Saudi Journal of Biological Sciences 26 (2019) 821–827

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Original article

Effects of dodder total flavone on polycystic ovary syndrome rat models

induced by DHEA combined HCG
Mingsan Miao ⇑, Mengfan Peng, Zhengwang Zhu, Xiaoli Yan, Zhenzhen Wei, Mengyan Li
College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450000, China

a r t i c l e i n f o a b s t r a c t

Article history: Aims: Explore the effects of dodder total flavone on polycystic ovary syndrome (PCOS) rat models
Received 15 August 2018 induced by dehydroepiandrosterone (DHEA) combined human chorionic gonadotropin (HCG).
Revised 19 February 2019 Methods: Except the blank group, the rest of the rats were injected with DHEA 6 mg/100 g on the back of
Accepted 19 February 2019
the neck and 1.5 IU HCG each day, for 21 consecutive days. On the 16th day of modeling, vaginal smear
Available online 19 February 2019
was performed to select the model rats, which were randomly divided into model group, dacin-35 group,
large, middle and small dose dodder total flavonoids groups, and given the medicine for three weeks. At
Keywords:
the end of the last administration, take samples, so as to calculate the ovaries and uterus indexes, mea-
PCOS
Pathological changes
sure serum LH/FSH ratio, P, PRL and INS levels, fixed the uterus and pancreas in 10% formalin solution and
Dodder total flavone stained with HE to observe the morphological changes of the organs. And measure the expression of TNF-
Biochemical indicators a and IGF-l proteins in ovaries by immunohistochemistry.
Results: Compared with the blank group, ovarian and uterine indexes, serum LH/FSH ratio, serum PRL and
INS levels, ovary TNF-a and IGF-l protein expression were significantly increased, and significant patho-
logical changes were observed in the uterine and pancreatic tissues in model group (P < 0.01). While the
serum P level decreased significantly (P < 0.01), Compared with the model group, the ovarian and uterine
indexes, serum LH/FSH ratio, serum P, PRL and INS levels, ovary TNF-a protein expression were signifi-
cantly decreased in large, middle and small dose dodder total flavonoids groups (P < 0.01); The expression
of IGF-1 protein was decreased and uterus pathological changes were improved in different extents
(P < 0.01 or P < 0.05), pancreas pathological changes were improved significantly (P < 0.01).
Conclusion: PCOS rat models was successfully replicated. Dodder total flavone can protect PCOS rats
induced by DHEA combined HCG by different action pathways.
Ó 2019 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction inflammatory reaction (Jamilian), obesity (Rezvan et al., 2018),

abnormal ovarian function and hyperpuberty are the etiology
Polycystic ovary syndrome (PCOS) is a reproductive endocrine and pathogenesis of PCOS (Leng and Wei, 2018; Zuo and Fu,
metabolic disorder characterized by insulin resistance accompa- 2018). PCOS belongs to the category of ‘‘late menstruation” and
nied by persistent ovulation disorder and hyperandrogenemia ‘‘amenorrhea” in traditional Chinese medicine (TCM). In TCM,
(Elbohoty Ahmed et al., 2016). Western medicine believes that ovum is called ‘‘reproductive sperm”, TCM believes that kidney
genetic factors, high luteinizing hormone, glycolipid metabolism storage sperm, leading to menstrual production. Deficiency of kid-
disorder (Daghestani, 2018), hyperinsulinemia and insulin resis- ney leads to deficiency of qi, blood and liver qi stagnation. In turn,
tance (Giandalia), hyperandrogenemia (Li et al., 2018), low degree it leads to spleen apoplexy, which leads to different TCM syn-
dromes of PCOS. Based on clinical data mining, kidney deficiency
ranks first among the TCM syndromes of PCOS, and is often accom-
⇑ Corresponding author. panied by blood deficiency, blood stasis, liver depression and other
E-mail address: miaomingsan@163.com (M. Miao). syndromes (Huang et al., 2018). TCM emphasizes the combination
Peer review under responsibility of King Saud University. of dialectic and disease differentiation. For the root cause of PCOS
disease is kidney deficiency, it is necessary to use Chinese medicine
to supplement kidney for intervention. Dodder is a kind of tradi-
tional Chinese medicine commonly used in the treatment of PCOS.
Production and hosting by Elsevier Studies have shown that its main chemical component flavonoids

