Inhibition of p53 Relieves Insulin Resistance in Fetal Growth Restriction Mice with Catch-Up Growth via Activating IGFBP3/IGF-1/IRS-1/Akt Signaling Pathway.

To investigate insulin resistance of the fetal growth restriction (FGR) mice with catch-up growth (CUG) and the underlying mechanism, in this study, low protein diet was used during pregnancy to establish the FGR mice model, and high fat diet was applied to establish the CUG model of FGR mice. The insulin and Pifithrin-α stimulation was performed via intraperitoneal injection. The physical characters, biochemical parameters, expression of related molecules in each group were detected via ELISA, RT-PCR, WB, etc. The results showed FBG, FINS and HOAM-IR in CUG-FGR group were higher than those in high fat feeding control group (NC+HF), but the content of IGF-1 in blood was lower than that in NC + HF group. Meanwhile, RT-PCR and WB showed that the expression of IGF was negatively correlated with the expression of P53/IGFBP3. Moreover, the expression of P-IRS/p-PI3K/p-Akt decreased with the increasing of HOAM-IR in IGF signaling pathway. When the mice were injected with Pifithrin-α, the phosphorylation level of IGF signaling pathway and insulin resistance index in the CUG-FGR group were increased and decreased, respectively. In conclusion, insulin resistance in CUG-FGR mice is correlated with the IGFBP3/IGF-1/IRS-1/Akt signaling pathway and inhibited p53 could activate this signaling pathway and relieve insulin resistance.

[Effect of metformin on insulin resistance during catch-up growth in mice with fetal growth restriction].

OBJECTIVE: To study the efficacy of metformin intervention on insulin resistance during catch-up growth in mice with fetal growth restriction (FGR). METHODS: Mouse models of FGR were established by low protein diet feeding of the pregnant mice. Both the newborn female mice with FGR and normal control (NC) mice were randomized for feeding with a standard diet (SF) or a high-fat diet (HF) after weaning and treatment with gavage of either metformin or normal saline. The mice were examined for vaginal opening time and the estrous cycle at the age of 8 weeks. At the age of 12 weeks, 6 mice in anestrus from each group were fasted for 12 h for measurement of body weight, height, poundera index (PI), fasting blood glucose (FBG), fasting insulin (Fins), follicle stimulating hormone (FSH) and anti-Mullerian hormone (AMH), and the HOMA-IR was calculated. The reproductive capacity of female mice was assessed by mixing them with male mice at the ratio of 2:1. The 3 × 2 factorial analysis was conducted to determine the interactions between FGR, high-fat feeding and metformin. RESULTS: Factorial analysis showed that FGR and high-fat feeding had significant effects on the PI index, Fins, HOMA-IR, vaginal opening time, and AMH (P<0.05). Metformin significantly affected the factors related to high-fat feeding including weight, PI, FPG, Fins, HOMA-IR and estrous cycle (P<0.05) and the factors related to FGR with the exception of height and FSH (P<0.05). FGR significantly affected the factors tested except for body weight (P<0.05); high-fat feeding affected all the factors but the FSH (P<0.05); metformin affected all the factors but the height and FSH (P<0.05). In the female mice treated with saline, the pregnancy rates differed significantly between FGR mice with high-fat feeding and control mice with standard feeding, and between FGR mice with standard feeding and high-fat feeding (P<0.05). CONCLUSION: FGR mice can present with delayed puberty with rare ovulation and adulthood insulin resistance, and high-fat feeding after birth can promote the catch-up growth of FGR mice. Metformin intervention is effective for improving insulin resistance and reproductive-endocrine disorders in FGR mice during catch-up growth.

[Relationship between fetal growth restriction and ovarian reserve in adulthood].

OBJECTIVE: To investigate the relationship between fetal growth restriction and decreased ovarian reserve (DOR) in adulthood to screen high-risk population for early interventions. METHODS: Forty-four patients with FGR and 88 normal women aged 18-40 years were enrolled. All the subjects were examined for serum levels of follicle-stimulating hormone (FSH), inhibin B (INH-B), and anti-mullerian hormone (AMH) using enzyme-linked immunosorbent assay method in the first 3-5 days of the menstrual cycle, and the counts of antrum ovarian follicle were detected by transvaginal or transabdominal ultrasonography. RESULTS: The serum levels FSH, INHB, AMH, and AFC in FGR group differed significantly from those in the control group (P<0.05). CONCLUSION: FGR will affect reproductive endocrine function in adulthood to cause a decreased ovarian reserve.

Requirement of miR-144 in CsA induced proliferation and invasion of human trophoblast cells by targeting titin.

MicroRNAs (miRNAs) are endogenous 19-25 nucleotide noncoding single-stranded RNAs that regulate gene expression by blocking the translation or decreasing the stability of mRNAs. In this study, with the treatment of CsA (Cyclosporin A), we showed that miR144 expression levels were decreased while titin mRNA expression levels were increased in human trophoblast (HT) cells, and identified titin as a novel direct target of miR-144. Overexpression of miR-144 suppressed titin and its downstream signaling molecule such as p-ERK1/2 and MMP2/9 expression, and attenuated cell proliferation and invasion. Forced expression of titin can partly rescue the inhibitory effect of miR-144 in the cells. Taken together, these findings will shed light to the role and mechanism of miR-144 in regulating HT cells proliferation and invasion via miR-144/titin axis, and miR-144 may serve as a potential therapeutic target in HT in the future.

