LUT inhibited the activation of NF-κB signal pathway in the rat bladder tissue after CYP exposure. LUT treatment can also reduce the NLRP3 inflammasome (NLRP3, ASC, and caspase-1) and TXNIP in the bladder. Finally, LUT can reduce the increase in the urination frequency and maximum urination pressure caused by cystitis. These results indicate that LUT displays effective anti-inflammatory, antioxidant, and antiapoptotic properties in CYP-induced acute hemorrhagic cystitis rats by inhibiting the TXNIP/NLRP3 and NF-κB pathways. LUT may be a potent therapeutic agent for the prevention and treatment of hemorrhagic cystitis.

Effect of taxifolin on cyclophosphamide-induced oxidative and inflammatory bladder injury in rats

“…In this study, taxifolin's effects on the oxidative and inflammatory bladder damage caused by cyclophosphamide in rats were studied biochemically and histopathologically. The balance between the oxidant and antioxidant systems in cyclophosphamide-induced oxidative bladder injury has been studied previously [8]. The level of MDA was increased and the level of tGSH was decreased in the animals with cyclophosphamide-induced bladder tissue injury, according to Abraham et al [18].…”

“…The increase in the level of malondialdehyde (MDA), a result of lipid peroxidation (LPO), and the decrease in the level of the endogenous antioxidant glutathione (GSH) have been demonstrated to cause the toxic effects of cyclophosphamide on the bladder. It has also been suggested that cyclophosphamide-associated cystitis is associated with the expression of proinflammatory cytokines, such as nuclear factor-κB (NF-κB), tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), and IL-6 [1,8]. According to evidence reported in the literature, antioxidant and anti-inflammatory medications may be beneficial in the treatment of cyclophosphamideinduced bladder injury.…”

Protective effect of luteolin against chemical and natural toxicants by targeting NF‐κB pathway

“…23 Some evidence revealed that numerous flavonoids especially LUT and its analogs such as methoxyluteolin exhibit potent anti-inflammatory properties by repressing the NF-κB signaling pathway. [24][25][26][27] It has been reported that LUT decreased NF-κB activation at both the transcriptional and translational levels in various disorders, such as psoriasis, atopic diseases, diabetic cardiomyopathy, osteoarthritis, and toxicities. [28][29][30][31][32] So, it seems that NF-κB has been considered a pro-inflammatory signaling pathway and a target for new anti-inflammatory medications.…”

“…Many agents disrupt the complex and activate the NF‐κB, including TNF‐α, IL‐1, ionizing radiation, and bacterial lipopolysaccharide (LPS) 23 . Some evidence revealed that numerous flavonoids especially LUT and its analogs such as methoxyluteolin exhibit potent anti‐inflammatory properties by repressing the NF‐κB signaling pathway 24–27 . It has been reported that LUT decreased NF‐κB activation at both the transcriptional and translational levels in various disorders, such as psoriasis, atopic diseases, diabetic cardiomyopathy, osteoarthritis, and toxicities 28–32 .…”

Phytochemicals, Biological Activities, Molecular Mechanisms, and Future Prospects of Plantago asiatica L.

“…Studies have shown that apigenin ( 1 ) administration blocks the secretion of pro-inflammatory cytokines and the activation of NF-κB; downregulates the expression of NLRP-3, TLR4, TNF-α, AMPK, and NF-κB; , and decreases the transcriptional activity of NF-κB and the phosphorylation of NF-κB, IκB, IKK, Lyn, Syk, MAPK, ERK, and JNK. , Similarly, luteolin ( 2 ) exerts an anti-inflammatory effect by downregulating the TLR4-mediated NF-κB/NLRP-3 and NF-κB phosphorylation. ,− The protective effects of acteoside ( 27 ) and isoacteoside ( 28 ) are mediated by phosphorylation of IKK, IκBα, NF-κB, and MAPK and the inactivation of TLR4-mediated NF-κB to modulate inflammation. ,− , Additionally, acteoside ( 27 ) restrains the inflammatory responses (TNF-α, IFN-γ, IL-6, and IL-12) by suppressing the JAK/STAT signaling pathway . Furthermore, plantamajoside ( 25 ) has anti-inflammatory properties via inhibition of the phosphorylation of IκBα, JNK, and MAPK, as well as nuclear translocation of NF-κB. , Unexpectedly, on the basis of the MAPK and NF-κB pathway, polysaccharides induce expression of MHC-II and CD86 to promote maturation of dendritic cells (DCs) and then accelerate the secretion of TNF-α and IL-12p70 so it may promote inflammatory effects .…”