Endometriosis is a common chronic gynecological disease and leads to continuous aggravation of pelvic adhesion, pain and infertility, which seriously affects women's fertility and quality of life. Studies related to vitamin D and endometriosis have received increasing attention, the response of vitamin D in target organs depends on the expression level and biological function of vitamin D receptor (VDR). Thus, the function and characteristics of VDR were summarized in this study, and the expression level, gene polymorphism, mechanism of VDR in endometriosis and the research progress of VDR agonists in the treatment of endometriosis were reviewed, providing new ideas for basic and clinical research on diagnosis and treatment of endometriosis.

Objective:To investigate the effect of endometriosis (EMT) on oocytes, embryo quality and pregnancy and delivery outcomes in infertility patients treated with in vitro fertilization/intracytoplasmic sperm injection and embryo transfer (IVF/ICSI-ET). Methods:A retrospective cohort study was conducted to select the EMT patients (383 cases, EMT group) and the infertility patients with tubal factor (1 613 cases, control group) who underwent IVF/ICSI-ET treatment in the Department of Reproductive Medicine, the First Affiliated Hospital of Harbin Medical University from January 2016 to December 2023. The cases were matched with the number of age, body mass index, anti-Müllerian hormone, proportion of infertility type, duration of infertility, ovulation stimulating therapy, insemination mode, number of previous IVF/ICSI cycles of the two groups by 1∶1 propensity score matching. Totally 285 patients with EMT and 285 patients in control group were finally included to analyze the effects of EMT on embryo quality and pregnancy outcome.Results:1) There were no statistically significant differences in the duration of gonadotropin (Gn) used, the total dosage and the initiating dosage of Gn used, and the levels of estradiol, luteinizing hormone, and progesterone on the human chorionic gonadotropin (hCG) injection day between the two groups (all P>0.05). 2) The total number of oocytes (7.48±5.15), the number of MⅡ oocytes (6.38±4.61), the number of transferable embryos (4.16±3.16), the number of high-quality embryos [2.00 (0.00, 3.00)] and the rate of two pronuclei (2PN) high-quality embryos [42.33% (602/1 422)] in EMT group were all lower than those in control group [8.45±4.86, P=0.021; 7.32±4.43, P=0.013; 4.95±3.19, P=0.003; 2.00 (1.00, 4.00), P=0.002; 48.76% (747/1 532), P=0.032], the differences were statistically significant. 3) There were no statistically significant differences in clinical pregnancy rate, embryo implantation rate, premature birth rate, early abortion rate, ectopic pregnancy rate, male/female ratio, number of weeks of delivery and cesarean section rate between the two groups with fresh cycle transplantation and with embryo freezing in fresh cycle and embryo transferred in the first resuscitation cycle (all P>0.05), the live birth rate of EMT patients with fresh cycle transplantation [29.71% (41/138)] was lower than that of control group [48.90% (89/182), P=0.023], and the difference was statistically significant. 4) EMT was not an independent factor of clinical pregnancy rate and live birth rate after IVF/ICSI treatment, but age and number of embryos transferred were independent factors of clinical pregnancy rate and live birth rate of IVF/ICSI treatment ( OR=0.923, 95% CI: 0.868-0.982, P=0.011; OR=0.890, 95% CI: 0.832-0.952, P=0.001; OR=2.408, 95% CI: 1.331-4.356, P=0.004; OR=3.838, 95% CI: 1.869-7.879, P<0.001). Conclusion:EMT may reduce the number of oocytes and MⅡ oocytes in infertility patients treated with IVF/ICSI-ET, and the quality of embryos in patients with EMT treated with IVF is worse, but it does not affect the clinical pregnancy outcome and delivery outcome in patients with EMT.

Endometriosis is a common chronic gynecological disease and leads to continuous aggravation of pelvic adhesion, pain and infertility, which seriously affects women's fertility and quality of life. Studies related to vitamin D and endometriosis have received increasing attention, the response of vitamin D in target organs depends on the expression level and biological function of vitamin D receptor (VDR). Thus, the function and characteristics of VDR were summarized in this study, and the expression level, gene polymorphism, mechanism of VDR in endometriosis and the research progress of VDR agonists in the treatment of endometriosis were reviewed, providing new ideas for basic and clinical research on diagnosis and treatment of endometriosis.

