Safflower yellow and its main component hydroxysafflor yellow A alleviate hyperleptinemia in diet-induced obesity mice through a dual inhibition of the GIP-GIPR signaling axis.

Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone secreted by K cells in the small intestine and is considered an obesity-promoting factor. In this study, we systematically investigated the anti-obesity effects of intragastric safflower yellow (SY)/hydroxysafflor yellow A (HSYA) and the underlying mechanism for the first time. Our results showed that intragastric SY/HSYA, rather than an intraperitoneal injection, notably decreased serum GIP levels and GIP staining in the small intestine in diet-induced obese (DIO) mice. Moreover, intragastric SY/HSYA was also first found to significantly suppress GIP receptor (GIPR) signaling in both the hypothalamus and subcutaneous White adipose tissue. Our study is the first to show that intragastric SY/HSYA obviously reduced food intake and body weight gain in leptin sensitivity experiments and decreased serum leptin levels in DIO mice. Further experiments demonstrated that SY treatment also significantly reduced leptin levels, whereas the inhibitory effect of SY on leptin levels was reversed by activating GIPR in 3 T3-L1 adipocytes. In addition, intragastric SY/HSYA had already significantly reduced serum GIP levels and GIPR expression before the serum leptin levels were notably changed in high-fat-diet-fed mice. These findings suggested that intragastric SY/HSYA may alleviate diet-induced obesity in mice by ameliorating hyperleptinemia via dual inhibition of the GIP-GIPR axis.

25-hydroxyvitamin D levels are inversely related to metabolic syndrome risk profile in northern Chinese subjects without vitamin D supplementation.

BACKGROUND: The comparatively low 25 hydroxyvitamin D [25(OH)D] levels have been reported in patients with metabolic syndrome (MetS). Herein we investigated the cross-sectional and longitudinal relationships between serum 25(OH)D levels and MetS risk profile in northern middle-aged Chinese subjects without vitamin D supplementation. METHODS: A cohort of 211 participants including 151 MetS patients and 60 controls at 20-69 years of age were enrolled from suburban Beijing, China. The recruited MetS patients were subjected to diet and exercise counselling for 1-year. All subjects at baseline and MetS patients after intervention underwent clinical evaluations. RESULTS: Serum 25(OH)D levels were significantly decreased in MetS patients. 25(OH)D levels were inversely related to MetS score, fasting blood glucose (FBG) and triglyceride-glucose index (TyG) after adjusting for cofounders (all P < 0.05). Participants in the lowest tertile of 25(OH)D levels had increased odds for MetS (P = 0.045), elevated FBG (P = 0.004) in all subjects, and one MetS score gain in MetS patients (P = 0.005). Longitudinally, the metabolic statuses as well as 25(OH)D levels of MetS patients were significantly improved (all P < 0.05), and the increase of 25(OH)D levels were inversely related to MetS scores, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), FBG, and TyG, while positively related to high-density lipoprotein cholesterol (HDL-C) after adjusting for confounders. CONCLUSIONS: 25(OH)D levels were significantly decreased in MetS patients, and it was negatively associated with metabolic dysfunctions at baseline and 1-year after. Metabolic aberrations of MetS patients were significantly ameliorated with 1-year follow-up counselling accompanying by notably elevated 25(OH)D levels.

Case Report: Identification of Potential Prognosis-Related TP53 Mutation and BCL6-LPP Fusion in Primary Pituitary Lymphoma by Next Generation Sequencing: Two Cases.

Background: Primary pituitary lymphoma (PPL) is an extremely rare disease with poor prognosis. Although PPL has been shown to be different from classical primary central nervous system lymphoma because of the embryological origin of structures, individual and precise treatment of PPL remains unknown. Methods: A 61-year-old man and a 65-year-old woman both diagnosed with primary pituitary diffuse large B cell lymphoma underwent genetic analysis of cerebrospinal fluid and tumor tissue by next generation sequencing. Results: In the first case, partial remission was achieved following R²-MTX chemotherapy. In the other case with TP53 mutation and BCL6-LPP fusion, disease progressed although different chemotherapy regimens were given. Conclusion: The gene mutation of TP53 and BCL6 may be identified as a marker responsible for prognostic difference in patients with PPL. Genetic analysis may provide a novel approach for precise management and prognosis prediction.