https://doi.org/10.1016/j.sjbs.2019.02.007
1319-562X/Ó 2019 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
822 M. Miao et al. / Saudi Journal of Biological Sciences 26 (2019) 821–827

can have a multidirectional effect on the endocrine function of domly divided into model group, dacin-35 group (0.3392 mg
kg 1),
hypothalamic-pituitary-gonads, such as improving the level of large, middle and small dose dodder total flavonoids groups
estrogen in the body, protecting spermatogenic cells of male rats, (200 mg
kg 1, 100 mg
kg 1, 50 mg
kg 1), 10 in each group, and
and improving glycolipid metabolism (Zhao et al., 2018; Ren given the medicine for three weeks. The blank group and the model
et al., 2018; Huang et al., 2016). However, there is no relevant group were given the same amount of solvent.
research report on the intervention of total flavonoids from dodder
in PCOS. Exogenous increase of DHEA level can create a high andro- 3.2. Test indicators and methods
gen state in patients with polycystic ovary syndrome, resulting in
decreased secretion of follicle-stimulating hormone in the body, Two hours after the last administration, draw blood from
follicular development blocked, follicular atresia and lack of ovula- abdominal aorta, and serum was separated to measureLH/FSH
tion (Liu et al., 2018). HCG can play the role of LH, and can simulate ratio, P, PRL and INS. Ovaries and uterus were weighed so as to cal-
the high LH environment in patients with polycystic ovary syn- culate viscera index. Uterus and pancreas were fixed in 10% forma-
drome (PCOS) due to gonadal axis disorder, aggravating the PCOS lin solution for HE staining and observe morphological changes.
secretion disorder. Therefore, making the PCOS rats induced by The aprotein expression of TNF-a and IGF-l in the ovary was mea-
DHEA combined with HCG as the research object, to observe the sured by immunohistochemistry.
effect of total flavonoids of dodder on PCOS rats.
4. Statistical methods
2. Experimental materials
SPSS21.0 statistical software was used to statistically process
2.1. Drugs and reagents the experimental results. The measurement data are expressed as
mean value ± standard deviation (x ± s). Single factor analysis of
Dodder total flavone, Nanjing zelang biotechnology co. LTD, the variance was used for inter-group comparison. The homogeneity
total flavonoid content of dodder was 51.25% by UV detection. of variance was tested by LSD method, and the heterogeneity of
Diane-35 (Ethinylestradiol and Cyproterone Acetate Tablets), variance was tested by Games-Howell method. The hierarchical
Schering GmbHCo. Produktions KG, batch no:333A; Dehy- data is validated with Ridit.
droepiandrosterone (DHEA), Aladdin, batch no: B1227012; Human
chorionic gonadotropin (HCG), Hangzhou animal medicine factory,
5. Experimental results
batch no: 161008, Veterinary drug approval number: veterinary
drug (2010) 110201281.
5.1. Effect of dodder total flavone on ovary index and uterus index of
Anti-GnRH, Anti-GnRH-R and Anti-TNF-a polyclonal antibody,
PCOS rat models induced by DHEA combined HCG
Beijing boorson biotechnology co. LTD, batch no: AC12243558S,
AF11177594S and AG06274 154S; Anti-AR polyclonal antibodies,
As shown in Table 1: Compared with the blank group, the ovary
Abcam. Batch number: GR310012-4; Peroxidase labeled sheep
index and uterus index of the model group were significantly
rabbit-IgG ii-antibody, Wuhan bode bio-engineering co. LTD, batch
increased (P < 0.01). Compared with the model group, dacin-35
no: BST12E27C55; Detection kits for LH, FSH, P, PRL and INS ELISA
group, large, middle and small dose dodder total flavonoids groups
in rats, Suzhou Calvin biotechnology co. LTD, batch no:
could significantly reduce the ovary index and uterus index of
20170623SR. Anti-IGF-1 polyclonal antibody, Wuhan bode bio-
PCOS rats (P < 0.01).
engineering co. LTD, Batch no: BST10E21C 54.
5.2. Effect of dodder total flavone on serum LH/FSH ratio of PCOS rat
2.2. Experimental animals models induced by DHEA combined HCG

