CN111110830B - Application of bioactive polypeptide PACAP in preparation of medicine for improving fertility of obese men - Google Patents
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Abstract
The invention discloses application of a bioactive polypeptide PACAP in preparation of a medicament for improving fertility of obese men, and belongs to the field of fertility impaired diseases of obese men. The bioactive polypeptide PACAP medicine disclosed by the invention can be used for remarkably preventing and relieving obesity-induced male fertility injury (mainly by improving blood lipid and sex hormone levels, reducing testis tissue oxidative stress level, improving obesity-induced testis spermatogenic cell injury, inhibiting high-lipid-induced spermatogenic cell GC-1 apoptosis, improving functions of sperm, early embryo quality after in vitro fertilization and the like), repairing pathological changes and reproductive system functions of obesity male fertility injury, and can be used for preliminarily understanding the relationship between obesity and male infertility, clarifying the protection effect of PACAP on obesity-induced male fertility injury and providing theoretical basis and experimental basis for clinical diagnosis and treatment of obesity male infertility and novel targeted treatment strategies.
Description
Technical Field
The invention belongs to the field of obese male fertility impaired diseases, and particularly relates to application of a bioactive polypeptide PACAP in preparation of medicines for improving the fertility of obese males; in particular to application of a bioactive polypeptide PACAP in preparing a medicine for preventing, treating or repairing the fertility injury diseases of obese men.
Background
Obesity is a chronic metabolic disease caused by interaction of various factors such as heredity, life style and environment, and is characterized by adipose tissue accumulation and systemic inflammation. Obesity is closely related to the occurrence and development of type 2 diabetes, metabolic syndrome, hypertension, cardiovascular and cerebrovascular diseases and various cancers. In addition to complications such as cardiovascular disease, the incidence of infertility is rising in obese or overweight people, however, the relationship between obesity and male infertility is poorly understood and is becoming more and more important. Studies have shown that some manifestations of father obesity may negatively impact basic sperm parameters such as sperm count, motility, and normal morphology. Excessive accumulation of fat in testis and epididymis can directly cause structural abnormality of testis and epididymis, and can release Reactive Oxygen Species (ROS), oxidative free radicals, inflammatory factors and the like, so that endocrine functions of testis tissues are affected, and the endocrine function of testis tissues and spermatogenesis processes are affected to different degrees. More and more studies have shown that obesity has a significant negative effect on the male reproductive system.
Obesity is now increasingly receiving attention in various medical fields as an epidemic. In the reproductive field, much attention is paid to the effect on male reproductive ability. Although there is growing evidence that obesity is an important cause of male infertility, the current research is mostly focused on the effect of obesity on surface phenomena such as sperm concentration, motility, morphology and serotonin, whether obesity promotes apoptosis of testicular spermatogenic cells and the exact mechanism of action is still unclear. It is also insufficient to overcome obesity by simple weight loss and exercise, so there is a need to explore the molecular mechanisms of obese male infertility to find key intervention targets and to find effective methods for preventing and treating obese male infertility.
Disclosure of Invention
In order to overcome the defects and shortcomings in the prior art, the invention aims to provide application of a bioactive polypeptide PACAP in preparation of medicines for improving fertility of obese men.
Another object of the present invention is to provide an application of the bioactive polypeptide PACAP in preparing a medicament for preventing, treating or repairing fertility injury diseases of obese men. The bioactive polypeptide PACAP can remarkably prevent and relieve obesity-induced male fertility injury, and repair pathological changes and reproductive system functions of the obesity male fertility injury.
The aim of the invention is achieved by the following technical scheme:
the invention provides application of a bioactive polypeptide PACAP in preparation of a medicament for improving fertility of obese men.
Further, the application of the bioactive polypeptide PACAP in preparing medicines for improving male fertility of high fat or nutritional obesity.
The invention provides application of a bioactive polypeptide PACAP in preparing a medicament for preventing, treating or repairing fertility injury diseases of obese men.
Furthermore, the application of the bioactive polypeptide PACAP in preparing medicaments for preventing, treating or repairing the fertility injury diseases of high-fat or nutritional obese men.
