Metronomic capecitabine with rapamycin exerts an immunosuppressive effect by inducing ferroptosis of CD4+ T cells after liver transplantation in rat

Wang, Hao; Yang, Ruining; Wang, Zhenglu; Cao, Lei; Kong, Dejun; Sun, Qian; Yoshida, Sei; Ren, Jiashu; Chen, Tao; Duan, Jinliang; Lu, Jianing; Shen, Zhongyang; Zheng, Hong

doi:10.1016/j.intimp.2023.110810

Cited by 4 publications

(1 citation statement)

References 43 publications

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“…Ferrostain-1 is an effective and selective ferroptosis inhibitor. It prevents membrane lipid damage through a reduction mechanism and eliminates lipid ROS produced by the body by inhibiting the enzyme-mediated process catalyzed by iron-dependent lipoxygenase, thereby inhibiting cell death [23][24][25][26][27][28] . SAS is an important drug for the treatment of ulcerative colitis and is also one of the most commonly used anti-inflammatory drugs in clinical practice.…”

Section: Discussionmentioning

confidence: 99%

Effect of sulfasalazine on ferroptosis during intestinal injury in rats after liver transplantation

Wu,

Bu,

Tan

et al. 2024

Sci Rep

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Using a rat autologous orthotopic liver transplantation (AOLT) model and liver cold ischemia–reperfusion (I/R)-induced intestinal injury, we clarified whether ferroptosis occurred in rat AOLT cold I/R-induced intestinal injury. Additionally, the role and possible mechanism of the ferroptosis activator sulfasalazine (SAS) in intestinal injury-induced ferroptosis in rats with AOLT liver cold I/R were investigated. Sixty specific pathogen free (SPF)-grade adult male Sprague‒Dawley (SD) rats were randomly divided into 5 groups using the random number table method (n = 12). Six rats were randomly selected at 6 hour (h) and 24 h after I/R. Inferior vena cava blood specimens were collected from the portal vein (PV) opening at 6 h and 24 h. The concentrations of serum malondialdehyde (MDA), serum interleukin 6 (IL-6) were determined by enzyme-linked immunosorbent assay (ELISA). Ileal tissue was obtained from the PV opening in rats in each group at 6 h and 24 h, and ileal tissue sections were observed under light microscopy. The contents of intestinal MDA, superoxide dismutase (SOD), glutathione(GSH), glutathione peroxidase 4 (GPX4), and tissue iron were determined by ELISA, and the expression of GPX4 and the cysteine glutamate reverse transporter light chain protein (xCT) was determined by Western blot. The experimental results show that ferroptosis is involved in the pathophysiological process of intestinal injury induced by cold hepatic ischemia–reperfusion in AOLT rats. In addition, SAS (500 mg/kg) may inhibit the cystine/glutamate antiporters (System Xc¯)/GSH/GPX4 signal axis in intestinal injury induced by cold I/R in rat AOLT liver, or iron overload after reperfusion, causing a massive accumulation of L-ROS and activating cellular ferroptosis, further aggravate the intestinal injury.

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Section: Discussionmentioning

confidence: 99%

Effect of sulfasalazine on ferroptosis during intestinal injury in rats after liver transplantation

Wu,

Bu,

Tan

et al. 2024

Sci Rep

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NOD2 reduces the chemoresistance of melanoma by inhibiting the TYMS/PLK1 signaling axis

Yun,

Wu,

et al. 2024

Cell Death Dis

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Nucleotide-binding oligomerization domain 2 (NOD2) is an immune sensor crucial for eliciting the innate immune responses. Nevertheless, discrepancies exist regarding the effect of NOD2 on different types of cancer. This study aimed to investigate these function of NOD2 in melanoma and its underlying mechanisms. We have validated the tumor suppressor effect of NOD2 in melanoma. NOD2 inhibited the proliferation of melanoma cells, hindering their migration and invasion while promoting the onset of apoptosis. Our study showed that NOD2 expression is closely related to pyrimidine and folate metabolism. NOD2 inhibits thymidylate synthase (TYMS) expression by promoting K48-type ubiquitination modification of TYMS, thereby decreasing the resistance of melanoma cells to 5-fluorouracil (5-FU) and capecitabine (CAP). TYMS was identified to form a complex with Polo-like Kinase 1 (PLK1) and activate the PLK1 signaling pathway. Furthermore, we revealed that the combination of the PLK1 inhibitor volasertib (BI6727) with 5-FU or CAP had a synergistic effect repressing the proliferation, migration, and autophagy of melanoma cells. Overall, our research highlights the protective role of NOD2 in melanoma and suggests that targeting NOD2 and the TYMS/PLK1 signaling axis is a high-profile therapy that could be a prospect for melanoma treatment.

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Rapamycin alleviates irradiation‐induced parotid injury by enhancing the whole gland homeostasis

Zhu,

Song,

Zhang

et al. 2024

Oral Diseases

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ObjectivesSalivary gland injury is one of the most common complications of radiotherapy in head‐and‐neck cancers. This study investigated the mechanism by which rapamycin prevents irradiation (IR)‐induced injury in the parotid glands.Materials and MethodsMiniature pigs either received (a) no treatment (NT), (b) IR in the right parotid gland for 5 consecutive days (IR), or intraperitoneal administration of rapamycin (Rap) 1 h prior to IR (IR + Rap). Tissues were collected at three distinct time points (24 h, 4 weeks, and 16 weeks) after IR. Histological analyses, western blot, and real‐time reverse transcriptase‐polymerase chain reaction were performed to explore the mechanisms of IR‐induced injury in the parotid gland.ResultsRapamycin treatment maintained parotid salivary flow 16 weeks post‐IR, preserved the number of acinar cells, and reduced parotid tissue fibrosis, as well as reduced apoptosis levels, decreased cleaved caspase‐3 expression, and increased the Bcl‐2/Bax ratio in the parotid glands. Autophagy marker LC3B was upregulated by rapamycin after IR, while P62 expression was downregulated. Rapamycin reduced the expression of pro‐inflammatory factors and the mesenchymal tissue fibrosis following IR.ConclusionsRapamycin maintains gland homeostasis after IR by decreasing apoptosis, reducing the expression of pro‐inflammatory factors, and enhancing autophagy.

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Metronomic capecitabine with rapamycin exerts an immunosuppressive effect by inducing ferroptosis of CD4+ T cells after liver transplantation in rat

Cited by 4 publications

References 43 publications

Effect of sulfasalazine on ferroptosis during intestinal injury in rats after liver transplantation

Effect of sulfasalazine on ferroptosis during intestinal injury in rats after liver transplantation

NOD2 reduces the chemoresistance of melanoma by inhibiting the TYMS/PLK1 signaling axis

Rapamycin alleviates irradiation‐induced parotid injury by enhancing the whole gland homeostasis

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