SD rats, SPF level, male, 23 days old, 70 subjects. Jinan Pengyue As shown in Table 2: Compared with the blank group, the serum
experimental animal breeding co, LTD. License no: SCXK (lu) LH/FSH ratiol in the model group increased significantly (P < 0.01).
20150005; Animal certificate no: 37009200006387; Training cer- Compared with the model group, the serum LH/FSH ratio in the
tificate no: 1612; Animal facilities use certificate no: 00013517. dacin-35 group, large, middle and small dose dodder total flavo-
noids groups decreased significantly (P < 0.01).
2.3. Experimental apparatus
5.3. Effect of dodder total flavone on serum P, PRL and INS levels of
BX61 electric microscope, OLYMPUS, Japan; AR1140/C elec- PCOS rat models induced by DHEA combined HCG
tronic analytical balance, Ohaos (Shanghai) co. LTD; Type 680
enzyme marker, Bio-rad company, USA; KDC-160HR high speed As shown in Table 3: Compared with the blank group, PRL and
refrigerating centrifuge, Hkust innovation LTD; TGL-168, high- INS levels in the serum of the model group increased significantly
speed table centrifuge, Shanghai anting science instrument fac- (P < 0.01), serum P level decreased significantly (P < 0.01). Com-
tory; HWS12 electric thermostat water bath, Shanghai yiheng sci- pared with the model group, the serum PRL and INS levels
entific instruments co. LTD. decreased significantly (P < 0.01), P level increased significantly
in (P < 0.01).
3. Experimental method
5.4. Effect of dodder total flavone on TNF-a and IGF-l protein
3.1. Moldeling and drug delivery (Miao et al., 2018) expression in ovariary of PCOS rat models induced by DHEA combined
HCG
Ten rats were randomly selected as the blank group, the rest of
the rats were injected with DHEA 6 mg/100 g on the back of the As shown in Table 4: Compared with the blank group, the mean
neck and 1.5 IU HCG each day, for 21 consecutive days. On the optical density of TNF-a and IGF-l protein in ovary of the model
16th day of modeling, vaginal smear was performed to select the group increased significantly (P < 0.01). Compared with the model
model rats. Rats with successful modeling were selected and ran- group, the mean optical density of TNF-a and IGF-l in ovary was
 M. Miao et al. / Saudi Journal of Biological Sciences 26 (2019) 821–827 823

Table 1
Effect of dodder total flavone on ovary index and uterus index of PCOS rat models induced by DHEA combined HCG.

Group n Dose (mg/kg) Uterus index (mg/g) Ovary index (mg/g)

Blank group 10 — 1.08 ± 0.17 0.45 ± 0.06
Model group 10 — 2.35 ± 0.27DD 0.56 ± 0.08DD
Dacin-35 group 10 0.339 1.04 ± 0.21** 0.43 ± 0.07**
Dodder total flavone 10 200 1.05 ± 0.15** 0.45 ± 0.07**
10 100 1.05 ± 0.07** 0.42 ± 0.07**
10 50 1.05 ± 0.10** 0.47 ± 0.07**

Note: Compared to the blank group, Drepresents P < 0.05, DD

represents P < 0.01; Compared to the model group, *represents P < 0.05, **represents P < 0.01.

Table 2
The uterine tissues of each group were measured according to
Effect of dodder total flavone on serum LH/FSH ratio of PCOS rat models induced by
DHEA combined HCG. the semi-quantitative standard, and the results were shown in
Table 5.
Group n Dose (mg/kg) LH/FSH
As shown in Table 5: By Ridit test, the uterine endometrium of
Blank group 10 — 3.55 ± 0.28 rats in the blank group was normal. Compared with the blank
Model group 10 — 4.68 ± 0.66DD
group, the endometrial glands showed significant hyperplasia
Dacin-35 group 10 0.339 3.61 ± 0.28**
Dodder total flavone 10 200 3.64 ± 0.33** and inflammatory infiltration in the model group (P < 0.01). Com-
10 100 3.80 ± 0.39** pared with the model group, the pathological changes of uterus
10 50 3.94 ± 0.54** in rats was significantly improved in the dacin-35 group, large,
Note: Compared to the blank group, Drepresents P < 0.05, DDrepresents P < 0.01;
middle dose dodder total flavonoids groups (P < 0.01), small dose
Compared to the model group, *represents P < 0.05, **represents P < 0.01. dodder total flavonoids group could obviously improve the patho-
logical changes of uterus in rats (P < 0.05).