Furthermore, the bioactive polypeptide PACAP is applied to the preparation of medicines for improving the blood fat and sex hormone level, reducing the oxidation stress level of testis tissues, improving the testis-induced sperm cell damage caused by obesity, inhibiting the high-fat-induced spermatogenic cell GC-1 apoptosis, improving the sperm function, improving the early embryo quality after in vitro fertilization and other functions.
Further, the bioactive polypeptide PACAP comprises PACAP38, a derivative of PACAP38, PACAP27 and at least one of the derivatives of PACAP 27; the bioactive polypeptide PACAP may be wild-type human PACAP, chemically synthesized PACAP, etc., but is not limited thereto.
Further, the medicament is combined with one or more other prophylactic/therapeutic agents to obtain a pharmaceutical composition.
Further, the fertility damaging disease of an obese male comprises a high fat diet stimulation injury or nutritional obesity inducing injury caused by one or more factors.
Further, the effective dose of the bioactive polypeptide PACAP is 0.4mg/kg mouse/d.
Compared with the prior art, the invention has the following advantages and effects:
the bioactive polypeptide PACAP medicine disclosed by the invention can be used for remarkably preventing and relieving obesity-induced male fertility injury (mainly by improving blood lipid and sex hormone levels, reducing testis tissue oxidative stress level, improving obesity-induced testis spermatogenic cell injury, inhibiting high-lipid-induced spermatogenic cell GC-1 apoptosis, improving functions of sperm, early embryo quality after in vitro fertilization and the like), repairing pathological changes and reproductive system functions of obesity male fertility injury, and can be used for preliminarily understanding the relationship between obesity and male infertility, clarifying the protection effect of PACAP on obesity-induced male fertility injury and providing theoretical basis and experimental basis for clinical diagnosis and treatment of obesity male infertility and novel targeted treatment strategies.
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FIG. 1 is the effect of PACAP on body weight and blood lipid and sex hormone levels in obese mice; wherein A: influence of PACAP on body weight of obese mice; b: influence of PACAP on food intake in obese mice; c: influence of PACAP on epididymal fat weight of obese mice; d: effect of PACAP on testis index in obese mice; e: influence of PACAP on fat mice blood lipid; f: effect of PACAP on sex hormone levels in obese mice.
FIG. 2 is a pathological change in the testis tissue structure of obese mice by PACAP.
FIG. 3 is the effect of PACAP on the expression of Sirt1/Ac-p53 pathway and apoptosis-related proteins in testes of obese mice.
FIG. 4 is the effect of PACAP on the acrosome response of sperm after testicular transfection of Sirt1 shRNA lentiviruses in obese mice.
FIG. 5 is the effect of PACAP on apoptosis after GC-1 cell high lipid damage transfection of Sirt1 shRNA lentiviruses.
FIG. 6 is the effect of PACAP on Sirt1/p53 pathway and apoptosis-related protein expression following GC-1 cell high lipid damage transfection of Sirt1 shRNA lentiviruses.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but embodiments of the present invention are not limited thereto.
The test methods for specific experimental conditions are not noted in the examples below, and are generally performed under conventional experimental conditions or under experimental conditions recommended by the manufacturer. The materials, reagents and the like used, unless otherwise specified, are those obtained commercially.
PACAP38 (. Gtoreq.95.95% (HPLC), cat No. 122105) was purchased from Gill Biochemical (Shanghai) Inc.
Example 1
1. PACAP38 drugs are selected for experimental verification (PACAP is uniformly written later):
cells and animals: the GC-1 mouse testis spermatogonial cell line (cell source: ATCC CRL-2053; cell characteristics: spermatogonial cells isolated from normal mouse testis, which can be propagation-cultured in a proliferation manner) was used for cell experimental study, and C57/BL6J mouse (purchased from medical laboratory animal center, SPF grade, guangdong province) was selected for animal experimental study.