Objective:To investigate the effect of endometriosis (EMT) on oocytes, embryo quality and pregnancy and delivery outcomes in infertility patients treated with in vitro fertilization/intracytoplasmic sperm injection and embryo transfer (IVF/ICSI-ET). Methods:A retrospective cohort study was conducted to select the EMT patients (383 cases, EMT group) and the infertility patients with tubal factor (1 613 cases, control group) who underwent IVF/ICSI-ET treatment in the Department of Reproductive Medicine, the First Affiliated Hospital of Harbin Medical University from January 2016 to December 2023. The cases were matched with the number of age, body mass index, anti-Müllerian hormone, proportion of infertility type, duration of infertility, ovulation stimulating therapy, insemination mode, number of previous IVF/ICSI cycles of the two groups by 1∶1 propensity score matching. Totally 285 patients with EMT and 285 patients in control group were finally included to analyze the effects of EMT on embryo quality and pregnancy outcome.Results:1) There were no statistically significant differences in the duration of gonadotropin (Gn) used, the total dosage and the initiating dosage of Gn used, and the levels of estradiol, luteinizing hormone, and progesterone on the human chorionic gonadotropin (hCG) injection day between the two groups (all P>0.05). 2) The total number of oocytes (7.48±5.15), the number of MⅡ oocytes (6.38±4.61), the number of transferable embryos (4.16±3.16), the number of high-quality embryos [2.00 (0.00, 3.00)] and the rate of two pronuclei (2PN) high-quality embryos [42.33% (602/1 422)] in EMT group were all lower than those in control group [8.45±4.86, P=0.021; 7.32±4.43, P=0.013; 4.95±3.19, P=0.003; 2.00 (1.00, 4.00), P=0.002; 48.76% (747/1 532), P=0.032], the differences were statistically significant. 3) There were no statistically significant differences in clinical pregnancy rate, embryo implantation rate, premature birth rate, early abortion rate, ectopic pregnancy rate, male/female ratio, number of weeks of delivery and cesarean section rate between the two groups with fresh cycle transplantation and with embryo freezing in fresh cycle and embryo transferred in the first resuscitation cycle (all P>0.05), the live birth rate of EMT patients with fresh cycle transplantation [29.71% (41/138)] was lower than that of control group [48.90% (89/182), P=0.023], and the difference was statistically significant. 4) EMT was not an independent factor of clinical pregnancy rate and live birth rate after IVF/ICSI treatment, but age and number of embryos transferred were independent factors of clinical pregnancy rate and live birth rate of IVF/ICSI treatment ( OR=0.923, 95% CI: 0.868-0.982, P=0.011; OR=0.890, 95% CI: 0.832-0.952, P=0.001; OR=2.408, 95% CI: 1.331-4.356, P=0.004; OR=3.838, 95% CI: 1.869-7.879, P<0.001). Conclusion:EMT may reduce the number of oocytes and MⅡ oocytes in infertility patients treated with IVF/ICSI-ET, and the quality of embryos in patients with EMT treated with IVF is worse, but it does not affect the clinical pregnancy outcome and delivery outcome in patients with EMT.

Objective:To analyze the prevalence and disease burden of male and female infertility in China from 1990 to 2019.Methods:The global disease burden database of 2019 was used to analyze the prevalence of male and female infertility and disability adjusted life years (DALY) in China from 1990 to 2019 among the total Chinese male and female population and different age groups.Results:In 2019, the number, prevalence, DALY and DALY rate of male infertility in China were 14 577 432, 2 011.18/100 000, 77 983 person years, 1 076/100 000, respectively. The number, prevalence, DALY and DALY rate of female infertility were 37 884 300, 5 431.22/100 000, 197 046 person years, 28.25/100 000, respectively. The prevalence and disease burden of female infertility were higher than those of male infertility. The age group with the highest male prevalence rate and DALY rate were 35-39 and 30-34 years old respectively, the age group with the highest female prevalence rate and DALY rate were 40-44 and 35-39 years old respectively, and the age group with the highest female prevalence rate and DALY rate was 5 years later than the male age group. From 1990 to 2019, the prevalence rate and DALY rate of male and female infertility increased in the first 20 years or so, and decreased in the last 10 years or so. The prevalence rate and DALY rate of male and female infertility in China were significantly higher than those in the whole world and different socio-demographic index (SDI) regions.Conclusion:Although the prevalence rate and DALY rate of male and female infertility in China have decreased in recent years, the population base of China is large, and the disease burden of male and female infertility in the world is still large. Active prevention and treatment measures should be taken to reduce the disease burden of male and female infertility.

