Combined tacrolimus and melatonin effectively protected kidney against acute ischemia‐reperfusion injury

Yang, Chih‐Chao; Sung, Pei‐Hsun; Chiang, John Y.; Chai, Han‐Tan; Chen, Chih‐Hung; Chu, Yi‐Ching; Li, Yi‐Chen; Yip, Hon‐Kan

doi:10.1096/fj.202100174r

Cited by 11 publications

(9 citation statements)

References 38 publications

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“…On the other hand, when looking at the situation of PrP C gene overexpression in H9C2 cells, we identified that not only the PI3K/Akt/m-TOR signaling but also the RAS/c-RAF/p-MEK1/2//p-ERK1/2 signaling were substantially upregulated, whereas the Stelazine (a PrP C inhibitor) treatment significantly downregulated and siRNA-PrP C further significantly downregulated the protein expressions of these two signaling pathways. Interestingly, recent studies demonstrated that PI3K/Akt/m-TOR [ 34 , 35 ] and MAPK family signaling cascades [ 36 ] were markedly upregulated in response to ischemic stimulation. In this way, our findings, in addition to corroborating with the findings of these studies [ 34 , 35 , 36 ], implied that these two cell-stress/cell-proliferation signalings were dependently regulated by PrP C expression, at least in the condition of cell culturing.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, recent studies demonstrated that PI3K/Akt/m-TOR [ 34 , 35 ] and MAPK family signaling cascades [ 36 ] were markedly upregulated in response to ischemic stimulation. In this way, our findings, in addition to corroborating with the findings of these studies [ 34 , 35 , 36 ], implied that these two cell-stress/cell-proliferation signalings were dependently regulated by PrP C expression, at least in the condition of cell culturing.…”

Section: Discussionmentioning

confidence: 99%

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Cellular Prion Protein Is Essential for Myocardial Regeneration but Not the Recovery of Left Ventricular Function from Apical Ballooning

et al. 2022

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This study tested the hypothesis that cellular prion protein (PrPC) played an essential role in myocardial regeneration and recovery of left ventricular ejection fraction (LVEF) from apical takotsubo cardiomyopathy (TCM) induced by transaortic constriction (TAC). In vitro study was categorized into G1 (H9C2), G2 (H9C2-overexpression-PrPC), G3 (H9C2-overexpression-PrPC + Stelazine/1 uM), and G4 (H9C2 + siRNA-PrPC), respectively. The results showed that the protein expressions of PrPC, cell-stress signaling (p-PI3K/p-Akt/p-m-TOR) and signal transduction pathway for cell proliferation/division (RAS/c-RAF/p-MEK/p-ERK1/2) were lowest in G1, highest in G2, significantly higher in G3 than in G4 (all p < 0.001). Adult-male B6 mice (n = 30) were equally categorized in group 1 (sham-control), group 2 (TAC) for 14 days, then relieved the knot and administered BrdU (50 ug/kg/intravenously/q.6.h for two times from day-14 after TAC) and group 3 (TAC + Stelazine/20 mg/kg/day since day 7 after TAC up to day 21 + BrdU administered as group 2), and animals were euthanized at day 28. The results showed that by day 28, the LVEF was significantly higher in group 1 than in groups 2/3 and significantly higher in group 3 than in group 2, whereas the LV chamber size exhibited an opposite pattern of LVEF (all p < 0.0001). The protein expressions of PrPC/p-PI3K/p-Akt/p-m-TOR/cyclin D/cyclin E and cellular-proliferation biomarkers (Ki67/PCNA/BrdU) exhibited an opposite pattern of LVEF (all p < 0.0001) among the three groups, whereas the protein expressions of RAS/c-RAF/p-MEK/p-ERK1/2 were significantly and progressively increased from groups 1 to 3 (all p < 0.0001). In conclusion, PrPC participated in regulating the intrinsic response of cell-stress signaling and myocardial regeneration but did not offer significant benefit on recovery of the heart function in the setting of TCM.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cellular Prion Protein Is Essential for Myocardial Regeneration but Not the Recovery of Left Ventricular Function from Apical Ballooning

et al. 2022

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“…The animals treated with tacrolimus with melatonin presented reduced laboratory parameters, such as malondialdehyde (MDA) (a marker of lipid peroxidation), tumour necrosis factor-alpha (TNF-α) and Interleukine-6 (IL-6), with a simultaneously higher Nitric Oxide (NO) level than the animals treated with tacrolimus without melatonin. Moreover, some findings suggest that the concomitant tacrolimus–melatonin therapy may potentially prevent acute kidney injury (AKI) resulting from ischemia-reperfusion injury more effectively than each drug separately [ 101 ]. Thus, the abovementioned data may suggest that the therapy involving tacrolimus in combination with melatonin may present less severe side effects [ 102 , 103 ].…”

