Lycopene attenuates the inflammation and apoptosis in aristolochic acid nephropathy by targeting the Nrf2 antioxidant system

Wang, Yu; Liu, Zhihui; Ma, Jun; Xv, Qingyang; Gao, Hongxin; Yin, Hang; Yan, Gao; Jiang, Xiaowen; Yu, Wenhui

doi:10.1016/j.redox.2022.102494

Cited by 42 publications

(20 citation statements)

References 83 publications

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“…The major nephrotoxic constituent of aristolochic acid (AA) is 8‐methoxy‐6‐nitrophenanthrene‐(3,4‐d)‐1,3‐dioxo‐5‐carboxylic acid (aristolochic acid I, AAI). There is evidence that oxidative stress injury is induced in the kidneys of mice after AAI exposure, resulting in tubular epithelial cell apoptosis (Wang et al, 2022) and histopathological features of tubular necrosis in a short‐term mouse model (Xian et al, 2021). The assembled NLRP3 inflammasome can activate caspase 1 to induce gasdermin D‐dependent pyroptosis (Huang et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase‐mediated silencing of PSTPIP2 expression contributes to aristolochic acid nephropathy‐induced PANoptosis

Xu,

Wang,

et al. 2024

British J Pharmacology

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Background and PurposeAristolochic acid nephropathy (AAN) is a progressive kidney disease caused by using herbal medicines. Currently, no therapies are available to treat or prevent AAN. Histone deacetylase (HDAC) plays a crucial role in the development and progression of renal disease. We tested whether HDAC inhibitors could prevent AAN and determined the underlying mechanism.Experimental ApproachHDACs expression in the aristolochic acid nephropathy model was examined. The activation of PANoptosis of mouse kidney and renal tubular epithelial cell were assessed after exposure to HDAC1 and HDAC2 blockade. Kidney‐specific knock‐in of Proline‐serine‐threonine‐phosphatase‐interacting protein 2 (PSTPIP2) mice were used to investigate whether PSTPIP2 affected the production of PANoptosome.Key ResultsAristolochic acid upregulated the expression of HDAC1 and HDAC2 in the kidneys. Notably, the HDAC1 and ‐2 specific inhibitor, romidepsin (FK‐228, Depsipeptide), suppressed aristolochic acid‐induced kidney injury, epithelial cell pyroptosis, apoptosis, and necroptosis (PANoptosis). Moreover, romidepsin upregulated PSTPIP2 in renal tubular epithelial cells, which was enhanced by aristolochic acid treatment. Conditional knock‐in of PSTPIP2 in the kidney protected against AAN. In contrast, the knockdown of PSTPIP2 expression in PSTPIP2‐knockin mice restored kidney damage and PANoptosis. PSTPIP2 function was determined in vitro using PSTPIP2 knockdown or overexpression in mTECs. Additionally, PSTPIP2 was found to regulate Caspase‐8 in Aristolochic acid nephropathy.Conclusion and ImplicationsHDAC‐mediated silencing of PSTPIP2 may contribute to aristolochic acid nephropathy. Hence, HDAC1 and ‐2 specific inhibitors or PSTPIP2 could be valuable therapeutic agents for preventing aristolochic acid nephropathy.

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Section: Discussionmentioning

confidence: 99%

Histone deacetylase‐mediated silencing of PSTPIP2 expression contributes to aristolochic acid nephropathy‐induced PANoptosis

Xu,

Wang,

et al. 2024

British J Pharmacology

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“…The major nephrotoxic constituent of aristolochic acid (AA) is 8-methoxy-6-nitrophenanthrene-(3,4-d)-1,3-dioxo-5-carboxylic acid (aristolochic acid I, AAI) (Shibutani, Dong, Suzuki, Ueda, Miller & Grollman, 2007). There is evidence that oxidative stress injury is induced in the kidneys of mice after AAI exposure, resulting in tubular epithelial cell apoptosis (Wang et al, 2022) and histopathological features of tubular necrosis in a short-term mouse model (Baudoux et al, 2012). The assembled NLRP3 inflammasome can activate caspase-1 to induce gasdermin D-dependent pyroptosis (Huang, Xu & Zhou, 2021;Shi et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase-mediated silencing of PSTPIP2 expression contributes to AAI-induced PANoptosis