significantly decreased in the dacin-35 group, large, middle dose

dodder total flavonoids groups (P < 0.01), small dose dodder total 5.6. Effect of dodder total flavone on islet tissue of PCOS rat models
flavonoids group could significantly reduce the mean optical den- induced by DHEA combined HCG
sity of TNF-a in ovary (P < 0.01) and obviously reduce the mean
optical density of IGF-l (P < 0.01). Pathological observation of islet tissue in rats (see Fig. 2): In
the blank group, the islet shape and structure of the rat pancreas
were normal, and the cells were arranged in a compact and
5.5. Effect of dodder total flavone on uterine tissue of PCOS rat models orderly manner. In the model group, abnormal lesions appeared
induced by DHEA combined HCG in pancreatic islet tissue. It suggests that patients with polycystic
ovary syndrome may have islet tissue lesions, and islet lesions
Pathological observation of uterine tissue in rats (see Fig. 1): In may also promote the occurrence of polycystic ovary syndrome
the blank group, endometrial glands were normal, papillary through relevant mechanisms, aggravating the patient’s condi-
arrangement, covered by a single layer of columnar epithelium. tion. Under the light microscope, it is obvious that the islet vol-
The nuclei were arranged in a neat arrangement, and no nuclear ume of PCOS model group is larger than that of the blank
consolidation or nuclear fragmentation was observed. In the model group. However, the islet volume of each group which were given
group, endometrial glandular hyperplasia, with microscopic pseu- drugs decreased significantly. The pancreas of each group of ani-
doplastic columnar epithelium. At magnification, the nuclei are mals was selected to measure 10 pancreas islets, and the mean
prominent but mostly fragmented, and inflammatory cells such value of the widest and narrowest part of the pancreas was
as neutrophils can be seen in the field of view. In the dacin-35 obtained by measuring microscale, then the diameter of the pan-
group, endometrial glands were irregular or tubular arrangement, creas islet was obtained, and the measured results were shown in
covered by a single layer of columnar epithelium, nuclei arranged Table 6.
neatly. In the large and middle dose dodder total flavonoids group, The uterine tissues of each group were measured according to
the glands were normal, papillary arrangement, and no inflamma- the semi-quantitative standard, and the results were shown in
tory cells were seen. In the small dose dodder total flavonoids Table 5.
group, endometrial gland was slightly hyperplasia, and the glands As shown in Table 5: Compared with the blank group, the pan-
are mostly papillary and tubular arrangement. The nuclei were creatic islet diameter in the model group increased significantly
arranged in a neat order, but the nucleoli were not obvious. A small (P < 0.01). Compared with the model group, dacin-35 group, large,
number of inflammatory cells can be seen in the stroma below the middle and small dose dodder total flavonoids groups could signif-
horizon. icantly reduced the diameter of pancreatic islets (P < 0.01).

Table 3
Effect of dodder total flavone on serum P, PRL and INS levels of PCOS rat models induced by DHEA combined HCG (x±s, n = 10).

Group n Dose (mg/kg) P (ng/mL) PRL (ng/mL) INS (mU/L)

Blank group 10 — 19.68 ± 1.19 26.18 ± 1.57 27.39 ± 2.66
Model group 10 — 17.59 ± 1.19DD 29.97 ± 1.83DD 30.60 ± 0.33DD
Dacin-35 group 10 0.339 19.47 ± 1.14** 26.45 ± 1.64** 27.96 ± 0.45**
Dodder total flavone 10 200 19.40 ± 1.18** 26.81 ± 1.26** 28.02 ± 1.18**
10 100 19.12 ± 1.02** 26.95 ± 1.39** 28.32 ± 1.48**
10 50 19.02 ± 1.08** 27.33 ± 1.93** 28.85 ± 0.90**

Note: Compared to the blank group, Drepresents P < 0.05, DD

represents P < 0.01; Compared to the model group, *represents P < 0.05, **represents P < 0.01.
824 M. Miao et al. / Saudi Journal of Biological Sciences 26 (2019) 821–827

Table 4
Effect of dodder total flavone on TNF-a and IGF-l protein expression in ovariary of PCOS rat models (mean light density).