Recovery of hypothalamus-pituitary-gonadal dysfunction after the treatment of suprasellar germ cell tumors.

OBJECTIVE: To investigate the incidence of hypothalamus-pituitary-gonadal (HPG) axis initiation/recovery after treatment and to identify predictive risk factors for noninitiation/recovery. METHODS: A total of 127 consecutive suprasellar germ cell tumor (GCT) patients managed at Peking Union Medical College Hospital (2006-2019) were retrospectively analyzed. Prepubertal patients (followed up until 13 years of age for girls and 14 years of age for boys) and patients with HPG dysfunction (followed up for 2 years) were divided into the initiation/recovery and noninitiation/recovery groups. RESULTS: Of the 127 suprasellar GCT patients, 75 met the follow-up criteria, 28 (37.3%) of whom experienced HPG axis initiation/recovery. Compared to the noninitiation/recovery group, the initiation/recovery group included more males and had shorter delayed diagnosis times, smaller tumor sizes, lower panhypopituitarism rates, thinner pituitary stalk widths, lower visual deficit rates, and higher serum testosterone and estradiol levels. The cutoff values of pituitary stalk width, tumor size, and delayed diagnosis time used to predict noninitiation/recovery were 6.9 mm, 6.9 mm and 1.7 years, respectively. Tumor size ≥6.9 mm (odds ratio (OR) = 7.5, 95% CI: 2.2-25.8, P = 0.001), panhypopituitarism (OR = 5.0, 95% CI: 1.4-17.6, P = 0.013), and delayed diagnosis time ≥1.7 years (OR = 5.7, 95% CI: 1.5-20.7, P = 0.009) were risk factors for noninitiation/recovery. CONCLUSIONS: Among suprasellar GCT patients, nearly one-third of prepubertal patients and patients with HPG dysfunction experience HPG axis initiation/recovery after treatment. Tumor size ≥6.9 mm, panhypopituitarism, and delayed diagnosis time ≥1.7 years were identified as predictive risk factors for noninitiation/recovery.

Lotus Leaf Aqueous Extract Reduces Visceral Fat Mass and Ameliorates Insulin Resistance in HFD-Induced Obese Rats by Regulating PPARγ2 Expression.

Objectives: Lotus leaf is a kind of traditional Chinese medicine. We aimed to explore the effects of lotus leaf aqueous extract (LLAE) on peroxisome proliferative activated receptor γ2 (PPARγ2) expression in preadipocytes and adipocytes and further investigate its effects on high fat diet (HFD)-induced obese rats. Methods: pGL3-Enhancer-PPARγ2 (625 bp)-Luc plasmid, a luciferase reporter gene expression plasmid containing PPARγ2 promoter, was stably transfected into 3T3-L1 preadipocytes. PPARγ2 promoter activities were determined by assaying the luciferase activities. Then PPARγ2 promoter activities in preadipocytes and PPARγ2 mRNA levels in human subcutaneous adipocytes were measured after the administration with LLAE. Additionally, the effects of LLAE on body weight, fat mass, glucose and lipid metabolism and the expression of PPARγ2, insulin receptor substrate 1 and glucose transporter 4 (GLUT4) in visceral adipose tissue (VAT) were measured in HFD-induced obese rats treated with low or high dose [0.5 or 3.0 g crude drug/(kg.d)] LLAE for 6 weeks. Results: Ten µg/ml LLAE significantly increased the luciferase activities in 3T3-L1 cells and the stimulatory action reached 2.51 folds of controls when LLAE was 1000 µg/ml (P < 0.01). After treating 3T3-L1 cells with 100 µg/ml LLAE, the stimulatory role peaked at 32 h where it was 2.58 folds of controls (P < 0.01). Besides, 100 µg/ml LLAE significantly increased PPARγ2 mRNA levels in human adipocytes to 1.91 folds of controls (P < 0.01). In HFD-induced obese rats, administration with both low and high dose LLAE notably reduced visceral fat mass by 45.5 and 58.4%, respectively, and significantly decreased fasting serum insulin levels (P < 0.05). The high dose LLAE also significantly decreased homeostasis model assessment of insulin resistance in obese rats (P < 0.05). Furthermore, the mRNA levels of PPARγ2 and GLUT4 in VAT of obese rats were significantly increased when compared with control rats, and were notably suppressed by LLAE intervention for 6 weeks (P < 0.05). Conclusion: LLAE significantly reduces visceral fat mass and ameliorates insulin resistance in HFD-induced obese rats. These beneficial effects of LLAE may associate with its role in stimulating PPARγ2 expression in preadipocytes and subcutaneous adipocytes and suppressing PPARγ2 and GLUT4 expression in VAT.