(1) High fat diet feeding a obese mouse model was constructed:
mice were randomly grouped and fed standard diet (Control diet, CD) and High Fat Diet (HFD) for 8 weeks, respectively, and body weight and food intake were monitored weekly for changesAnd (5) melting. Obese mice were judged to be successfully modeled when the HFD mice exceeded the CD group body weight by 20%. Subsequently, mice were intraperitoneally injected with PACAP (0.1 mg/kg,0.2mg/kg,0.4 mg/kg) or sterile saline (control group) at various concentrations daily for four consecutive weeks, and the mice were monitored for changes in body weight and feeding weekly as well. A portion of mice was kept for injection of Sirt1 shRNA lentivirus and control lentivirus (ctrl shRNA for short) (Sirt 1 shRNA lentivirus, control lentivirus were purchased from us Cyagen Biosciences), each injected with 10 μl of lentiviral suspension (10 8 transducing units/mL), for 7 days. Mice were euthanized after the end of the experiment. Measuring four blood lipid items (triglyceride: TG, total cholesterol: TC, low density lipoprotein cholesterol: LDL-C, high density lipoprotein cholesterol: HDL-C) and serum sex hormone level (testosterone: T, estradiol: E2, follicle stimulating hormone: FSH, luteinizing hormone: LH) by using a full-automatic biochemical detector; weighing epididymal fat and testis, and calculating testis weight/body weight ratio; fixing a part of testis specimens with neutral paraformaldehyde to be subjected to HE staining and slicing; the remaining tissues were stored in a-80℃ultra-low temperature refrigerator to be used as Western Blot (WB).
(2) Palmitic acid induction establishes a high lipid damage cell model:
GC-1 cells were cultured and inoculated in 96-well plates at a volume of 100. Mu.L/well, 3X 10 3 Individual cells/well, 37℃in 5% CO 2 Culturing in an incubator. When the cell density reached about 80%, PBS, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7 and 0.8mM Palmitic Acid (PA) was added to each of the above materials, and the mixture was placed at 37℃with 5% CO 2 Culturing was continued in the incubator for 1, 3, 6, 12 and 24 hours. After the treatment time has elapsed, 10. Mu.L of CCK-8 reagent is added to each well, immediately incubated in an incubator at 37℃for 2 hours, and the absorbance (OD) at 450nm is measured with a microplate reader. Based on the OD values of the groups, GC-1 cell viability was calculated as: survival = [ (OD damaged group-OD blank)/(OD undamaged group-OD blank)]X 100%. After the high fat injury cell model is established, PBS and 10 are respectively added -9 、10 -8 、10 -7 、10 -6 、10 -5 PACAP of M, 37 ℃,5% CO 2 Culturing in the incubator for 48 hours. The position of the partAfter the completion of the treatment time, 10. Mu.L of CCK-8 solution was added to each well, incubated in an incubator at 37℃for 2 hours, and the absorbance at 450nm was measured by using a microplate reader. Based on the OD values of the groups, the GC-1 cell proliferation rate was calculated as: proliferation rate = [ (OD experimental group-OD blank group)/(OD negative control group-OD blank group)]×100％。
According to the pre-experiment results of the influence of different PA and PACAP dosing doses on the activity of GC-1 cells, taking the cost performance of drugs into consideration and the like, the experiment selects the PA concentration and time with the cell survival rate of about 70%, namely 0.5mM PA acts for 6 hours to construct a high-fat damage cell model; PACAP function of 100nM for 48h was selected as the optimal condition for GC-1 cell repair of high lipid lesions.
(3) Sirt1 shRNA lentivirus transfected GC-1 cells:
the day before the experiment, GC-1 cells were seeded in 6-well plates at an amount of about 3X 10 5 1mL of DMEM medium containing 10% fetal bovine serum was added to each cell/well. The lentivirus transfection was started after overnight incubation to a cell confluence of about 30%. According to the transfection index (Multiplicity of infection, MOI, refer to the number of viruses transfected per cell) of lentiviral transfected GC-1 cells calculated by pre-experiments, the most suitable lentiviral volume and final concentration of 5 mug/mL Polybrene (Polybrene) were added per well (which can increase the transfection efficiency), and after mixing, placed at 37℃and 5% CO 2 Incubate overnight. After 12h the lentivirus-containing medium was replaced with fresh complete medium. Culturing was continued for 48 hours, and the expression of EGFP in GC-1 cells was observed under a fluorescence microscope (green fluorescence). The number of EGFP-positive cells was counted as a percentage of the total number of counted cells to determine the transfection efficiency of lentiviruses by randomly selecting 5 low power fields. Because the Sirt1 shRNA lentiviral vector is provided with an anti-puromycin element, the Sirt1 shRNA lentiviral vector is replaced by a culture medium containing 1 mug/mL puromycin, and the culture medium is continuously screened for 48 hours, so that a Sirt1 knockdown GC-1 stable transgenic cell strain is obtained.