Objective:To analyze the prevalence and disease burden of male and female infertility in China from 1990 to 2019.Methods:The global disease burden database of 2019 was used to analyze the prevalence of male and female infertility and disability adjusted life years (DALY) in China from 1990 to 2019 among the total Chinese male and female population and different age groups.Results:In 2019, the number, prevalence, DALY and DALY rate of male infertility in China were 14 577 432, 2 011.18/100 000, 77 983 person years, 1 076/100 000, respectively. The number, prevalence, DALY and DALY rate of female infertility were 37 884 300, 5 431.22/100 000, 197 046 person years, 28.25/100 000, respectively. The prevalence and disease burden of female infertility were higher than those of male infertility. The age group with the highest male prevalence rate and DALY rate were 35-39 and 30-34 years old respectively, the age group with the highest female prevalence rate and DALY rate were 40-44 and 35-39 years old respectively, and the age group with the highest female prevalence rate and DALY rate was 5 years later than the male age group. From 1990 to 2019, the prevalence rate and DALY rate of male and female infertility increased in the first 20 years or so, and decreased in the last 10 years or so. The prevalence rate and DALY rate of male and female infertility in China were significantly higher than those in the whole world and different socio-demographic index (SDI) regions.Conclusion:Although the prevalence rate and DALY rate of male and female infertility in China have decreased in recent years, the population base of China is large, and the disease burden of male and female infertility in the world is still large. Active prevention and treatment measures should be taken to reduce the disease burden of male and female infertility.

Objective: To investigate the relationship of National Institute of Health Stroke Scale(NIHSS)with heart rate variability(HRV)and cardiac complication in elderly patients with acute cerebral infarction, and to clarify the effect of early drug intervention on the regulation of autonomic nerve function in patients with high NIHSS score. Methods: One hundred twenty-six inpatients with first-onset acute cerebral infarction(ACI)(the cerebral infarction group)and 40 healthy subjects with no history of stroke(the control group)were retrospectively enrolled.All subjects underwent examinations of NIHSS and 24 h dynamic electrocardiogram.According to NIHSS score, patients in the cerebral infarction group were divided into 3 subgroups: NIHSS score 0-4 group(n=32), NIHSS score 5-15 group(n=66)and NIHSS score ≥ 15 group(n=28). The difference in HRV parameters were compared between ACI patients and the controls.Ninety-four ACI patients with NIHSS score ≥5 were randomly divided into 2 groups: (1)the traditional treatment group(n=44), taking routine drugs for cerebral infarction; (2)the special treatment group(n=42), taking metoprolol sustained release tablet and Shensonyangxin capsule as add-on to the routine drugs for cerebral infarction.The 24 h dynamic electrocardiogram examination were conducted 30 days after treatment.The differences in HRV parameters and cardiac complications were compared between the two treatment groups. Results: In patients with acute cerebral infarction, the time-domain parameters of normal-to-normal intervals(NNI), standard deviation of normal-to-normal intervals(SDNN), square root of the mean squared successive differences between normal-to-normaI RR intervals(RMSSD), percentage of adjacent normal-to-normal intervals that differed more than 50 ms(PNN50), frequency domain parameters low-frequency(LF)power and high-frequency(HF)power were significantly reduced as compared with those in the control group(P<0.05). While, pulse rate and frequency domain parameters of sympathetic vagus balance index(LF/HF)were significantly increased(P<0.05). The time-domain parameters(NNI, SDNN, RMSSD and PNN50)and frequency domain parameters(LF, HF)were significantly reduced in the NIHSS score 5-15 group and NIHSS score ≥15 group as compared with the control group and the NIHSS score 0-4 group(P<0.05). The time-domain parameters(RMSSD and PNN50)and frequency domain parameters(LF and HF)were reduced(P<0.05), and the frequency domain parameters(LF/HF)were increased(P<0.05)in NIHSS score ≥15 group compared with in NIHSS score 5-15 group(P<0.05). Compared with pre-treatment, the special treatment group after treatment showed that the time domain parameters(NNI, SDNN, RMSSD and PNN50)and frequency domain parameters(LF and HF)were significantly