The prevalence and risk factors of preterm small-for-gestational-age infants: a population-based retrospective cohort study in rural Chinese population.

BACKGROUND: Preterm birth and small for gestational age (SGA) are strong indicators of neonatal adverse outcomes. With the growing importance of preterm SGA infants, we aim to evaluate the prevalence and risk factors for preterm SGA in China. METHOD: We analyzed the data of parents and infants from a population-based cohort research of the free National Pre-pregnancy Checkups Project (NPCP) in rural China. Only singleton live births that occurred between 24 weeks +0 days and 36 weeks +6 days of pregnancy were included in this study. SGA was defined as birth weight less than the 10th percentile of the reference birth-weight-for-gestational-age population. A multiple logistic regression model was built using the statistically significant variables from the 371 variables in the questionnaire. RESULTS: A total of 11,474 singleton, preterm, live-birth infants were included. Of the total infants, 317 (2.77%) were preterm SGA infants. A higher risk of preterm SGA infants was observed among mothers who were on oral contraceptives (OR: 8.162, 95% CI: 1.622-41.072), mothers who had syphilis (OR: 12.800, 95% CI: 1.250-131.041), and mothers with a high eosinophil percentage (OR: 13.292, 95% CI: 1.282-135.796). Maternal intake of folic acid at least 3 months before pregnancy (OR: 0.284, 95% CI:0.124-0.654) and paternal intake of egg and meat (OR: 0.097,95% CI:0.030-0.315) were protective factors. Compared with North China, the incidence of preterm SGA infants was higher in South China. CONCLUSION: Preterm SGA infants were associated with both maternal and paternal factors.

Hormone-sensitive lipase is involved in the action of hydroxysafflor yellow A (HYSA) inhibiting adipogenesis of 3T3-L1cells.

BACKGROUND: Safflor yellow A (SY) has been demonstrated to be beneficial to cardiovascular system. Our previous study showed that hydroxysafflor yellow A (HSYA), a main component of SY, could increase peroxisome proliferator-activated receptor γ mRNA expression. In this study, we investigate the effect of HSYA on the proliferation and adipogenesis of mouse 3T3-L1 preadipocytes. METHODS: The proliferation and adipogenesis of 3T3-L1 cells treated with HSYA was studied by 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyl tetrazolium bromide (MTT) spectrophotometry, Oil Red O staining and intracellular triglyceride assay methods. HSL mRNA expression and promoter activity were studied by real-time quantitative RT-PCR, transient transfection and dual luciferase reporter gene methods. RESULTS: HSYA (0.1 mg/L) significantly inhibited the proliferation of 3T3-L1 cells when compared with control cells in 8 h. This effect was further enhanced with the extension time (24 to 96 h) and an increase of concentration of HSYA (1-10 mg/L). The maximal inhibitory action was observed at 0.1 mg/L HSYA in 72 h (86±11.8% vs. 100±4.1%, p<0.01). HSYA notably reduced the amount of intracellular lipid and triglyceride content in adipocytes to 85% (1 mg/L) and 75% (100 mg/L) on Day 4 following the differentiation, respectively, while increased HSL mRNA expression and promoter activities to 2.7 fold and 1.55 fold, respectively (p<0.01), in differentiated 3T3-L1 adipocytes. CONCLUSIONS: HSYA inhibits the proliferation and adipogenesis of 3T3-L1 preadipocytes. The inhibitory action of HYSA on adipogenesis may be due to the promotion of lipolytic-specific enzyme HSL expression by increasing HSL promoter activity.

[Human pregnane X receptor-mediated transcriptional regulation of cytochrome P450 3A4 by some phytochemicals].

