CN110151700A - Nano-MitoPBN is preparing the application in anti-oxidant and treatment diabetes medicament - Google Patents
Nano-MitoPBN is preparing the application in anti-oxidant and treatment diabetes medicament Download PDFInfo
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Abstract
The invention belongs to biology and medicine technology field, specially Nano-MitoPBN is preparing the application in anti-oxidant and treatment diabetes medicament.In the present invention, Nano-MitoPBN can remove the mitochondria superoxides/hydrogen peroxide generated by the single electron leakage of liver mitochondrion electron transport chain due to its micro- compartmentation effect, increase the respiratory rate of mitochondria state 3, respiration control rate increases the synthesis of ATP, promotes mitochondrial function；In addition, Nano-MitoPBN reduces gluconeogenesis by reducing ROS, while increasing glycolysis, the liver glycometabolism that ROS is mediated in reverting diabetes animal is rearranged, to reduce the periphery blood glucose level of diabetic animal and restore the glucose tolerance of diabetic animal.Material of the Nano-MitoPBN as preparation treatment diabetes medicament, can target liver prevention, improve and treat diabetes, it is only necessary to which very little dosage can be obtained significant curative effect.
Description
Technical field
The invention belongs to biology and medicine technology fields, and in particular to the mitochondria spin traps Nano- of liver target
MitoPBN is preparing the application in anti-oxidant and change diabetic supersession abnormal drug.
Background technique
Diabetes (DM) are a kind of metabolic disturbance diseases, are attributable to hypoinsulinism, insulin action weaken or
Insulin resistance, and have become an emerging global health problem.Currently, only a small number of effective therapeutic strategies can be fought
This multifactorial disease, however, every kind of therapy has its limitation and disadvantage.For example, although most widely used drug diformazan
Liver glucose level can be effectively reduced in biguanides, but its mechanism is very complicated, currently without any specific molecular target, and this
Drug has side effect to gastrointestinal tract.Other drugs also have side effect, lead to hyperinsulinemia or hypoglycemia.Therefore, urgently
Need to develop diabetes new treatment.
Blood glucose divides from exogenous enteron aisle from the absorption in food, the generation (gluconeogenesis) of endogenous glucose and glycogen
It solves (decomposition of glycogen).Imbalance in liver between glucose release and the glucose uptake of peripheral tissues can lead to lasting height
Blood glucose, this is the pathogenetic principal element of glycosuria.Therefore, in order to maintain normal blood glucose level, the potential treatment of diabetes B
Glucose is absorbed in generation or stimulation peripheral tissues including inhibiting glucose in liver.As it can be discharged into blood circulation in
The main producers of source property glucose, liver is an especially important organ for controlling blood glucose level, but how to target liver
It is dirty so that blood glucose level normalization need further to study.
In the past few decades, the potentiality in terms of being improved delivery efficiency and therapeutic effect due to nano particle (NPs),
So attracting attention in drug delivery field.However, using the clinical application of NP still in very early stage, mainly by
In there are monocyte phagocytosis system (MPS).In vivo, MPS prevents NP to reach expected target.Therefore, it is ground in bio distribution
It has been shown that liver and spleen are the major organs of chelating retention nano material in studying carefully.Further, since blood flow is lower, liver
In Kupffer cell than Macrophage in Spleen absorb nano material become apparent from, this show liver be retain nano material master
Want position.Therefore, nanoparticle technology can be used as a kind of strategy for targeting liver.
Known DM and its related complication and oxidative stress are closely related.There are many sources in vivo for ROS oxidative stress.It rises
The mitochondrial respiratory chain that high blood glucose level will pass through respectively in a variety of organ cells, hexosamine biosynthesis pathway, polyalcohol
Approach and nadph oxidase dependence advanced glycosylation end product approach generate ROS.Wherein, the electronics in mitochondrial respiratory chain
Leakage is the main source that superoxides/ROS is generated, and accounts for 95% or more of endogenous cellular ROS.It is reported that the line that ROS is mediated
Mitochondria function obstacle leads to insulin resistance, so as to cause diabetes.Meanwhile mitochondria is still ROS and peroxide injury
The damage of main target, the especially film to mitochondria rich in polyunsaturated fatty acid is bigger.ROS can also destroy mitochondria
DNA.These are statistics indicate that antioxidant targets the important function of hepatic mitochondria to treating diabetes.Recently, one about novel
3 phases of antidiabetic medicine imeglimin test display, are reduced by reducing mitochondria ROS and improving liver mitochondrial function
Glucose level.In this patent, we are absorbed in the strategy for developing treatment diabetes, it can pass through selectively targeted liver line
The ROS that mitochondrial respiratory chain generates plays antioxidation.By reprograming internal abnormal glucose metabolism access, Wo Menshi
Figure explores the new method for improving treating diabetes effect.