increased(P<0.05), the frequency domain parameters(LF/HF)were significantly reduced(P<0.05)and the incidence of cardiac complication(total incidence of atrial arrhythmias and ventricular arrhythmias and cardiac complication)were significantly reduced(P<0.05). As compared with the traditional treatment group after treatment, the special treatment group after treatment showed that the time domain parameters(NNI, SDNN, RMSSD and PNN50)and frequency domain parameters(LF and HF)were significantly increased(P<0.05), frequency domain parameters(LF/HF)were significantly reduced(P<0.05)and the total incidence of cardiac complication were significantly reduced(18.4% or 7 cases vs.40.0% or 16 cases, P<0.05). Conclusions The HRV is decreased in patients with acute cerebral infarction.The reduction degree of HRV is more significant along with the higher NIHSS scores, which suggests that patients with high NIHSS scores are prone to an impairment of autonomic nerve function.For patients with high NIHSS scores after stroke, early drug intervention for regulating autonomic nerve function can effectively prevent the occurrence of cardiac emergencies and improve the prognosis of stroke.

Objective To investigate the role and mechanism of the regulation of nuclear factor-κB (NF-κB) by heparin binding-epidermal growth factor-like growth factor (HB-EGF) in paclitaxel resistance of ovarian cancer in vitro and in vivo. Methods (1) The detection of NF-κB expression: parental (A2780) and paclitaxel-resistant (A2780/Taxol) ovarian carcinoma cells were divided into four groups, named A2780 group, A2780+cross-reacting material 197 (CRM197, HB-EGF inhibitor) group, A2780/Taxol group and A2780/Taxol+CRM197 group. Among four groups, the expression level HB-EGF and epidermal growth factor receptor (EGFR) were examined by immunofluorescence double staining on confocal microscopy. Western blot was used to detect the expression level of NF-κB. In vivo, A2780 and A2780/Taxol cells were injected intraperitoneally to nude mouse to determine the expression level of NF-κB of the tumors from these four groups by immunohistochemistry method. (2) The detection on the function of NF-κB: A2780/Taxol cells were divided into four groups, named transfected with empty vector+saline group, NF-κB small interference RNA (siRNA)+saline group, empty vector+CRM197 group and NF-κB siRNA+CRM197 group respectively. Among four groups, the 50% inhibitory concentrations (IC50) of A2780/Taxol cells to paclitaxel, the expression level of plasma membrane glycoprotein (P-gp) and the effect of intracellular rhodomine123 (Rh123) accumulation were detected. Results (1) The detection of NF-κB expression: the expression scores of HB-EGF protein among four groups were 5.6±1.3, 2.1±1.2, 11.7±3.5 and 6.2±1.4; the expression scores of EGFR protein were 5.1±1.6, 2.8±0.6, 10.4±3.1 and 5.6±1.9, respectively. The expression levels of NF-κB protein in the cells of the group named A2780, A2780+CRM197, A2780/Taxol and A2780/Taxol+CRM197 group were 1.89±0.23, 0.74±0.12, 3.45±0.16 and 1.31±0.08, respectively; the expression scores of NF-κB protein in the tissue tumors from four groups were 3.3±1.1, 1.4±0.4, 8.7±2.3 and 3.6±1.2, respectively. The expression level of HB-EGF, EGFR and NF-κB protein between A2780 and A2780/Taxol groups in vivo and in vitro were higher than these in A2780+CRM197 and A2780/Taxol+CRM197 group, while the expression level of HB-EGF, EGFR and NF-κB protein in A2780 group were lower than those in A2780/Taxol groups in vivo and in vitro (P＜0.05). (2) The examination of NF-κB function: the IC50 of A2780/Taxol cells to paclitaxel in groups transfected with empty vector+saline, NF-κB siRNA+saline, empty vector+CRM197 and NF-κB siRNA+CRM197 group were respectively (39.4±0.8), (7.6±0.6), (6.7±0.5) and (4.2±0.4) μmol/L, while the expression levels of P-gp protein among four groups were respectively 3.11±0.23,1.45±0.16, 1.73± 0.21 and 0.68±0.14, the cellular Rh123 accumulation among four groups were respectively 110±15, 246±19, 231 ± 22 and 296 ± 24. The expression levels of IC50 and P-gp protein in groups transfected with NF-κB siRNA+saline, empty vector+CRM197 and NF-κB siRNA+CRM197 group were significantly higher than those in group transfected with empty vector+saline group (P<0.01), while the cellular Rh123 accumulation among three groups were significantly lower than that in group transfected with empty vector+saline (P<0.01). Conclusions The expression of NF-κB may contributes to the paclitaxel resistance to ovarian cancer. HB-EGF may induce the paclitaxel resistance of ovarian cancer by the regulation of EGFR/NF-κB/P-gp pathway.