OBJECTIVE: To test the effect on human pregnane X receptor (hPXR)-mediated transcription regulation of CYP3A4 by five selected phytochemicals. METHODS: Transient cotransfection reporter gene assays in HepG(2) cells were performed with the hPXR expression plasmid and the reporter gene plasmid which contains XRE in the promoter of CYP3A4 linked to luciferase. RESULTS: In the dose-effect study, soybean isoflavone, luteolin and curcumin induced the CYP3A4 transcription via PXR in an evident dose-dependent manner, but isorhamnetin and rutin did not. The inducibility of soybean isoflavone, luteolin and curcumin was also increased in concentrations between 1 micromol/L and 50 micromol/L, 24 h after induction, 50 micromol/L soybean isoflavone, luteolin and curcumin exhibited a 5.46-fold, 2.87-fold, and 2.07-fold increase respectively, compared with 0.1% DMSO treated cells. In the time-effect study, 10 micromol/L and 50 micromol/L soybean isoflavone, luteolin and curcumin induced CYP3A4 transcription between 12 h and 48 h, the strongest induction appeared in 48 h. 48 h after induction, 50 micromol/L soybean isoflavone, luteolin and curcumin exhibited a 6.72-fold, 3.24-fold, and 2.13-fold increase respectively, compared with 0.1% DMSO treated cells. CONCLUSION: Three phytochemicals, i.e. soybean isoflavone, luteolin and curcumin stimulate the PXR-mediated transcription of CYP3A4. Isorhamnetin and rutin have no effect on the CYP3A4 transcription via PXR.

[Effect of kaempferol on the pharmacokinetics of nifedipine in rats].

OBJECTIVE: To investigate the effect of kaempferol on the pharmacokinetics of nifedipine (NFP) in rats. METHODS: Twenty male SD rats, weighing 220-260 g, were distributed randomly into 4 groups. The animals were fasted, but allowed free access to water for 12 h before the administration of drugs. NFP dissolved in corn oil was administered via gastric intubation to the rats in control group at a dose of 10 mg/kg. Kaempferol was administered orally to the other three groups with dose of 5, 10, 15 mg/kg, respectively, followed by oral administration of NFP 10 mg/kg. Blood samples were collected through tail vein in heparinized plastic microcentrifuge tubes before and after drug administration. The plasma concentration of NFP was monitored with reversed phase high-performance liquid chromatography (RP-HPLC). Nimodipine was used as the internal standard. Statistical data evaluation was performed with Student's t-test and one-way analysis of variances. RESULTS: The maximal plasma concentration (C(max)) of the three treated groups were 0.51, 0.70 and 0.81 microg/ml, respectively. The area under the concentration-time curve (AUC(0-8)) were 1.81, 2.83 and 3.63 microg/(h.ml(-1)), respectively. The C(max), AUC(0-8) and the mean retention time (MRT(0-8)) of NFP were significantly increased by simultaneous oral treatment with kaempferol (P<0.01). On the other hand, there were no significant differences in the mean peak value time in plasma (T(max)) and the elimination half-life (t1/2(ke)) between the control and the treated groups. CONCLUSION: The concomitant oral use of kaempferol with NFP may influence the pharmacokinetic parameters of NFP in rats, which suggests that kaempferol might reduce the first-pass metabolism of NFP.

[Effects of phytoestrogens on gap junctional intercellular communication].

OBJECTIVE: To observe effects of phytoestrogens quercetin (QC), Genistein (GEN), coumestrol (COM), and enterolactone (ENL) on gap junctional intercellular communication (GJIC) in HaCaT cells. METHODS: HaCaT cells were exposed to QC, GEN, COM, and ENL at 0.1, 1.0, 10.0 and 100.0 micromol/L for 24 hours. The effects of phytoestrogens on GJIC were determined by fluorescence redistribution after photobleaching (FRAP) technique of using a laser scanning confocal microscope (LSCM). RESULTS: QC did not affect the GJIC at 0.1-10.0 micromol/L, whereas, GEN, COM, and ENL exhibited inhibition on the GJIC in some extent at 0.1-10.0 micromol/L without showing significant cytotoxicity. The ratio of fluorescence recovery were between 31.77% to 37.06%, which were significantly decreased compared the vehicle control (44.74%). CONCLUSION: The phytoestrogens GEN, COM, and ENL, but not QC, could inhibit the GJIC function in HaCaT cells at concentrations could be reached in human serum in some instance, indicating they could, under certain conditions, be cancer promoters. Therefore, it should be prudent to use these chemicals as pharmaceuticals or dietary supplements.