We use the targeting scavenger-MitoPBN of mitochondria free radical, come from α-phenyl-N- tert-butylnitrone
(PBN).MitoPBN is made of PBN and cation lipid triphenylphosphine, and MitoPBN is allowed to be selectively positioned in mitochondria
On film.In isolated mitochondria, which is proved to be able to selectively capture the free radical of carbon center also to generate stabilization
Spin adduct (adduct), to prevent the peroxidating of mitochondrial membrane lipid and reduce Oxidative Damage In Vitro.However,
The internal effect still unknown (Murphy etc., 2003) of MitoPBN.
In order to realize that MitoPBN micro- compartmentation targeting hepatic mitochondria, the present invention can utilize previous patent system in vivo
The standby preparation method of Liposome nanaparticle Nano-MitoPBN(liposome MitoPBN, the patent No.:
201610208549.9).We, which encapsulate MitoPBN using lipophilicity bilayer liposomes, has higher biomembrane affinity to be formed
Nano particle, overcome its low aqueous solubility and enhance liver target transhipment and internal liver specificity intake.Meanwhile we also adopt
With intraperitoneal injection, this is a kind of effective and is easy to the administration route that drug reaches animal's liver, imitates the effect of oral administration.Mouthful
Clothes administration can reach liver by intestines vein and portal vein.Therefore, MitoPBN can be efficiently absorbed in circulation and discharge
Into the cytoplasm of liver cell.
In the present invention, report: Nano-MitoPBN has been predominantly targeting liver mitochondrion, leads to liver cell and organizes interior oxygen
Change stress be reduced, and increased the oxidation breathing of state 3 (3 oxidative respiration of state) and ATP synthesis, protected mitochondria
With inhibition gluconeogenesis.Therefore, Nano-MitoPBN is a kind of promising material for preparing liver target drug, can be by anti-
The mitochondria dysfunction and liver metabolism that only ROS is mediated in liver treat diabetes extremely.
Summary of the invention
The purpose of the present invention is to provide Nano-MitoPBN to prepare anti-oxidant and change diabetic supersession abnormal drug
In application.
The present invention is through a large number of experiments and studies have shown that Nano-MitoPBN has following critical function effect:
(1) Nano-MitoPBN can be targeted by micro- compartmentation effect and be removed ROS in liver mitochondrion；
(2) Nano-MitoPBN can effectively reduce the oxidative stress of diabetes, promote mitochondrial function.；
(3) Nano-MitoPBN can inhibit gluconeogenesis process, and the periphery blood glucose level of diabetic animal is effectively reduced, and restore Portugal
Grape sugar tolerance.
Therefore, Nano-MitoPBN is known as liver mitochondrion targeting free radical scavenger by us, or is liver target
Mitochondria spin traps.
Based on above-mentioned function, Nano-MitoPBN can be swallowed by the kupffer cell in animal's liver, be then passed to liver
Cell can be enriched in liver, while its triphenylphosphine group can be selectively positioned at mitochondrial inner membrane
Upper (such as Fig. 1).
Based on above-mentioned function, Nano-MitoPBN(2.5 mg/kg) pass through significant reduction level of postprandial blood sugar and increase
Intraperitoneal Glucose tolerance improves the hyperglycemia and glucose-tolerant damage of diabetic mice.Diabetic mice is in Nano-
Blood plasma MDA is horizontal under the intervention of MitoPBN, and hepatic tissue 4-HNE and DNPH- protein carbonylation is restored, and blood plasma is total
The horizontal up-regulation (see figure 2) of oxidation resistance (T-AOC).
Based on above-mentioned function, Nano-MitoPBN can reduce the breathing of state 4, while promote the breathing of state 3, to change
Kind RCR；Nano-MitoPBN improves diabetic mice liver cell mitochondria energy coupling efficiency and succinate oxidation phosphoric acid simultaneously
Change ability (see figure 3).The present invention analyzes the metamorphosis of mitochondria using transmission electron microscope (TEM).In normal oxygen pressure
Under, the seemingly relatively regular arrangement of mitochondrial cristae.However, orbicule and vacuole, line is presented in most of mitochondria in anoxic
Plastochondria ridge is disorganized.However, in Nano-MitoPBN processing group, it can be observed that the ball of orderly mitochondrial cristae and reduction
Shape body and vacuole (see figure 4).
Based on above-mentioned function, Nano-MitoPBN significantly reduces phosphoric acid enol form propanone in cell and animal model
The protein expression of sour carboxylase (PEPCK) inhibits gluconeogenesis flux in cell and animal (see Fig. 5-Fig. 6).