Group n Dose (mg/kg) TNF-a IGF-1

Blank group 10 — 0.260 ± 0.018 0.203 ± 0.008
Model group 10 — 0.307 ± 0.015DD 0.222 ± 0.009DD
Dacin-35 group 10 0.339 0.256 ± 0.010** 0.201 ± 0.006**
Dodder total flavone 10 200 0.253 ± 0.015** 0.201 ± 0.005**
10 100 0.268 ± 0.023** 0.206 ± 0.010**
10 50 0.258 ± 0.019** 0.210 ± 0.011*

Note: Compared to the blank group, Drepresents P < 0.05, DD

represents P < 0.01; Compared to the model group, *represents P < 0.05, **represents P < 0.01.

A B C

D E F

Fig. 1. Effect of dodder total flavone on uterine tissue of PCOS rat models induced by DHEA combined HCG (A: Blank group; B: Model group; C: Dacin-35 group; D: Large dose
dodder total flavone group; E: Middle dose dodder total flavone group; F: Small dose dodder total flavone group).

Table 5
Effects on uterine tissue of PCOS rat models.

Group n Dose (mg/kg) + ++ +++

Blank group 10 — 10 0 0 0
Model group 10 — 0 1 7 2
Dacin-35 group 10 0.339 8 1 1 0
Dodder total flavone 10 200 6 3 1 0
10 100 5 3 2 0
10 50 4 4 1 1

‘‘ ” normal, endometrial gland epithelial cells in a single column, the surface of the villi arranged neatly; ‘‘+” glandular epithelial cells are basically normal, occasional
inflammatory cells, slight chronic inflammation; ‘‘++” glandular epithelial cells were mildly proliferated, a small number of uterine cavity or deep gland were dilated, most
inflammatory cells were observed, and moderate chronic inflammation was observed; ‘‘+++” glandular epithelial cell hyperplasia, most uterine cavity or deep gland dilate, a
large number of inflammatory cells, moderate-severe chronic inflammation.

6. Discuss der infertility, cause long-term complication such as amenorrhea,

glucose and lipid metabolism disorder, endometrial hyperplasia
The clinical manifestations of PCOS are highly heterogeneous, or cancer, endanger the long-term health of the body (Gui et al.,
and it is a chronic endocrine disorder with multiple causes and sys- 2018; Siddamalla et al., 2018). TCM emphasizes the combination
tems. PCOS can cause non-ovulation infertility and ovulation disor- of dialectic and disease differentiation. There is no unanimous con-
 M. Miao et al. / Saudi Journal of Biological Sciences 26 (2019) 821–827 825

A B C

D E F

Fig. 2. Effect of dodder total flavone on islet tissue of PCOS rat models induced by DHEA combined HCG (A: Blank group; B: Model group; C: Dacin-35 group; D: Large dose
dodder total flavone group; E: Middle dose dodder total flavone group; F: Small dose dodder total flavone group).

