CN113855684B - Use of orlistat for the preparation of a medicament for reducing or ameliorating cisplatin-induced acute kidney injury - Google Patents
Use of orlistat for the preparation of a medicament for reducing or ameliorating cisplatin-induced acute kidney injury Download PDFInfo
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Abstract
The invention discloses an application of orlistat in preparation of a medicament for relieving or improving cisplatin-induced acute kidney injury, which can remarkably improve acute kidney injury kidney structure and function, DNA injury, tubular cell apoptosis, inflammatory reaction, cisplatin-induced mitochondrial injury, cisplatin-induced oxidative stress reduction, cisplatin-induced mitochondrial dysfunction and the like by using Olesoxime on a cisplatin mouse model and in vitro cells for intervention treatment.
Description
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to application of orlistat in preparation of a medicine for relieving cisplatin-induced acute kidney injury.
Background
In the 70 s of the 20 th century, cisplatin is beginning to be widely used clinically for treating various malignant tumors, including bladder cancer, cervical cancer, head and neck malignant tumors, small cell or non-small cell lung pain and the like, and is one of the most effective and commonly used chemotherapeutic drugs for treating solid tumors, but because cisplatin has a killing effect on tumor cells, cisplatin can cause a series of serious adverse reactions of normal tissues and organs, and the clinical application of cisplatin is greatly limited. Adverse reactions of cisplatin mainly include a series of systemic injury reactions such as renal toxicity, hepatotoxicity and blood system toxicity. Nephrotoxicity is common, and about 1/3 of patients have renal dysfunction after cisplatin treatment, which leads to acute renal failure. For a long time, the mechanism of cisplatin causing normal cell damage is not completely defined,numerous studies have found that DNA damage, oxidative stress, cell necrosis, apoptosis, autophagy and the like can be all the reasons for the damage of normal tissues and organs caused by cisplatin 1 。
Although the platinum chemotherapeutic drugs are gradually replaced by novel chemotherapeutic drugs in recent years, the traditional platinum drugs and derivatives thereof still play important clinical roles in the aspects of resisting solid tumors and the like, however, the toxic and side effects of the platinum drugs on kidney injury and the like greatly limit the clinical use of the drugs, and the effective drugs for treating the acute kidney injury induced by the cisplatin are still lacking in the clinical application at present, so that the development of new and effective related drugs capable of improving the acute kidney injury induced by the cisplatin has important clinical significance.
Oleoxin (Alilesexime) is a neuroprotective drug that acts on the mitochondrial outer membrane protein and reduces opening of the mitochondrial membrane permeability transition pore to relieve oxidative stress, and key clinical efficacy studies on Amyotrophic Lateral Sclerosis (ALS) are currently underway and are also being developed for the treatment of Spinal Muscular Atrophy (SMA) 2 The molecular formula is as follows:
in different in vivo and in vitro models, olesoximes have shown strong neuroprotective effects. It belongs to the cholesterol oxime family, takes the outer membrane protein of mitochondria as a target point, gathers in mitochondria and prevents the opening of osmotic transition pores mediated by oxidative stress 3 。
No association between Olesoxime and cisplatin-induced acute injury has been reported.
Reference:
1.McSweeney,K.R.et al.Mechanisms of Cisplatin-Induced Acute Kidney Injury:Pathological Mechanisms,Pharmacological Interventions,and Genetic Mitigations.Cancers(Basel).13,(2021).
2.Bordet,T.,Berna,P.,Abitbol,J.-L.&Pruss,R.M.Olesoxime(TRO19622):A Novel Mitochondrial-Targeted Neuroprotective Compound.Pharmaceuticals(Basel).3,345–368(2010).
