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

Jiang Zhao,Chengfei Yang,Shanhong Yi,Lucian Hritcu,Zhenxing Yang,Xin Liu,Hengshuai Zhang,Qudong Lu,Jie Xu,Longkun Li,Bishao Sun,Shuai Li

doi:10.1155/2021/1718709

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.

Highlights

Cyclophosphamide (CYP) is a commonly used drug for chemotherapy of tumors and autoimmune diseases, but it has side effects on organs such as the bladder, liver, and kidneys [1]
LUTcan protect the bladder epithelium from E. coli infection by inhibiting cAMP-phosphodiesterase [18]. e therapeutic effect of LUT on chemical toxicity injury and lower urinary tract disease indicates that it may have a protective effect on CYP-induced hemorrhagic cystitis. erefore, this study aims to verify the therapeutic effect of LUT on acute hemorrhagic cystitis in rats and to further determine whether the Nuclear factor-κB (NF-κB) signal pathway and the TXNIP/NODlike receptor protein 3 (NLRP3) axis are the therapeutic targets of LUTagainst bladder injury
On the fifth day of the experiment, the CYP group and CYP + LUT group were injected with CYP (150 mg/kg) (HY17420, MCE, USA) by intraperitoneal injection to induce acute hemorrhagic cystitis [20], and the CON group and CON + LUT group received normal saline solution intraperitoneally. e experiment was terminated on day 7

Summary

Introduction

Cyclophosphamide (CYP) is a commonly used drug for chemotherapy of tumors and autoimmune diseases, but it has side effects on organs such as the bladder, liver, and kidneys [1]. A recent study showed that nearly one-quarter of patients using high-dose CYP suffer from hemorrhagic cystitis [3]. E pathological mechanism of CYP-induced hemorrhagic cystitis is related to its metabolite acrolein. Acrolein is a product of CYP metabolism in the liver, and it accumulates in the bladder after being excreted by the kidneys. Acrolein can induce the production of reactive oxygen species (ROS) and nitric oxide (NO) to promote oxidative stress and inflammation and induce hemorrhagic cystitis through a variety of cascade reactions [4]. Mesna is the preferred drug for the prevention and treatment of hemorrhagic cystitis, but it is not ideal due to adverse reactions and instability of treatment [5]. Mesna is the preferred drug for the prevention and treatment of hemorrhagic cystitis, but it is not ideal due to adverse reactions and instability of treatment [5]. erefore, exploring new drugs for the prevention or treatment of hemorrhagic cystitis has important clinical significance

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