According to above-mentioned function, we improve diabetic animal by using based on the ROS scavenger of Nano-MitoPBN
Liver glucose homeostasis and its mitochondria dysfunction make nanoparticle in liver mitochondrion by liver-specific therapy
In the accumulation of small compartment, to establish the novel method for the treatment of of diabetes.
Therefore Nano-MitoPBN is used to prepare anti-oxidant and treatment diabetes drugs by the present invention.
According to the present invention, Nano-MitoPBN can also be used for preparing diet that is anti-oxidant and improving diabetic supersession exception and add
Add agent.
To sum up, the present invention has developed the Nano-MitoPBN of the targeting hepatic mitochondria of liposome, due to its microcell
Room effect, it can remove the mitochondria super oxygen generated by the single electron leakage of liver mitochondrion electron transport chain (ETC)
Object/hydrogen peroxide, increase mitochondria state 3(mitochondrial state 3) respiratory rate, respiration control rate (RCR),
To reduce NADH:NAD+ratio, increase the synthesis of ATP, promote mitochondrial function.In addition, Nano-MitoPBN is by subtracting
Few ROS reduces gluconeogenesis, while increasing glycolysis, and the liver glycometabolism that ROS is mediated in diabetic animal has been reversed to rearrange.
To significantly reduce the periphery blood glucose level of diabetic animal and restore the glucose tolerance of diabetic animal.
Nano-MitoPBN can target liver prevention as a kind of material for treating treatment diabetes medicament, improve and treat diabetes,
The dosage of very little is only needed to can be obtained significant curative effect.
Detailed description of the invention
Fig. 1 is that Nano-MitoPBN improves mouse glucose tolerance level view.
Fig. 2 is that Nano-MitoPBN improves mouse MDA level view.
Fig. 3 is that Nano-MitoPBN improves mouse total antioxidant capacity figure.
Fig. 4 is that Nano-MitoPBN improves diabetic mice liver cell mitochondria respiratory function figure.
Fig. 5 is that Nano-MitoPBN improves diabetic mice liver cell ATP/AMP ratio figure.
Fig. 6 is that Nano-MitoPBN improves diabetic mice liver cell mitochondria structural damage figure.
Fig. 7 is the 13C- glutamine metabolism level view that Nano-MitoPBN inhibits hepatic gluconeogenesis.
Fig. 8 is the metabolic water that Nano-MitoPBN inhibits diabetic mice liver 13C-Lactate label animal gluconeogenesis
Flat figure.
Fig. 9 is principle of the invention diagram.
Specific embodiment
The present invention is further described below by embodiment combination attached drawing.
Embodiment 1:Nano-MitoPBN targeting improves blood glucose in diabetic mice and impaired glucose tolerance after removing mitochondria ROS
STZ stress mouse 3 weeks visible diabetic mice random blood sugar values obviously rise, Nano-MitoPBN intervene after reduce
The increase for the blood glucose in diabetic mice that STZ is caused.Abdominal cavity glucose tolerance measurement result reflect diabetic mice sugar tolerance by
Damage, Nano-MitoPBN intervene the impaired glucose tolerance situation for improving diabetic mice.As shown in Figure 1, in figure, C is represented
Normal group of control, D is represented diabetes group (STZ+HFD), and D+NM represents diabetes Nano-MitoPBN intervention group, and D+V is represented
Diabetes+empty carrier group.
Embodiment 2:Nano-MitoPBN reduces diabetic mice vivo oxidation stress level
The intracorporal oxidative stress of biology be by oxidative damage with antioxidant system is unbalance causes.Malonaldehyde (MDA) is in organism
The oxidation final product of peroxidization occurs in lipid for Free Radical, and the level of MDA can reflect biological vivo oxidation damage
Level.As the result is shown diabetic mice MDA content increase (see figure 2), internal total antioxidant capacity (TAOC) be substantially reduced (see
Fig. 3), the expression of internal antioxidase dies down, and illustrates in diabetic mice there are a degree of oxidative damage, and Nano-
MitoPBN intervention significantly reduces diabetic mice oxidative stress.In figure, C represents normal group of control, and D represents glycosuria
Sick group (STZ+HFD), D+NM represents diabetes Nano-MitoPBN intervention group, and D+V represents diabetes+empty carrier group.