3.Zakyrjanova,G.F.,Gilmutdinov,A.I.,Tsentsevitsky,A.N.&Petrov,A.M.Olesoxime,a cholesterol-like neuroprotectant restrains synaptic vesicle exocytosis in the mice motor nerve terminals:Possible role of VDACs.Biochim.Biophys.Acta-Mol.Cell Biol.Lipids 1865,158739(2020).
disclosure of Invention
The invention provides application of an open drug Olesoxime which acts on mitochondrial outer membrane proteins in a targeted manner and reduces mitochondrial membrane permeability transition pores in preparation of acute kidney injury drugs, application of the drug in preparation of drugs for relieving cisplatin-induced acute kidney injury related symptoms, and solves the technical problem that no appropriate drug for treating cisplatin-induced kidney structural and functional damage in the prior art is available.
The invention aims to provide application of Olesoxime in preparation of a medicament for relieving cisplatin-induced acute kidney injury related symptoms.
The invention uses the Olesoxime on a mouse model and an in vitro cell model for cisplatin-induced acute kidney injury, and discusses the application of the Olesoxime as a neuroprotective drug taking a mitochondrial membrane voltage-dependent anion channel as a target point to a drug for relieving cisplatin-induced acute kidney injury related symptoms. The results show that the intervention treatment by using the Olesoxime on a cisplatin mouse model and in vitro cells can obviously improve the kidney structure and function of acute kidney injury, DNA (deoxyribonucleic acid) injury, renal tubular cell apoptosis and inflammatory reaction, improve the mitochondrial injury induced by the cisplatin, relieve the oxidative stress reaction induced by the cisplatin, improve the mitochondrial dysfunction induced by the cisplatin and the like; our findings would most likely provide effective clinical drugs for the control of AKI.
Drawings
Figure 1 shows that Olesoxime improves kidney injury and kidney function in a cisplatin-induced acute kidney injury model;
figure 2 shows that in a cisplatin-induced acute kidney injury model, the oleosome treatment ameliorated cisplatin-induced apoptosis and inflammatory responses;
figure 3 shows that Olesoxime treatment ameliorated cisplatin-induced mitochondrial injury in a cisplatin-induced acute kidney injury model;
FIG. 4 shows that Olesoxime can alleviate cisplatin-induced oxidative stress in a cisplatin-induced acute kidney injury model;
figure 5 shows that in an in vitro cisplatin model of tubular epithelial cells, olesoxime treatment ameliorated cisplatin-induced mitochondrial dysfunction;
FIG. 6 shows that in an in vitro cisplatin model of tubular epithelial cells, olesoxime treatment ameliorated cisplatin-induced apoptosis;
figure 7 shows that Olesoxime has no significant effect on cis-platinum anti-tumor activity.
Detailed Description
The present invention will be described in further detail with reference to specific examples, which will help to understand the present invention, but the scope of the present invention is not limited to the examples described below.
Example 1 materials and methods
1) Materials and reagents
The oleosome compound was purchased from MCE, NGAL, DRP-1 antibody from Abcam, KIM-1 antibody from R & D Systems, and cleaned caspase3 from CST, beta-actin, BAX, VDAC, OPA-1, ATPB, SOD2, ND1, and MPO antibodies from proteintech. The Mitotracker, mPTP, mitosox and TMRM test kits were purchased from petunia corporation. TUNEL and MDA detection kits were purchased from norgestrel, and apoptosis detection kits were purchased from B & D, usa.
2) Cisplatin-induced acute kidney injury cell model
Mouse tubular epithelial cells (mPTCs) were cultured in DMEM/F12 medium containing 10% fetal bovine serum at 37 ℃ in 5% carbon dioxide and 95% air. When mPTC grows to 70% density, the mPTC is cultured by changing into DMEM/F12 culture medium containing 1% fetal bovine serum, and is added with Olesoxime (dissolved in DMSO) for pretreatment for 1h or treated by the same treatment of DMSO, 5g/ml cis-platinum is added for stimulation after 1h, after the cells are incubated in an incubator for 24h, finally the cells are collected for qRT-PCT, western Blot detection, flow cytometry analysis of apoptosis and other tests.