Objective To investigate the effect and mechanism of CRM197, the heparin binding-epidermal growth factor-like growth factor (HB-EGF) inhibitor, on the reverse of the resistance ofovarian cancer to paclitaxel. Methods (1)The effect of CRM197 on the 50% inhibitory concentrations (IC50) of human ovarian carcinoma cell line A2780 and paclitaxel-resistant ovarian carcinoma cell line A2780/Taxol was tested by methyl thiazolyl tetrazolium (MTT) assay. Western blot was used to detect the effect of CRM197 on the expression of HB-EGF,epidermal growth factor receptor (EGFR) and plasma membrane glycoprotein (P-gp) protein in A2780 and A2780/Taxol cells. Real-time PCR was used to examine the MDR1 mRNA expression in these cells. (2) A2780/Taxol cells were divided into 4 groups, including the cells transfected with empty vector and saline treatment (empty vector group), MDR1 small interference RNA (siRNA)vector and saline treatment (MDR1 siRNA group),empty vector and CRM197 treatment (empty vector+CRM197 group) and MDR1 siRNA vector and CRM197 treatment (MDR1 siRNA+CRM197 group), respectively. Flow cytometry was used to detecte the effect of intracellular rhodomine 123 (Rh123) accumulation, and caspase-3 activity assay was used to test the effect of apoptosis in four groups of A2780/Taxol cells. (3) In experiments in vivo, A2780/Taxol cells were inoculated to nude mouse subcutaneously to determine the EGFR and P-gp protein expression following CRM197 treatment by immunohistochemistry. Results (1)In vitro,MTT examination showed that the IC50 of A2780/Taxol cells to paclitaxel in A2780/Taxol+CRM197 group [(6.4±0.3)μmol/L] was significantly lower than the IC50 in A2780/Taxol group [(34.1± 0.5)μmol/L,P<0.01], and the reveral fold of CRM197 was 5.3. The expression level of HB-EGF protein in A2780/Taxol+CRM197 group (1.44 ± 0.29) was significantly lower than HB-EGF protein in A2780/Taxol group (2.72 ± 0.32),respectively (P<0.05). The expression level of EGFR protein (0.71 ± 0.25) and P-gp protein (0.82±0.19) in A2780/Taxol+CRM197 group was significantly lower than EGFR protein (1.87±0.31) and P-gp protein (1.84 ± 0.27) of A2780/Taxol group (P<0.05). Compared with A2780/Taxol group(1.78 ± 0.27), MDR1 mRNA was significantly down-regulated in A2780/Taxol+CRM197 group (0.79 ± 0.13,P<0.05). (2) The fluorescence intensity of Rh123 of the A2780/Taxol cells in empty vector group, MDR1 siRNA group,empty vector+CRM197 group, MDR1 siRNA+CRM197 group was 33.4±1.6, 56.3±3.3, 43.5± 3.1,100.4 ± 7.4, and the pNA of the A2780/Taxol cells was(11.4 ± 1.2),(52.8 ± 0.9),(71.2 ± 3.6),(82.7 ± 3.8)μmol/L. The expression levels in MDR1 siRNA+CRM197 group were both higher than the expression levels in empty vector+CRM197 group, and the expression levels in empty vector+CRM197 group, MDR1 siRNA group were both higher than the expression levels in empty vector group (P<0.05). (3) In vivo, the expression scores of EGFR protein in A2780/Taxol+CRM197 tumors (4.4 ± 1.4) were lower than that in A2780/Taxol tumors (10.2 ± 3.1,P<0.05). The expression scores of P-gp protein in A2780/Taxol+CRM197 tumors (3.8 ± 1.1) were lower than that in A2780/Taxol tumors (8.8 ± 2.7,P<0.05). Conclusion CRM197 reverses the resistance of ovarian cancer to paclitaxel by increasing caspase-3 activity to advance apoptosis via EGFR/MDR1/P-gp pathway.