Chen

Wang

et al. 2023

Preprint

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Background and Purpose: Aristolochic acid nephropathy (AAN) is a progressive kidney disease caused by using herbal medicines. Currently, no therapies are available to treat or prevent AAN. Histone deacetylase (HDAC) plays a crucial role in the development and progression of renal disease. We tested whether HDAC inhibitors could prevent AAN and determined the underlying mechanism. Experimental Approach: HDACs expression in the kidneys was examined. Mouse kidney and renal tubular epithelial cell damage were assessed after exposure to HDAC1 and HDAC2 blockade (FK-228). Conditional knock-in of Proline-serine-threonine-phosphatase-interacting protein 2 (PSTPIP2) in the kidney and knockdown of PSTPIP2 expression in PSTPIP2-knockin mice, pathological parameters, and kidney injuries were assessed. Key Results: Aristolochic acid upregulated the expression of HDAC1 and HDAC2 in the kidneys. Notably, the HDAC1 and -2 specific inhibitor, romidepsin (FK228, Depsipeptide), suppressed aristolochic acid-induced kidney injury, epithelial cell pyroptosis, apoptosis, and necroptosis (PANoptosis). Moreover, romidepsin upregulated PSTPIP2 in renal tubular epithelial cells, which was enhanced by aristolochic acid treatment. Conditional knock-in of PSTPIP2 in the kidney protected against AAN. In contrast, the knockdown of PSTPIP2 expression in PSTPIP2-knockin mice restored kidney damage and PANoptosis. PSTPIP2 function was determined in vitro using PSTPIP2 knockdown or overexpression in mTEC. Additionally, PSTPIP2 was found to regulate Caspase-8 in Aristolochic acid nephropathy. Conclusion and Implications: HDAC-mediated silencing of PSTPIP2 may contribute to aristolochic acid nephropathy. Hence, HDAC1 and -2 specific inhibitors or PSTPIP2 could be valuable therapeutic agents for the prevention of aristolochic acid nephropathy.

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“…Finally, it is also possible that lycopene stimulated the gene expression of these enzymes. Studies demonstrated that lycopene potentially protected tissue injuries caused by oxidative stress by enhancing the expression of antioxidant enzymes via activation of Nrf2 [ 31 , 32 ]. Nrf2 (nuclear factor (erythroid-derived 2)-like-2 factor) is a transcription factor involved in the regulation of the intracellular redox homeostasis that induces the expression of antioxidant and cytoprotective enzymes under conditions of oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Combined Effects of Lycopene and Metformin on Decreasing Oxidative Stress by Triggering Endogenous Antioxidant Defenses in Diet-Induced Obese Mice

et al. 2022

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Since lycopene has antioxidant activity, its combination with metformin may be useful to contrast diabetic complications related to oxidative stress. This study aimed to investigate the effects of metformin combined with lycopene on high-fat diet (HFD)-induced obese mice. Seventy-two C57BL-6J mice were divided into six groups: C (control diet-fed mice), H (HFD-fed mice for 17 weeks), H-V (HFD-fed mice treated with vehicle), H-M (HFD-fed mice treated with 50 mg/kg metformin), H-L (HFD-fed mice treated with 45 mg/kg lycopene), and H-ML (HFD-fed mice treated with 50 mg/kg metformin + 45 mg/kg lycopene). Treatments were administered for 8 weeks. Glucose tolerance, insulin sensitivity, fluorescent AGEs (advanced glycation end products), TBARS (thiobarbituric acid-reactive substances), and activities of antioxidant enzymes paraoxonase-1 (PON-1; plasma), superoxide dismutase, catalase and glutathione peroxidase (liver and kidneys) were determined. Metformin plus lycopene reduced body weight; improved insulin sensitivity and glucose tolerance; and decreased AGEs and TBARS in plasma, liver and kidneys. Combined therapy significantly increased the activities of antioxidant enzymes, mainly PON-1. Lycopene combined with metformin improved insulin resistance and glucose tolerance, and caused further increases in endogenous antioxidant defenses, arising as a promising therapeutic strategy for combating diabetic complications resulting from glycoxidative stress.

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Lycopene attenuates the inflammation and apoptosis in aristolochic acid nephropathy by targeting the Nrf2 antioxidant system

Cited by 42 publications

References 83 publications

Histone deacetylase‐mediated silencing of PSTPIP2 expression contributes to aristolochic acid nephropathy‐induced PANoptosis

Histone deacetylase‐mediated silencing of PSTPIP2 expression contributes to aristolochic acid nephropathy‐induced PANoptosis

Histone deacetylase-mediated silencing of PSTPIP2 expression contributes to AAI-induced PANoptosis

Combined Effects of Lycopene and Metformin on Decreasing Oxidative Stress by Triggering Endogenous Antioxidant Defenses in Diet-Induced Obese Mice

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