(4) GC-1 cells were seeded in 6-well plates at an inoculum size of approximately 3X 10 5 1mL of DMEM medium containing 10% fetal bovine serum was added to each cell/well. After constructing a model of high fat damage cells by using GC-1 cells with 0.5mM PA for 6h after overnight culture until the cell confluency is about 70%, 2. Mu.M STR1720 or 2. Mu.M EX527 were usedGC-1 cells were pretreated for 24h and further 100nM PACAP was added to treat GC-1 cells and incubated for 48h.
2. Results:
(one), PACAP slows down weight gain of mice and improves blood lipid and sex hormone level
1. Mice in the HFD and CD groups increased in body weight with increasing age, with the HFD group increasing significantly faster in body weight than the CD group. 0.4mg/kg PACAP significantly slowed the weight gain of the high fat-induced mice, and the weight-loss effect of PACAP was dose-and time-dependent (FIG. 1A). * P <0.05, <0.01,HFD+PACAP 0.4mg/kg vs. hfd+vehicle (hfd+vehicle refers to High fat diet fed (High fat diet) mice injected with sterile saline group equivalent to PACAP volume
2. PACAP did not affect mice feeding in the dose range used in this experiment (fig. 1B).
3. The epididymal fat weight of mice in the HFD+Vehicle group was significantly heavier than that of mice in the CD+Vehicle group, and the epididymal fat weight of HFD mice after PACAP treatment at high dose (0.4 mg/kg) was significantly reduced (FIG. 1C). * P <0.05, <0.001,CD+Vehicle or HFD+PACAP 0.4mg/kg vs. hfd+vehicle (cd+vehicle is a standard Control diet fed (Control diet) mice were injected with sterile saline group equivalent to PACAP volume
4. The high dose (0.4 mg/kg) of PACAP increased the testis index compared to the HFD+Vehicle group (FIG. 1D). * P <0.01, P <0.001,CD+Vehicle or HFD+PACAP 0.4mg/kg vs. hfd+vehicle.
5. High doses (0.4 mg/kg) of PACAP were effective in lowering Triglycerides (TG), total Cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) in serum of high-fat diet mice (FIG. 1E). * P <0.05, <0.01,HFD+PACAP 0.4mg/kg vs. hfd+vehicle; p <0.05,HFD+PACAP 0.2mg/kg vs. HFD+Vehicle.
6. PACAP significantly increased T and decreased E2 in obese mice, PACAP also increased FSH and LH secretion in obese mice (fig. 1F). #p <0.05, #p <0.01,HFD+Vehicle vs.CD+Vehicle; * P <0.05, <0.01,HFD+PACAP 0.4mg/kg vs. hfd+vehicle.
(II) PACAP improves obesity-induced testis injury
1. The seminiferous tubules of the two testis groups, CD+Vehicle and CD+PACAP 0.4mg/kg, are orderly and densely arranged, the seminiferous cells in the seminiferous tubules are tightly combined with the basement membrane, the seminiferous cells of each stage are closely arranged, the layers are distinct, the number of sperms in the lumen is large, and the morphological structures of the testis of the two testis groups are normal (figure 2A, B).
2. The arrangement of spermatogenic cells in the seminiferous tubules of the mice in the HFD+Vehicle group is loose and disordered, and the number of mature sperms in the lumen is small; the seminiferous cells were loose with the basement membrane, even with peeling, reduced numbers of seminiferous epithelium, damaged testis cells and apoptosis (fig. 2C).
3. With the increase of PACAP concentration, the testis injury degree is gradually reduced, the seminiferous epithelium thickness is obviously recovered, the number of seminiferous cells is increased, and the effect of improving testis injury by the PACAP with high dosage of 0.4mg/kg is best, which indicates that the PACAP can repair the seminiferous cell injury caused by obesity, improve the seminiferous epithelium structure and layer, improve the spermatogenic environment, and improve the sperm quality, thereby improving the reproductive function (figure 2D, E, F).
