Recombinant soluble thrombomodulin attenuates cisplatin-induced intestinal injury by inhibiting intestinal epithelial cell-derived cytokine secretion

Yamaguchi, Takanori; Gaowa, Arong; Park, Eun Jeong; Tawara, Isao; Shimaoka, Motomu

doi:10.1007/s11033-023-08762-1

Cited by 4 publications

(2 citation statements)

References 26 publications

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“…Cisplatin known as one of the renal toxins is the first-line chemotherapy prescribed to 10–20% of patients with cancer 4 . Several lines of accumulating evidence implied that cisplatin exerts nephrotoxicity 4 , ototoxicity 5 , neurotoxicity 5 , hepatotoxicity 6 , and gastrointestinal toxicity 7 as harmful side effects. Actually, AKI occurred in 30% of patients treated with a single dose of cisplatin, eventually resulting in the discontinuation of administration 4 .…”

Section: Introductionmentioning

confidence: 99%

“…TM also has well-defined anti-inflammatory functions 18 . Actually, TM administration attenuated cisplatin-induced intestinal toxicity though the suppression of cytokine production in intestinal epithelial cells of mice 7 , and Cheng and colleagues demonstrated that TM could regulate keratinocyte differentiation, eventually promoting wound healing 19 . Clinically, several lines of accumulating evidence implied that TM treatment showed therapeutic effects for acute pancreatitis 20 and fulminant hepatitis 21 .…”

Section: Introductionmentioning

confidence: 99%

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Protective roles of thrombomodulin in cisplatin-induced nephrotoxicity through the inhibition of oxidative and endoplasmic reticulum stress

Yamamoto,

Ishida,

Zhang

et al. 2024

Sci Rep

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Cisplatin is an effective chemotherapeutic agent widely used for the treatment of various solid tumors. However, cisplatin has an important limitation in its use; currently, there is no method to ameliorate cisplatin-induced acute kidney injury (AKI). Thrombomodulin (TM) is well known not only for its role as a cofactor in the clinically important natural anticoagulation pathway but also for its anti-inflammatory properties. Here, we investigated the effects of TM in cisplatin-induced AKI. In mice intraperitoneally injected with 15 mg/kg cisplatin, TM (10 mg/kg) or PBS was administered intravenously at 24 h after cisplatin injection. TM significantly attenuated cisplatin-induced nephrotoxicity with the suppressed elevation of blood urea nitrogen and serum creatinine, and reduced histological damages. Actually, TM treatment significantly alleviated oxidative stress-induced apoptosis by reducing reactive oxygen species (ROS) levels in cisplatin-treated renal proximal tubular epithelial cells (RPTECs) in vitro. Furthermore, TM clarified cisplatin-induced apoptosis by reducing caspase-3 levels. In addition, TM attenuated the endoplasmic reticulum (ER) stress signaling pathway in both renal tissues and RPTECs to protect the kidneys from cisplatin-induced AKI. These findings suggest that TM is a potential protectant against cisplatin-induced nephrotoxicity through suppressing ROS generation and ER stress in response to cisplatin.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Protective roles of thrombomodulin in cisplatin-induced nephrotoxicity through the inhibition of oxidative and endoplasmic reticulum stress

Yamamoto,

Ishida,

Zhang

et al. 2024

Sci Rep

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Irisin promotes intestinal epithelial cell proliferation via Wnt/β-catenin and focal adhesion kinase signaling pathways