3) Mouse model for cisplatin-induced acute kidney injury and experimental grouping
The mice were randomly divided into four groups of 6 mice, each group being a placebo group (vehicle), an oxirane group, a cisplatin model group (cispin), and an oxirane-treated group (cispin + oxirane). Olesoxime was dissolved in PEG300+ TWEEN80+ DMSO and administered by gavage at a dose of 20 mg/kg. Mice in the control group or the Olesoxime-treated group were administered the vehicle or the Olesoxime, respectively, once daily by intraperitoneal injection starting 72h before cisplatin injection. Cisplatin model mice were injected with 20mg/kg of cisplatin at a time intraperitoneally, and mice were sacrificed and harvested 72h after cisplatin injection. Mice in the blank control group (vehicle) and the Olesoxime group received the same dose of saline injection. After 72h, all groups of mice were euthanized and kidney and blood samples were collected. All animal experiments followed the Chinese regulations for the management and use of experimental animals.
4) Renal function detection
The serum components are collected after the blood specimen of the mouse is centrifuged, and serum creatinine and serum urea nitrogen indexes are detected on a full-automatic biochemical instrument of a child hospital clinical laboratory in Nanjing.
5) Renal tubular injury score
The degree of tubular injury was observed in PAS pathological staining of the kidney and evaluated according to a semiquantitative injury score, with 0 for normal tubular tissue, 1 for tubular injury less than 30%, 2 for tubular injury between 30% and 60%, and 3 for tubular injury greater than 60%.
6) Histological and immunostaining with fluorescent dye
Kidney tissues were fixed with paraformaldehyde, paraffin-coated, sectioned and immunohistochemically stained. The concentration of the 4-HNE primary antibody is 1. DAPI staining was performed according to the label instructions.
7) Western blotting (Western blot)
Kidney tissue was extracted with protein according to literature procedures. Results of Western immunoblotting (Western blot) were subjected to grayscale analysis using ImageJ software.
8) Real-time quantitative PCR (qRT-PCR)
Kidney tissue was extracted RNA according to literature methods, reverse transcribed and quantitative real-time PCR (qRT-PCR).
9) Flow cytometric detection of apoptosis
The apoptosis level of the cells is analyzed by a flow cytometer after the mice are cultured in the tubular epithelial cells and are pretreated for 1h by the Olesoxime, and then cis-platinum is added for 24h for treatment.
10 Mitotracker, mPTP, mitosox, TMRM, TUNEL and MDA assays
The procedures were as described in the test kit.
9) Statistical analysis
Cell experiments were repeated three times and counted, and data were expressed using mean SD. Multiple comparisons were performed using one-way analysis of variance (ANOVA) and two data comparisons were performed using T-test. P <0.05 is statistically significant.
Example 2 olesoximes improve kidney injury and kidney function in a cisplatin-induced acute kidney injury model.
In order to evaluate and detect the effect of Olesoxime in cisplatin-induced acute kidney injury, related biochemical indexes of kidney in mouse serum are detected, urea nitrogen and serum creatinine indexes are obviously increased 72 hours after cisplatin is injected into an abdominal cavity, renal tubular lumens are expanded, renal tubular epithelial cells are swollen, the pathological injury of kidney such as vacuolated change or cell shedding, exposed basement membrane, disappearance of microvilli structure and the like is serious, and the corresponding renal function indexes are obviously reduced after the Olesoxime is treated (fig. 1A). In addition, the tubular injury score also suggested that the iolisoxime treatment significantly ameliorated cisplatin-induced pathological kidney injury (fig. 1B). These results indicate that Olesoxime can protect cisplatin-induced acute kidney injury, and that it has not seen significant nephrotoxicity by itself.
To further demonstrate the role of Olesoxime in protecting cisplatin-induced acute kidney injury, we examined specific biomarkers, NGAL and KIM-1, early in acute kidney injury. Western blot detection results show that KIM-1 and NGAL are highly expressed in the kidney of a mouse with acute kidney injury induced by cisplatin, and the expression level of the KIM-1 and NGAL is remarkably reduced after the Olesoxime is treated (figure 1C), which indicates that the Olesoxime can improve the acute kidney injury induced by the cisplatin.