Objective To examine the expression of heparin binding-epidermal growth factor-like growth factor (HB-EGF) in paclitaxel-resistant ovarian cancer and elucidate the relationship between HB-EGF and the resistance of ovarian cancer to paclitaxel. Methods The human ovarian carcinoma cell line A2780 and the paclitaxel-resistant human ovarian carcinoma cell line A2780/Taxol were cultured in vitro. Western blot was used to dectect the expression of HB-EGF protein in A2780 and A2780/Taxol groups. The A2780 cells were treated with cross-reacting material 197 (CRM197 and A2780 + CRM197 group) or dimethyl sulphoxide (DMSO;A2780 group), while the A2780/Taxol cells were treated with CRM197 (A2780/Taxol+CRM197 group) or DMSO (A2780/Taxol group). The effects of CRM197 on growth and proliferation was tested by methyl thiazolyl tetrazolium( MTT) and the results were showed as absorbance (A).The effects of CRM197 on cell cycles was tested by flow cytometry, while the effects of CRM197 on apoptosis was examined by caspase-3 activity assay and the results were showed as p-nitroaniline(pNa). In animal experiment, four groups of cells were inoculated to BALB/c nude mouse subcutaneously to observe tumor formation ability following CRM197 treatment. Immunohistochemistry was used to determine the expression of HB-EGF protein in A2780 and A2780/Taxol group. Results The expression level of HB-EGF protein in A2780/Taxol group (2.11±0.41) was significantly higher than that of A2780 group (0.75±0.20;P<0.01). The inhibition effect of CRM197 on the cell growth of A2780+CRM197 and A2780/Taxol+CRM197 group was accompanied by the acceleration of CRM197 concentration(P<0.01). When CRM197≥1 μg/ml, the inhibition effect of CRM197 on the cell growth of A2780/Taxol+CRM197 group was significantly higher than that in A2780/Taxol group(P<0.05). In cell cycle experiment, CRM197 induced the cell-cycle arrest at the G0/G1 phase in A2780+CRM197 cells[(67 ± 4)%] compared with A2780 cells[(54 ± 6)%;P<0.01], while CRM197 significantly induced the cell-cycle arrest at the G0/G1 phase in A2780/Taxol+CRM197 cells [(72± 4)%] compared with A2780/Taxol cells [(24±8)%;P<0.01]. CRM197 treatment in A2780+CRM197 group [(40 ± 6)μmol/L] led to the acceleration of the caspase-3 activity when compared to A2780 group [(6 ± 6)μmol/L;P<0.01], while CRM197 treatment in A2780/Taxol+CRM197 group [(66 ± 12)μmol/L] led to significant acceleration of the caspase-3 activity when compared to A2780 group [(9 ± 6)μmol/L;P<0.01]. In experiments in vivo, the expression scores of HB-EGF protein in A2780/Taxol tumors(10.8 ± 3.3) were higher than that in A2780 tumors (5.0±2.2;P<0.01). The tumor size and tumor weight of the A2780/Taxol+CRM197 group were both higher than those of the A2780+CRM197 group [(546 ± 85) mm3 vs (1 355 ± 119) mm3,(0.56 ± 0.09) g vs (1.31 ± 0.27) g; all P<0.01]. The CRM197 inhibition rate of the A2780+CRM197 and A2780/Taxol + CRM197 group were 43% and 68% respectively, showed that CRM197 significantly suppressed the growth of A2780/Taxol xenografts in vivo(P<0.01). Conclusions HB-EGF is over-expressed in paclitaxel-resistant ovarian cancer and may be contributes to drug resistance. Inhibition of HB-EGF expression potently enhances apoptosis and inhibit the growth of paclitaxel-resistant ovarian cancer, shedding light on the HB-EGF-targeted therapy options for chemoresistant ovarian cancer patients.