A mixed blessing for liver transplantation patients — Rapamycin

Fan, Guanghan; Zhang, Chen-Zhi; Gao, Fengqiang; Wei, Xuyong; Ling, Sunbin; Wang, Kai; Wang, Jianguo; Zheng, Shusen; Nikfarjam, Mehrdad; Xu, Xiao

doi:10.1016/j.hbpd.2022.10.004

Cited by 8 publications

(6 citation statements)

References 109 publications

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“…A revision of several retrospective studies conducted between 1999 and 2022 identified the advantages of a sirolimus-based regimen over other immunosuppressive options in LT recipients [ 64 ]. A lower recurrence rate was found when sirolimus was the drug of choice, particularly in patients within the Milan criteria [ 64 ]. A positive impact on recurrence-free survival (RFS) has also been demonstrated in patients treated with sirolimus.…”

Section: Mtori and Hcc Recurrencementioning

confidence: 99%

“…Considering mTOR role in lipid metabolism regulation, inhibition of its pathway can result in the alteration of serum lipid levels. The effect is due to inhibiting lipid uptake and storage in adipocytes, hepatic lipogenesis stimulation, and lipid clearance impairment with consequent accumulation in the bloodstream [ 64 ]. While dyslipidemia has also been observed after administering mTOR-free immunosuppressive regimens, a stronger correlation was found in patients treated with sirolimus or everolimus [ 105 ].…”

Section: Tolerability and Aesmentioning

confidence: 99%

“…While dyslipidemia has also been observed after administering mTOR-free immunosuppressive regimens, a stronger correlation was found in patients treated with sirolimus or everolimus [ 105 ]. Rapamycin administration is associated with hypertriglyceridemia and hypercholesterolemia in 50% and 45% of the patients, and drug discontinuation improves these alterations [ 64 ]. The consensus from an Italian study group identified dyslipidemia as a dose-dependent adverse effect of everolimus-based regimens in patients undergoing LT, especially when drug levels are higher than 8 ng/mL [ 78 ].…”

Section: Tolerability and Aesmentioning

confidence: 99%

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The Role of mTOR Inhibitors after Liver Transplantation for Hepatocellular Carcinoma

Todeschini,

Cristin,

Martinino

et al. 2023

Current Oncology

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Liver transplantation is a treatment option for nonresectable patients with early-stage HCC, with more significant advantages when Milan criteria are fulfilled. An immunosuppressive regimen is required to reduce the risk of graft rejection after transplantation, and CNIs represent the drugs of choice in this setting. However, their inhibitory effect on T-cell activity accounts for a higher risk of tumour regrowth. mTOR inhibitors (mTORi) have been introduced as an alternative immunosuppressive approach to conventional CNI-based regimens to address both immunosuppression and cancer control. The PI3K-AKT-mTOR signalling pathway regulates protein translation, cell growth, and metabolism, and the pathway is frequently deregulated in human tumours. Several studies have suggested the role of mTORi in reducing HCC progression after LT, accounting for a lower recurrence rate. Furthermore, mTOR immunosuppression controls the renal damage associated with CNI exposure. Conversion to mTOR inhibitors is associated with stabilizing and recovering renal dysfunction, suggesting an essential renoprotective effect. Limitations in this therapeutic approach are related to their negative impact on lipid and glucose metabolism as well as on proteinuria development and wound healing. This review aims to summarize the roles of mTORi in managing patients with HCC undergoing LT. Strategies to overcome common adverse effects are also proposed.

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Section: Mtori and Hcc Recurrencementioning

confidence: 99%

Section: Tolerability and Aesmentioning

confidence: 99%

Section: Tolerability and Aesmentioning

confidence: 99%

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The Role of mTOR Inhibitors after Liver Transplantation for Hepatocellular Carcinoma

Todeschini,

Cristin,

Martinino

et al. 2023

Current Oncology

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“…On the one hand, rapamycin inhibits lipid storage in adipose tissue ( 82 – 86 ). On the other hand, it can cause lipid accumulation in the blood and liver, according to clinical data ( 87 – 90 ). In summary, the mTOR pathway may be a potential target to regulate immune cells by manipulating cellular lipid metabolism.…”

Section: Targets In Lipid Metabolismmentioning

confidence: 99%

Therapeutically targeting essential metabolites to improve immunometabolism manipulation after liver transplantation for hepatocellular carcinoma

Zhang

et al. 2023

Front. Immunol.