Example 3 in a cisplatin-induced acute kidney injury model, olesoxime treatment ameliorated cisplatin-induced apoptosis and inflammatory responses.
In order to evaluate and detect the apoptosis condition of the cells of the Olesoxime in the cisplatin-induced acute kidney injury, the kidney tissue section is subjected to TUNEL staining, and positive cells are observed under a fluorescent microscope to determine the influence of the Olesoxime on the apoptosis (figure 2A), so that the result shows that the Olesoxime can obviously improve the cisplatin-induced apoptosis; further, western blot results showed that apoptosis-related proteins, cleared caspase3 and BAX, were significantly up-regulated in the cisplatin model group, and significantly down-regulated after the oleoxime treatment (fig. 2B).
We used qRT-PCR method to detect the levels of inflammation indicators-MCP-1, TNF-alpha, IL-6 and IL-1 (figure 2C) in kidney tissues, and the results show that Olesoxime can significantly improve the inflammatory reaction caused by cisplatin.
Example 4 in a cisplatin-induced acute kidney injury model, the oleoximae treatment ameliorated cisplatin-induced mitochondrial injury.
Mitochondrial ultrastructure in mouse tubular cells was observed under a transmission electron microscope, cisplatin was injected into the abdominal cavity to cause swelling, cristae disappearance, vacuolar change and the like of the renal mitochondria of WT mice, and mitochondrial structural change after the treatment with the oleoxime was reduced (fig. 3A), suggesting that the treatment with the oleoxime can protect the mitochondrial structure of cisplatin-induced acute kidney injury. The mitochondrial copy number and the expression of the mitochondrial related genes are detected by using a qRT-PCR method, and the result shows that cisplatin can cause that the mitochondrial copy number and the expression of the related genes (TFAM, SOD2, mt-ND1, mt-ND2, mt-COX1, mt-COX2, mt-CYTB, mt-ATP6 and mt-ATP 8) mRNA in the kidney of a mouse are respectively and obviously reduced compared with a control group (figures 3B and 3C), and the mitochondrial copy number and the expression of the related genes are obviously increased after the treatment of the Olesoxime.
The oleosome is a drug taking a mitochondrial membrane voltage-dependent anion channel as a target, and in order to further prove the effect of the oleosome on mitochondria in protecting cisplatin-induced acute kidney injury, we detected a mitochondrial membrane voltage-dependent anion channel (VDAC) and a mitochondrial fission-related protein (DRP 1) level mitochondrial fusion-related protein (OPA 1). The Western blot detection result shows that DRP1 is highly expressed in the kidney of the cisplatin-induced acute kidney injury mouse, OPA1 is low expressed in the kidney, and the expression level is remarkably recovered after the treatment of the oleoxime (figure 3D), which indicates that the oleoxime can improve the over-mitosis and the reduction of fusion of mitochondria caused by the cisplatin. The results all suggest that mitochondrial damage caused by cisplatin can be obviously improved after the Olesoxime treatment.
Example 5 in a cisplatin-induced acute kidney injury model, olesoxime can reduce cisplatin-induced oxidative stress.
Cisplatin can cause oxidative stress and produce excessive ROS, which can lead to lipid peroxidation and the production of reactive lipids, such as 4-HNE. Cytochrome C (Cytochrome C) also plays an important role in regulating the production of ROS. Immunohistochemistry results showed that renal 4-HNE and cytochrome C protein levels were significantly reduced following Olesoxime treatment (figure 4a &4b). We further tested the mitochondrial associated proteins ATPB and ND1, and the superoxide dismutase 2 (SOD 2) protein level that scavenges oxygen radicals. Western blot results showed that cisplatin treatment significantly down-regulated the protein levels of ATPB, ND1 and SOD2 in kidney tissue, while Olexisome treatment significantly improved this trend (fig. 4C).