Embodiment 3:Nano-MitoPBN improves diabetic mice liver cell mitochondria function
Mitochondria respiratoring control rate (RCR) reflects mitochondrial function, and commonly using the ratio between respiratory rate indicates, refers to 3 respiratory rate of state
It is to evaluate structure of mitochondria integrality and oxidative phosphorylation couples the sensitive indexes of degree the ratio between with 4 respiratory rate of state.RCR increases
Gao represents that mitochondrial function enhancing is hyperfunction, and RCR is reduced, and more indicates mitochondrial respiratory chain and oxidative phosphorylation uncoupling closer to 1,
Impaired mitochondrial function.Pass through the measurement to murine liver tissue mitochondrial RCR, it has been found that diabetic mice mitochondrial respiratory function
It can obviously be damaged, and the mitochondrial respiratory function of diabetic mice is restored (see figure 4) after Nano-MitoPBN intervention.ATP
It is energy source important in vivo, is mainly generated by mitochondria, ATP content also reflects the function of mitochondria indirectly.Hepatic tissue
ATP assay shows that ATP content is remarkably decreased in diabetes body, and Nano-MitoPBN has significantly raised ATP water after intervening
Flat and these results of ATP/AMP ratio illustrate that it is impaired that there are energy in diabetic mice, and Nano-MitoPBN can improve
Energy compromise state (see figure 5).These results all directly or indirectly react in diabetes body that there are structure of mitochondria and function
Can be abnormal, and Nano-MitoPBN targeting significantly improves the breathing of diabetic individual tissue Mitochondria after removing mitochondria ROS
The exception of function.
Embodiment 4:Nano-MitoPBN improves diabetic mice liver cell mitochondria structural damage
Transmission electron microscope results figure shows that Mitochondrial Shape is normal in the liver cell of normal mouse, and ridge is high-visible；Fig. 6 display sugar
Sick mouse liver cell mitochondrial swelling deformation is urinated, and occurs vacuole structure in mitochondria, shows that STZ stress lead to diabetic mice
Liver cell mitochondria structure is damaged；Fig. 4 illustrates that Nano-MitoPBN intervenes after mitochondria ROS is removed in targeting and is obviously improved
The damage of structure of mitochondria.
The metaboilic level of embodiment 5:Nano-MitoPBN inhibition hepatic gluconeogenesis
In cell experiment, PEPCK activity dramatically increases after glucose deprivation, and MitoPBN processing significantly inhibits this increasing
Add.Meanwhile in the present invention, using stable isotope labeling13C- glutamine come reflect PEPCK mediate gluconeogenesis work
Property.The formation of+6 citric acid of m comes from m+3 pyruvic acid of+4 OAA and m, and the catalysis for mainly passing through PEPCK generates 5C.
As shown in fig. 7, coming from U-13+ 6 citric acid of m of the gluconeogenesis of C- glutamine is formed in significant in the case where no glucose
Increase, but significantly reduced after Nano-MitoPBN processing, shows Nano-MitoPBN pairs13C-glutamine source liver is thin
The inhibiting effect of gluconeogenesis intracellular.
The metaboilic level of embodiment 6:Nano-MitoPBN inhibition diabetic mice liver gluconeogenesis
Nano-MitoPBN processing significantly reduces increased pepck protein expression in diabetic mice, pyruvic acid tolerance test
(PTT) it also indicates that Nano-MitoPBN processing significantly reduces the blood glucose level of HFD mouse, shows that the sugar in pyruvic acid source is different
It is raw to reduce (see figure 8).It utilizes13The gluconeogenesis ability of C-Lactate label animal, the results showed that Nano-MitoPBN pairs13C -
The inhibiting effect of animal tissue's liver gluconeogenesis in the source lactate.
Claims (3)
1. Nano-MitoPBN is preparing the application in anti-oxidant and treatment diabetes medicament.
2. Nano-MitoPBN is preparing the application in dietary supplement that is anti-oxidant and improving diabetic supersession exception.
3. application according to claim 1 or 2 characterized by comprising
(1) Nano-MitoPBN is targeted by micro- compartmentation effect and is removed ROS in liver mitochondrion；
(2) Nano-MitoPBN promotes mitochondrial function by the way that the oxidative stress of diabetes is effectively reduced；
(3) Nano-MitoPBN is effectively reduced the periphery blood glucose level of diabetic animal, restores Portugal by inhibiting gluconeogenesis process
Grape sugar tolerance.
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| CN107510848A (en) * | 2016-06-15 | 2017-12-26 | 常州莱道斯生物医药科技有限公司 | Applications of the Mitochondrially targeted preparation MitoPBN in diabetes are prevented and treated |
| CN112999232A (en) * | 2021-02-28 | 2021-06-22 | 复旦大学 | Application of nitric oxide spin-trapping nano-targeted antioxidant in preparation of drugs for preventing diabetes |
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Application publication date: 20190823 |