Section: Resultsmentioning

confidence: 99%

Controversial Interactions of Tacrolimus with Dietary Supplements, Herbs and Food

Miedziaszczyk

Bajon²,

Jakielska³

et al. 2022

Pharmaceutics

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Tacrolimus is an immunosuppressive calcineurin inhibitor used to prevent rejection in allogeneic organ transplant recipients, such as kidney, liver, heart or lung. It is metabolized in the liver, involving the cytochrome P450 (CYP3A4) isoform CYP3A4, and is characterized by a narrow therapeutic window, dose-dependent toxicity and high inter-individual and intra-individual variability. In view of the abovementioned facts, the aim of the study is to present selected interactions between tacrolimus and the commonly used dietary supplements, herbs and food. The review was based on the available scientific literature found in the PubMed, Scopus and Cochrane databases. An increase in the serum concentration of tacrolimus can be caused by CYP3A4 inhibitors, such as grapefruit, pomelo, clementine, pomegranate, ginger and turmeric, revealing the side effects of this drug, particularly nephrotoxicity. In contrast, CYP3A4 inducers, such as St. John’s Wort, may result in a lack of therapeutic effect by reducing the drug concentration. Additionally, the use of Panax ginseng, green tea, Schisandra sphenanthera and melatonin in patients receiving tacrolimus is highly controversial. Therefore, since alternative medicine constitutes an attractive treatment option for patients, modern healthcare should emphasize the potential interactions between herbal medicines and synthetic drugs. In fact, each drug or herbal supplement should be reported by the patient to the physician (concordance) if it is taken in the course of immunosuppressive therapy, since it may affect the pharmacokinetic and pharmacodynamic parameters of other preparations.

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“…Chronic TAC kidney injury is associated with multiple factors, but oxidative stress is regarded as a common mechanism of TAC kidney injury, and apoptotic cell death is closely related to TAC-induced oxidative stress [23,24]. Oxidative stress in cells is often accompanied by abnormal accumulation of ROS [25].…”

Section: Discussionmentioning

confidence: 99%

CTLA4-Ig protects tacrolimus-induced oxidative stress via inhibiting the AKT/FOXO3 signaling pathway in rats

Jin¹,

Shen²,

Xu³

et al. 2023

Korean J Intern Med

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Background/Aims: Although the conversion from tacrolimus (TAC) to cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin (CTLA4-Ig) is effective in reducing TAC-induced nephrotoxicity, it remains unclear whether CTLA4-Ig has a direct effect on TAC-induced renal injury. In this study, we evaluated the effects of CTLA4-Ig on TAC-induced renal injury in terms of oxidative stress.Methods: In vitro study was performed to assess the effect of CTLA4-Ig on TAC-induced cell death, reactive oxygen species (ROS), apoptosis, and the protein kinase B (AKT)/forkhead transcription factor (FOXO) 3 pathway in human kidney 2 cells. In the in vivo study, the effect of CTLA4-Ig on TAC-induced renal injury was evaluated using renal function, histopathology, markers of oxidative stress (8-hydroxy-2’-deoxyguanosine) and metabolites (4-hydroxy-2-hexenal, catalase, glutathione S-transferase, and glutathione reductase), and activation of the AKT/FOXO3 pathway with insulin-like growth factor 1 (IGF-1).Results: CTLA4-Ig significantly decreased cell death, ROS, and apoptosis caused by TAC. TAC treatment increased apoptotic cell death and apoptosis-related proteins (increased Bcl-2-associated X protein and caspase-3 and decreased Bcl-2), but it was reversed by CTLA4-Ig treatment. The activation of p-AKT and p-FOXO3 by TAC decreased with CTLA4-Ig treatment. TAC-induced renal dysfunction and oxidative marker levels were significantly improved by CTLA4-Ig in vivo. Concomitant IGF-1 treatment abolished the effects of CTLA4-Ig.Conclusions: CTLA4-Ig has a direct protective effect on TAC-induced renal injury via the inhibition of AKT/FOXO3 pathway.

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Combined tacrolimus and melatonin effectively protected kidney against acute ischemia‐reperfusion injury

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 11 publications

References 38 publications

Cellular Prion Protein Is Essential for Myocardial Regeneration but Not the Recovery of Left Ventricular Function from Apical Ballooning

Cellular Prion Protein Is Essential for Myocardial Regeneration but Not the Recovery of Left Ventricular Function from Apical Ballooning

Controversial Interactions of Tacrolimus with Dietary Supplements, Herbs and Food

CTLA4-Ig protects tacrolimus-induced oxidative stress via inhibiting the AKT/FOXO3 signaling pathway in rats

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