In addition, western blot results showed that cisplatin induced peroxidase (MPO) expression in kidney tissues was significantly upregulated, while oxisome treatment significantly inhibited upregulation of MPO protein levels (fig. 4D); malondialdehyde (MDA) is a natural product of lipid oxidation in organisms, and a lipid peroxymalondialdehyde assay kit is used to detect malondialdehyde, and the results show that Olexisome can significantly alleviate malondialdehyde production caused by cisplatin (fig. 4E). The results show that the oximesome can obviously improve the occurrence of cisplatin-induced renal tissue oxidative stress.
Example 6 in an in vitro cisplatin model of tubular epithelial cells, olesoxime treatment ameliorated cisplatin-induced mitochondrial dysfunction.
The mitochondria morphology is detected by using MitoTracker, and simultaneously the mitochondria respiratory function is observed by using mTP, mitoSox and TMRM staining and Oxygen Consumption Rate (OCR) method. Our data show that cisplatin stimulation promotes mPTP opening, leading to increased superoxide production in mitochondria and severe mitochondrial membrane potential depolarization, while the oleoxime treatment significantly ameliorated cisplatin-induced mitochondrial dysfunction (shown in figures 5A-F).
Example 7 in an in vitro cisplatin model of tubular epithelial cells, olesoxime treatment improved cisplatin-induced apoptosis.
Further, in a cisplatin model of tubular epithelial cells cultured in vitro, the harvested cells were tested for apoptosis level by flow cytometry, and the results showed that the oleoxime could significantly improve cisplatin-induced apoptosis (fig. 6A); western blot results showed that apoptosis-related protein clear caspase3 was significantly down-regulated after oleoximae treatment (fig. 6B); furthermore, we examined the LDH content in the cell supernatant, and the results showed that the LDH content was significantly increased in the cisplatin-induced kidney injury cell model, while the LDH content was decreased after the oleosome treatment (fig. 6C). Taken together, olesoxime treatment improved cisplatin-induced apoptosis in an in vitro cisplatin model of tubular epithelial cells.
Example 8 no significant effect of Olesoxime on cis-platinum anti-tumor activity.
Finally, we evaluated whether olesoximes affected the antitumor activity of cisplatin. Flow cytometry analysis showed that Olesoxime had no effect on cisplatin-induced apoptosis in MCF7 cells (human breast cancer cell line) and a459 cells (human non-small cell lung cancer cell), suggesting that Olesoxime did not reduce cisplatin anti-tumor activity (figure 7).
In conclusion, the invention provides application of a neuroprotective drug Olesoxime taking a mitochondrial membrane voltage-dependent anion channel as a target spot in preparing a drug for relieving cisplatin-induced acute kidney injury related symptoms, wherein the drug is administrated in a gastric perfusion mode, the dosage is 20mg/kg, the drug acts on mitochondrial outer membrane proteins and reduces opening of mitochondrial membrane permeability transition pores, and by improving mitochondrial injury and dysfunction, oxidative stress and apoptosis are further reduced, and acute kidney injury is improved.
The above-mentioned embodiments are intended to illustrate the objects, technical solutions and advantages of the present invention in further detail, and it should be understood that the above-mentioned embodiments are only exemplary embodiments of the present invention, and are not intended to limit the present invention, and any modifications, equivalents, improvements and the like made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (5)
1. Use of orlistat for the preparation of a medicament for reducing or ameliorating cisplatin-induced acute kidney injury.
2. Use according to claim 1, characterized in that orlistat improves cisplatin-induced apoptosis and inflammatory responses.
3. Use according to claim 1, characterized in that orlistat ameliorates cisplatin-induced mitochondrial damage.
4. Use according to claim 1, characterized in that orlistat reduces cisplatin-induced oxidative stress.
5. Use according to claim 1, characterized in that orlistat ameliorates cisplatin-induced mitochondrial dysfunction.
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| CN112996494A (en) * | 2018-06-26 | 2021-06-18 | 利博诺瓦公司 | Methods of treating mitochondrial dysfunction |
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