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Hepatocellular carcinoma (HCC) is the most prevalent primary liver malignancy worldwide and is associated with a poor prognosis. Sophisticated molecular mechanisms and biological characteristics need to be explored to gain a better understanding of HCC. The role of metabolites in cancer immunometabolism has been widely recognized as a hallmark of cancer in the tumor microenvironment (TME). Recent studies have focused on metabolites that are derived from carbohydrate, lipid, and protein metabolism, because alterations in these may contribute to HCC progression, ischemia-reperfusion (IR) injury during liver transplantation (LT), and post-LT rejection. Immune cells play a central role in the HCC microenvironment and the duration of IR or rejection. They shape immune responses through metabolite modifications and by engaging in complex crosstalk with tumor cells. A growing number of publications suggest that immune cell functions in the TME are closely linked to metabolic changes. In this review, we summarize recent findings on the primary metabolites in the TME and post-LT metabolism and relate these studies to HCC development, IR injury, and post-LT rejection. Our understanding of aberrant metabolism and metabolite targeting based on regulatory metabolic pathways may provide a novel strategy to enhance immunometabolism manipulation by reprogramming cell metabolism.

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“…Acute rejection (AR), a common cause of poor prognosis after liver transplantation, occurs in approximately 20%‒30% of patients within the first 12 months [2] . Although immunosuppressive protocols have improved the prognosis of patients after liver transplantation, some studies have shown that immunosuppressive drugs have some adverse effects, including metabolic disorders, severe infection, and tumor recurrence, which limits their application in liver transplantation [ 3 , 4 ]. Therefore, more studies are required to elucidate AR pathogenesis to establish novel therapeutic targets for AR.…”

Section: Introductionmentioning

confidence: 99%

Salidroside ameliorates acute liver transplantation rejection in rats by inhibiting neutrophil extracellular trap formation

Qin,

Wang,

et al. 2024

ABBS

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Acute rejection is an important factor affecting the survival of recipients after liver transplantation. Salidroside has various properties, including anti-inflammatory, antioxidant, and hepatoprotective properties. This study aims to investigate whether salidroside can prevent acute rejection after liver transplantation and to examine the underlying mechanisms involved. An in vivo acute rejection model is established in rats that are pretreated with tacrolimus (1 mg/kg/d) or salidroside (10 or 20 mg/kg/d) for seven days after liver transplantation. In addition, an in vitro experiment is performed using neutrophils incubated with salidroside (1, 10, 50 or 100 μM). Hematoxylin-eosin staining, terminal deoxynucleotidyl transferase dUTP nick-end labeling staining, immunosorbent assays, immunofluorescence analysis, Evans blue staining, and western blot analysis are performed to examine the impact of salidroside on NET formation and acute rejection in vitro and in vivo . We find that Salidroside treatment reduces pathological liver damage, serum aminotransferase level, and serum levels of IL-1β, IL-6, and TNF-α in vivo . The expressions of proteins associated with the HMGB1/TLR-4/MAPK signaling pathway (HMGB1, TLR-4, p-ERK1/2, p-JNK, p-P38, cleaved caspase-3, cleaved caspase-9, Bcl-2, Bax, IL-1β, TNF-α, and IL-6) are also decreased after salidroside treatment. In vitro experiments show that the release of HMGB1/TLR-4/MAPK signaling pathway-associated proteins from neutrophils treated with lipopolysaccharide is decreased by salidroside. Moreover, salidroside inhibits NETosis and protects against acute rejection by regulating the HMGB1/TLR-4/MAPK signaling pathway. Furthermore, salidroside combined with tacrolimus has a better effect than either of the other treatments alone. In summary, salidroside can prevent acute liver rejection after liver transplantation by reducing neutrophil extracellular trap development through the HMGB1/TLR-4/MAPK signaling pathway.

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A mixed blessing for liver transplantation patients — Rapamycin

Cited by 8 publications

References 109 publications

The Role of mTOR Inhibitors after Liver Transplantation for Hepatocellular Carcinoma

The Role of mTOR Inhibitors after Liver Transplantation for Hepatocellular Carcinoma

Therapeutically targeting essential metabolites to improve immunometabolism manipulation after liver transplantation for hepatocellular carcinoma

Salidroside ameliorates acute liver transplantation rejection in rats by inhibiting neutrophil extracellular trap formation

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