Table 6 The classification of PCOS in Chinese medicine and the rule of

Effect of dodder total flavone on islet tissue of PCOS rat models induced by DHEA drug use were summarized in the literature, the results showed
combined HCG (x ± s).
that kidney deficiency was widely considered to be the main patho-
Group n Dose (mg/kg) Islet diameter (lm) genic factor of the disease. And kidney-tonifying Yang medicinefre-
Blank group 10 — 142.28 ± 12.78 quently appeared in the treatment of the disease. However, the
Model group 10 — 241.52 ± 18.32DD clinical application of tonifying kidney-yang medicine in PCOS is
Dacin-35 group 10 0.339 153.07 ± 8.80** often combined with other drugs in the form of prescription. In
Dodder total flavone 10 200 177.24 ± 8.15**
order to further clarify the rationality of kidney-tonifying Chinese
10 100 178.83 ± 9.72**
10 50 182.08 ± 15.22** medicine intervention and treatment of PCOS, and confirm its effi-
cacy, it is necessary to study single Chinese medicine. In view of this
Note: Compared to the blank group, Drepresents P < 0.05, DDrepresents P < 0.01;
phenomenon, it is proposed to use kidney-tonifying Yang medicine
Compared to the model group, *represents P < 0.05, **represents P < 0.01.
to treat gynecological diseases. Based on different animal models to
confirm the curative effect of kidney-tonifying Yang medicine com-
clusion on the etiology and pathogenesis of PCOS. Most scholars monly used in clinical prescription, it has been found that Chinese
believe that renal, liver and spleen functions jointly influence medicine for kidney-yang has significant effects on perimenopausal
PCOS, and mostly treated from the perspective of kidney (Wang syndrome (Fu et al., 2018), perimenopausal depression (Liu et al.,
et al., 2017). Common TCM syndromes of PCOS include kidney defi- 2012), uterine dysplasia and dysmenorrhea. Dodder is a kind of tra-
ciency and blood stasis, kidney deficiency and sputum stasis, kid- ditional Chinese medicine commonly used for kidney-tonifying,
ney deficiency and phlegm dampness, and phlegm dampness which has many pharmacological effects, such as regulating immu-
block, kidney deficiency can be seen almost throughout the PCOS. nity, anti-aging, protecting liver, regulating reproductive system,
PCOS belongs to the categories of ‘‘infertility”, ‘‘amenorrhea”, protecting cardiovascular and cerebrovascular, lowering blood glu-
‘‘avulsion” and ‘‘menstrual disorder” in TCM. Systematic cluster cose. Flavonoids are its main active components (Miao et al., 2017).
analysis showed that gynecological diseases such as female infer- In this study, the polycystic ovary syndrome model of rats was
tility, menstrual disorder, amenorrhea, ovulation free, polycystic established by DHEA combined with HCG to explore the interven-
ovary syndrome in Chinese and western medicine were the first tion effect of total flavonoids of dodder on PCOS rats.
category of diseases related to kidney deficiency (Liu et al., PCOS patients have certain follicular excretion disorder, which
2012), which further verified the essence of kidney deficiency in to some extent leads to ovarian hyperplasia (Zhang et al., 2016;
PCOS patients. Throughout the history of Chinese medicine for var- Wang et al., 2012) and increased uterine volume. The total flavo-
ious gynecological diseases, there is no lack of application of Chi- noids of dodder could reduce ovarian and uterine indices, so as
nese medicine for tonifying kidney. In the treatment of PCOS, to improve the PCOS rat model. High LH/FSH (follicular stimulating
TCM mostly use the methods of tonifying kidney, which reflects hormone) level is one of the typical characteristics of PCOS. High
the principle of ‘‘regulating menstruation, must tonify kidney”. LH (luteinizing hormone) inhibits follicular stimulating hormone
826 M. Miao et al. / Saudi Journal of Biological Sciences 26 (2019) 821–827

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In conclusion, total flavonoids of dodder can decrease the ovary Miao, M.S., Tian, S., Guo, L., Bai, M., Fang, X.Y., Liu, S.Y., 2017. The effect of
and uterus index, affect the secretion of serum hormones (LH/FSH, curculigoside on mouse model of perimenopausal depression. Saudi J. Biol. Sci.
24 (8), 1894–1902.
PRL, INS and P), regulate ovarian protein expression (TNF-a and Miao, M.S., Peng, M.F., Yan, X.L., 2018. Effects of dodder total flavone on polycystic
IGF-1); improving endometrial hyperplasia, inflammatory infiltra- ovary syndrome rat models. Chin. J. Exp. Trad. Med. Formulae, 1–8. https://doi.
tion and islet tissue lesions, so as to achieve the protective effect org/10.13422/j.cnki.syfjx.20190506.
Ren, X.Q., Zheng, G.Z., Su, H., Zhang, X., Zhai, W.S., Tang, J.F., Li, W.X., Ding, Y., 2018.
on PCOS rat models induced by DHEA combined HCG. Influence of flavonoids from Cuscutae Semen on cell cycle arrest, apoptosis and
protein expression of spermatogenic cells induced by multi-glycoside from
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quercetin supplementation enhances adiponectin receptor transcript
This research was financially supported by NSFC (Natural expression in polycystic ovary syndrome patients: a randomized placebo-
Science Foundation of China: 81274154) and Zhong Yuan Scholars controlled double-blind clinical trial. Cell J. 19 (4), 627–633.
Seyam, Emaduldin, Hefzy, Enas, 2018. Long-term effects of combined simvastatin
(162101510003). and metformin treatment on the clinical abnormalities and ovulation
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