(III) PACAP activates the testis Sirt1/p53 pathway to improve obesity-induced apoptosis of testis spermatogenic cells
Compared with the CD control group, the expression of Sirt1 protein in the testis tissue of the HFD group is reduced by 44.21%, while the expression of Ac-p53 protein is obviously increased by 32.89%, so that apoptosis signal channels downstream of p53 are activated, such as increased expression of clear caspase 3, clear caspase 9 and clear PARP, the ratio of Bax/Bcl-2 is increased, and the increase of testis apoptosis of the HFD group is indicated; as PACAP concentration increases, sirt1 protein expression tends to increase, while pro-apoptotic Ac-p53, clean caspase 3, clean caspase 9, and clean PARP expression gradually decrease. The decrease in Bax/Bcl-2 ratio indicates that PACAP can improve obesity-induced testis spermatogenic apoptosis (FIG. 3A, B, C, D). * P <0.001, P <0.01vs. cd+vehicle; #P <0.05, #P <0.01, #P <0.001vs. HFD+Vehicle, where PACAP (-) +HFD (-) means CD+Vehicle and PACAP (-) +HFD (+) means HFD+Vehicle.
(IV) PACAP improves the response rate of sperm acrosomes of obese mice
The acrosome response of sperm from the HFD+Vehicle group was significantly lower than that of the CD+Vehicle group by 30.40%, and the acrosome response of sperm from PACAP (0.4 mg/kg) treatment was recovered (55.61%) but still less than that of CD+Vehicle (64.14%). This effect of PACAP was impaired (47.69%) after intratesticular knockdown of Sirt1 gene (fig. 4A, B). * P <0.001, P <0.01, P <0.05,ns,no significant difference.
(V) PACAP inhibits high-fat-induced GC-1 apoptosis
The PA can induce apoptosis, the apoptosis rate of the PA+PBS group cells is up to 39.22%, and the PA+PBS group cells have a significant difference compared with a normal control group; after PACAP treatment, the apoptosis rate is obviously reduced, and the apoptosis induced by PA can be effectively inhibited; cells treated with STR1720 (CAS: 1001645-58-4) showed a significant decrease in apoptosis compared to the PA+PBS group, but no significant difference compared to the PA+PACAP group; when GC-1 cells were pretreated with EX527 (SIRT 1 inhibitor, routinely marketed) or SIRT1 knocked down intracellularly, PACAP inhibition of PA-induced apoptosis was blocked, with a significant difference compared to the pa+pacap group (fig. 5A, B). * P <0.01,PA+PACAP vs.PA+PBS; p >0.05,PA+STR1720 vs.PA+PACAP; # P <0.01, # P <0.05,PA+PACAP+EX527 or PA+PACAP+Sirt1 shRNA vs.PA+PACAP.
(VI) Sirt1/p53 pathway mediates the protective effect of PACAP on GC-1 cells
PA significantly reduced Sirt1 expression compared to the normal control group, thereby enhancing Ac-p53, bax, clear caspase 3, clear caspase 9 and cleaved caspase PARP expression, causing apoptosis. PACAP can reverse the apoptotic effects of PA by up-regulating Sirt1 expression, either in normal control or PA-treated cells. Pretreatment of cells with EX527 or intracellular knockdown of Sirt1, apoptosis inhibition by PACAP was blocked. Sirt1 agonist STR1720 acts in a manner opposite to EX527 or knockdown Sirt1 and can more effectively inhibit GC-1 apoptosis. The above results indicate that PACAP inhibits p 53-induced apoptosis by promoting Sirt1 expression and reducing p53 acetylation levels, suggesting that PACAP protection of high-lipid-induced GC-1 cells is associated with Sirt1/p53 signaling pathways (fig. 6A, B, C, D). #p <0.05,PACAP vs.PBS; * P <0.01, P <0.001,PACAP+EX527 orPACAP+Sirt1 shRNA vs.PACAP; Φp <0.05,STR1720 vs.PACAP; p >0.05,STR1720 vs.PACAP.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (3)
1. The application of a bioactive polypeptide PACAP in the preparation of an agent for improving obesity-induced testicular seminiferous apoptosis is characterized in that: the use is for non-disease therapeutic purposes.
2. The use according to claim 1, characterized in that: the improvement of the obesity-induced testicular seminiferous apoptosis is to inhibit the high-fat-induced spermatogenic cell GC-1 apoptosis.
3. The use according to claim 1, characterized in that: the bioactive polypeptide PACAP comprises PACAP38, a derivative of PACAP38, PACAP27 and at least one of the derivatives of PACAP 27.
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