Gaowa,

Leangpanich,

Park

et al. 2024

Sci Rep

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The regeneration of epithelia is crucial for maintaining intestinal homeostasis. Irisin is an exercise-induced hormone originally found to be secreted by skeletal muscles, thereby regulating energy metabolism. Recent studies have revealed that irisin protected against gut inflammation. However, the direct effects of irisin on the intestinal epithelial cells remain to be elucidated. In this study, mouse intestinal organoids were used to assess the effects of irisin on the proliferation of the intestinal epithelial cells. At a concentration of 100 ng/mL irisin significantly increased the growth of the intestinal organoids and upregulated the Wnt/β-catenin and focal adhesion kinase (FAK) signaling pathway genes. Notably, a FAK inhibitor 14 blocked the effects of irisin on the proliferation of the intestinal epithelial cells by inhibiting FAK phosphorylation, as well as the expressions of Wnt target genes. Furthermore, irisin (100 ng/mL) improved the recovery of the intestinal organoids from cellular damages caused by TNF-α, and markedly increased the expression of Wnt target genes in the intestinal epithelial cells. Taken together, irisin activates Wnt/β-catenin and FAK signaling pathways in the intestinal epithelial cells, thereby promoting intestinal epithelial self-renewal under normal homeostatic conditions and intestinal epithelial regeneration upon damages.

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Ginsenoside Rh4 Ameliorates Cisplatin-Induced Intestinal Toxicity via PGC-1α-Mediated Mitochondrial Autophagy and Apoptosis Pathways

Liu,

Sun,

Wang

et al. 2024

Am. J. Chin. Med.

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Cisplatin-evoked profound gastrointestinal symptomatology is one of the most common side effects of chemotherapy drugs, causing further gastrointestinal cell and intestinal mucosal injury. Ginsenoside Rh4 (G-Rh4), an active component extracted from red ginseng, possesses beneficial anti-oxidative and anti-apoptosis effects. This study aimed to assess the effectiveness of pharmacological intervention with G-Rh4 mitigating intestinal toxicity evoked by cisplatin in a murine model and in IEC-6 cells in vitro. Following oral administration for 10 days, G-Rh4 (10[Formula: see text]mg/kg and 20[Formula: see text]mg/kg) significantly increased the indicators of diamine oxidase (DAO) affected by cisplatin (20[Formula: see text]mg/kg) in mice, and histopathological analysis further indicated that G-Rh4 could effectively improve intestinal tissue morphology, as well as the expression of peroxisome proliferator-activated receptor-gamma coactivator 1 [Formula: see text] (PGC-1[Formula: see text] pathway and autophagy-related proteins. Moreover, in vitro experiments demonstrated that G-Rh4 exerted a concentration-dependent increase in cell viability, while also inhibiting cytotoxicity and abnormal rise of reactive oxygen species (ROS). Notably, ROS also activate PGC-1[Formula: see text] protein and mediate the occurrence of mitochondrial autophagy and apoptosis pathways. The molecular docking approach was employed to dock G-Rh4 with PGC-1[Formula: see text] and AMPK, revealing a binding energy of [Formula: see text]7.3[Formula: see text]kcal/mol and [Formula: see text]8.1[Formula: see text]kcal/mol and indicating a tight interaction between the components and the target. G-Rh4 could reduce the expression of autophagy-related protein p62/p53, reduce the accumulation of autophagy products, and promote the flow of autophagy. In conclusion, G-Rh4 exerted protective effects against cisplatin-induced intestinal toxicity, at least partially through PGC-1[Formula: see text]-mediated autophagy and apoptosis.

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Recombinant soluble thrombomodulin attenuates cisplatin-induced intestinal injury by inhibiting intestinal epithelial cell-derived cytokine secretion

Cited by 4 publications

References 26 publications

Protective roles of thrombomodulin in cisplatin-induced nephrotoxicity through the inhibition of oxidative and endoplasmic reticulum stress

Protective roles of thrombomodulin in cisplatin-induced nephrotoxicity through the inhibition of oxidative and endoplasmic reticulum stress

Irisin promotes intestinal epithelial cell proliferation via Wnt/β-catenin and focal adhesion kinase signaling pathways

Ginsenoside Rh4 Ameliorates Cisplatin-Induced Intestinal Toxicity via PGC-1α-Mediated Mitochondrial Autophagy and Apoptosis Pathways

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