CN113546092B - Application of gold nanoclusters and medicine for reducing male reproductive toxicity of copper ions - Google Patents

Application of gold nanoclusters and medicine for reducing male reproductive toxicity of copper ions Download PDF

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CN113546092B
CN113546092B CN202110863797.8A CN202110863797A CN113546092B CN 113546092 B CN113546092 B CN 113546092B CN 202110863797 A CN202110863797 A CN 202110863797A CN 113546092 B CN113546092 B CN 113546092B
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copper ions
gold nanoclusters
cucl
medicine
reproductive toxicity
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CN113546092A (en
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李文清
孙斐
黄莹莹
龚胜男
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Nantong University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/242—Gold; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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Abstract

The invention provides an application of gold nanoclusters and a medicine for reducing male reproductive toxicity of copper ions, which relate to the technical field of biomedicine and are technically characterized in that: the gold nanoclusters are used for reducing cytotoxicity of copper ions; reducing cell death; realizes the treatment of testicle copper metabolic disorder and reduces the damage of copper ions to organisms.

Description

Application of gold nanoclusters and medicine for reducing male reproductive toxicity of copper ions
Technical Field
The invention relates to the technical field of biological medicine, in particular to application of gold nanoclusters and a medicine for reducing male reproductive toxicity of copper ions.
Background
Copper is a trace element necessary for biological growth, next to the third most abundant trace element of iron and zinc, which has an important role in maintaining body homeostasis. However, too much copper can lead to oxidative damage of proteins and nucleic acids, lipid peroxidation and enzyme inhibition. Copper contamination becomes one of the heavy metal contaminants in the environment. It has been reported that chronic copper poisoning has a significant effect on the liver, and can lead to hepatolenticular degeneration and the like. There are also studies reporting that excessive copper can affect the reproductive system, reduce testosterone levels, reduce sperm motility and survival, reduce testicle weight, lead to reduced male/male fertility and even male infertility. How to remove copper ions and reduce the male reproductive toxicity effect of copper ions is an important and urgent research direction.
With the continuous development of nanotechnology, new nanomaterials are used in different research fields. Among them, the application of nanomaterials in biomedical fields is particularly important. Nanomaterials include liposomes, polymers and branched polymers, metal-based, magnetic and silica-based, etc., which have made significant progress as drugs, additives or carriers in the fields of gene therapy, drug delivery, imaging, and novel drug discovery technologies.
The research shows that copper ions can cause serious reproductive toxicity, damage the structure of seminiferous tubules and cause cavitation damage and apoptosis. It has been shown that intraperitoneal injection of supplemental iron can improve copper liver accumulation due to excessive calcium in the body. L-carnitine has an improving effect on toxicity and sperm quality of copper-exposed rat testes. The curcumin extract has protective effect on testis injury induced by copper oxychloride, and improves sperm health parameters.
Currently existing technologies for treating copper metabolic disorders mainly include metal chelators, such as: penicillamine, trientine; and zinc salts. For increasing excretion or decreasing absorption, but similar abnormal nerve deterioration occurs in different metal chelating treatments, and hepatic copper metabolism disorders require careful use of zinc salts, which has prompted the search for safer treatments.
Disclosure of Invention
The invention aims to solve the problems of serious reproductive toxicity and improved toxic effect caused by copper ions, so that a new medicine for relieving the male reproductive toxic effect of the copper ions is urgently needed to be developed, and the prior art has no more effective scheme for dealing.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
use of gold nanoclusters for reducing cytotoxicity of copper ions.
Preferably, the gold nanoclusters are used to reduce the male reproductive toxicity effects of CuCl 2.
The application also provides a medicine for relieving male reproductive toxicity of copper ions, which is characterized in that: the gold nanocluster can adsorb copper ions in vivo and treat male reproductive toxicity effect caused by the copper ions.
The gold nanoclusters are applied to reduce cytotoxicity of copper ions, so that death of cells is reduced; meanwhile, the gold nanoclusters are nontoxic, so that the gold nanoclusters are more beneficial to playing important drug carrying functions in drug improvement in the future or are more directly used for nanocrystallizing drugs, the targeting property, biocompatibility and the like of the drugs are enhanced, the absorption and metabolism paths of the drugs can be possibly changed, and the absorption rate of the drugs is improved.
Drawings
FIG. 1 is a drawing showing an electron micrograph of gold nanoclusters, (-) in accordance with example 1 of the present inventionB) Is gold nanocluster and CuCl 2 A comparison schematic added into the gold nanoclusters;
FIG. 2 is a drawing corresponding to embodiment 2 of the present invention, wherein (A) represents CuCl of different concentrations 2 Toxic effects on GC1 cells, (B) represents gold nanoclusters on CuCl 2 Is effective in cytotoxicity;
FIG. 3 is a schematic diagram of the reproductive system of a mouse according to the embodiment 3 of the present invention; (B) Schematic drawing of the histomorphometric structure of each testis in example 3, (C) the apoptosis result of germ cells in each testis in example 3, and (D) the statistical analysis of the apoptosis of germ cells in each mouse testis.
Detailed Description