Identification of genes and microRNAs involved in ovarian carcinogenesis.

MicroRNAs (miRNAs) play roles in the clinic, both as diagnostic and therapeutic tools. The identification of relevant microRNAs is critically required for ovarian cancer because of the prevalence of late diagnosis and poor treatment options currently. To identify miRNAs involved in the development or progression of ovarian cancer, we analyzed gene expression profiles downloaded from Gene Expression Omnibus. Comparison of expression patterns between carcinomas and the corresponding normal ovarian tissues enabled us to identify 508 genes that were commonly up-regulated and 1331 genes that were down-regulated in the cancer specimens. Function annotation of these genes showed that most of the up-regulated genes were related to cell cycling, and most of the down-regulated genes were associated with the immune response. When these differentially expressed genes were mapped to MiRTarBase, we obtained a total of 18 key miRNAs which may play important regulatory roles in ovarian cancer. Investigation of these genes and microRNAs should help to disclose the molecular mechanisms of ovarian carcinogenesis and facilitate development of new approaches to therapeutic intervention.

[Morbidity regularity of severe complications of hypertensive disorder complicating pregnancy in clinics].

OBJECTIVE: To analyse incidence of the severe complications of hypertensive disorder complicating pregnancy and the influence on the outcome of pregnancy. METHODS: A retrospective study of 4107 cases among 71 020 cases who delivered in hospitals from 1995 to 2004 in Guangzhou was conducted. RESULTS: The morbidity of hypertensive disorder complicating pregnancy was 5.78%, in which the morbidity of severe pre-eclampsia was 27.78% (1141/4107), of mitis pre-eclampsia was 72.22% (2966/4107). Maternal mortality rate was 0.19% (8/4107), and the specific mortality rate was 11.26/100 000. The proportion of severe complications of hypertensive disorder complicating pregnancy from high to low was as follows: placental abruption 1.68% (69/4107), DIC 1.36% (56/4107), hypertensive disorder complicating pregnancy induced cardiopathy (induced cardiopathy) 1.05% (43/4107), renal failure 0.97% (40/4107), cerebrovascular accident 0.58% (24/4107), and hemolysis, elevated liver enzymes and low platelet (HELLP) syndrome 0.51% (21/4107). Mortality caused by severe complications of hypertensive disorder complicating pregnancy were as follows: cerebrovascular accident 17% (4/24), HELLP syndrome 10% (2/21), DIC 5% (3/56) and induced cardiopathy 2% (1/43). The proportion of perinatal mortality from severe complications were as follows: placental abruption 43% (33/77), HELLP syndrome 42% (10/24), DIC 34% (22/64), renal failure 25% (11/44), cerebro vascular accident 24% (6/25) and induced cardiopathy 16% (8/49). CONCLUSIONS: (1) The morbidity of severe complications from high to low are: placental abruption, DIC, induced cardiopathy, renal failure, cerebro vascular accident and HELLP syndrome. (2) The main causes of mortality for gravida and puerperant are: cerebro vascular accident, HELLP syndrome, DIC and induced cardiopathy. (3) The major complications harmful to perinatal newborns are in the order of: placental abruption, HELLP syndrome, DIC, renal failure, cerebro vascular accident and induced cardiopathy.

[Clinical application of GnRHa before uterine myomectomy: report of 20 cases].

OBJECTIVE: To study the clinical application of GnRHa prior to uterine myomectomy and its effect on the clinical outcome of pregnancy. METHODS: A retrospective review of the medical records in 20 cases of uterine myomectomy over a period of 6 years was performed. The changes of uterus and myoma volumes in response to preoperative GnRHa was observed, and the rate of relapse in the follow-up, time of impregnation, spontaneous abortion after the impregnation, time of delivery after the operation and the aura threatening uterine rupture, and uterine rupture during the delivery were assessed. RESULTS: Application of GnRHa produced significant improvement in the clinical symptoms and resulted in obviously reduced volumes of the uterus and myoma. The myoma volume reduction was close to 50% in these cases, and relapse occurred in only 1 case. No spontaneous abortion was found after GnRHa application. The average time of pregnancy was 34+/-3.5 weeks, and aura for uterine rupture was found in 1 case at 33 weeks of pregnancy after GnRHa application. CONCLUSION: Application of GnRHa can correct anemia, decrease the relapse rate of myoma, reduce uterus and myoma volumes, to make possible smaller incision for uterine myomectomy that leaves smaller scar in the uterus and decrease intraoperative bleeding, also relieving endometrial injuries to promote the conditions for impregnation and minimize the risks of uterine rupture and total hysterectomy for the benefit of normal delivery.