The present invention will be described in further detail with reference to specific examples in order to make the objects, technical solutions and advantages of the present invention more apparent.
Partial noun interpretation:
BSA: bovine serum albumin.
PBS: the phosphate buffer salt solution (phosphate buffer saline) generally acts as a solvent to dissolve the protective agent.
AuNC s Gold nanoclusters.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, however, the present invention may be practiced otherwise than as described herein, and therefore the present invention is not limited to the specific embodiments of the disclosure that follow.
Use of gold nanoclusters for reducing cytotoxicity of copper ions, in one embodiment for reducing CuCl 2 Male reproductive toxicity effects of (a).
The application also provides a medicine for relieving male reproductive toxicity of copper ions, which comprises gold nanoclusters.
To further validate the present application, the inventors employed the following validation experiments.
Example 1: gold nanocluster specifically absorbs copper ions
The method comprises the following specific steps:
first, auNCs were synthesized: in one embodiment, chloroauric acid (5 mL, 10 mmol/L) and BSA (5 mL, 50 mg/mL) were stirred at 37 degrees for 2 minutes. NaOH (0.5 mL, 1.0M) was then added and the mixture was rapidly stirred at 37℃and reacted for 12 hours to give gold nanoclusters of 2 to 5 nanometers as shown in FIG. 1 (A).
Adding the synthesized gold nanoclusters to CuCl with different concentrations 2 In the solution, a fluorescence diagram as shown in FIG. 1 (B) was obtained. It can be found that the gold nanoclusters can capture CuCl 2 At the same time CuCl 2 Can change AuNC s Can quench AuNC under 365 nm ultraviolet light s Is a fluorescent light of (a) and (b).
Example 2: in vitro experiments show that the gold nanoclusters reduce cytotoxicity of copper ions:
specifically, two experiments were included:
a first group: investigation of different concentrations of CuCl 2 Is (are) cytotoxicity test
The steps are as follows:
1) 96-well plates were plated with 6000 GC1 cells per well.
2) Culturing for 24 hours.
3) Using CuCl of different concentrations 2 Cells were treated for 24 hours.
4) Mu.l of CCK8 reagent was added, and the mixture was placed in a 37℃incubator, and absorbance at 450nm was measured after 1 hour.
Referring to FIG. 2 (A), when CuCl 2 The higher the concentration, the lower the survival of GC1 cells,
second group: study of AuNC at different concentrations s Is CuCl-reducing 2 Is (are) cytotoxicity test
The specific steps are as follows:
1) 96-well plates were plated with 6000 GC1 cells per well.
2) Culturing for 24 hours.
3) GC1 cells were treated as follows.
control groups were treated with PBS.
CuCl 2 Group addition of 15. Mu.g/mL CuCl 2 Treating cells, and adding 0-360 mug/mL AuNC respectively s .
4) Cells were treated for 24 hours.
5) Mu.l of CCK8 reagent was added and absorbance at 450nm was measured after 1 hour.
FIG. 2A shows CuCl 2 The effect on GC1 cell activity in vitro can result in programmed cell death. FIG. 2B shows that the gold nanoclusters reduce CuCl after reaching a certain concentration 2 Toxicity after GC1 cells are treated, and the survival rate of the cells is improved.
Example 3: gold nanoclusters to reduce CuCl 2 Male reproductive toxicity effects of (a).
The specific steps are as follows:
c57BL/6N male mice were selected.
Four groups of mice were treated as follows:
group A: PBS group (mice 3): 200 μl PBS was injected per intraperitoneal injection.
Group B: auNC (Aunc) s Group (mice 3): 200 μl AuNC per tail vein injection s (18 mg/mL) and 200. Mu.l of AuNC were again injected into the tail vein 1 hour apart s 。
Group C: cuCl 2 Group (mice 4): each of the injections was prepared by intraperitoneal injection of CuCl at a weight (4. Mu.g/g) 2 A solution.
Group D: cuCl 2 +AuNC s Group (mice 4): each of the injections was prepared by intraperitoneal injection of CuCl at a weight (4. Mu.g/g) 2 A solution. 200 μl AuNC was injected immediately into tail vein s (18 mg/mL) and 200. Mu.l of AuNC were again injected into the tail vein 1 hour apart s . Two-sided testes were sacrificed 48 hours later and paraffin sections of testis tissue were made after 4% PFA fixation 48 hours, and HE staining and TUNEL detection experiments were made for each group after sections, comparing the differences of each group.
Referring to FIG. 3, it can be seen that CuCl 2 Resulting in death of germ cells in the mouse testis, resulting in destruction of testis tissue morphology, cuCl 2 +AuNC s Can alleviate CuCl 2 Resulting histological destruction of the testes (fig. 3B). AuNC (Aunc) s After treatment, mice were examined for testis tissue morphology andcontrol (PBS) was not different, suggesting AuNC s There was no reproductive toxicity (fig. 3B). In addition, through apoptosis detection experiments, it is found that CuCl2 causes significant increase of germ cell apoptosis in mouse testis, and CuCl 2 +AuNC s Can alleviate CuCl 2 The resulting apoptotic effect of spermatogenic cells (fig. 3C, 3D). AuNC (Aunc) s After treatment, there was no difference between spermatogenic apoptosis in testis and control (PBS) in mice, suggesting AuNC s There was no reproductive toxicity (fig. 3C, 3D). Thus demonstrating that AuNCs have obvious therapeutic effect on testicular copper metabolic disorder, thus proving AuNC in vivo s Can reduce the damage of copper ions to the body.
The above description is only an example of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the scope of the claims of the present invention.

Claims (1)

1. An application of gold nanoclusters, which is characterized in that: the gold nanoclusters are used for preparing light CuCl 2 Copper ions in the composition.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1398186A (en) * 1999-12-24 2003-02-19 株式会社韩国新科学技术中心 Pharmaceutical compsn. comprising pectin effective in inhibiting male productive toxxicity

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1977754A1 (en) * 2007-04-02 2008-10-08 Universität Duisburg-Essen Treatment of diseases with nanoparticles having a size-dependent cytotoxicity

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1398186A (en) * 1999-12-24 2003-02-19 株式会社韩国新科学技术中心 Pharmaceutical compsn. comprising pectin effective in inhibiting male productive toxxicity

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