A two-year study of parental obesity status and childhood obesity in China.

BACKGROUND AND AIMS: We evaluated the association between parental obesity and their children's obesity parameters [e.g., percentage of body fat (PBF)] over time. METHODS AND RESULTS: The study included 2066 Chinese parents-children trios (n = 1001 girls and 1065 boys, aged 6-14 years). Children's height, weight, waist circumference (WC) and PBF (bioelectrical impedance analysis) were annually assessed from 2014 (baseline) to 2016. Information on parental height and body weight, and children's diet and physical activity was collected in 2014. The association between parental obesity and changes in their children's PBF during follow-up was analyzed using a mixed effects model. We also examined changes in children's BMI and WC in secondary analyses. Baseline mean BMI, WC, and PBF for children were 17.6 ± 3.5 kg/m2, 60.5 ± 9.6 cm, and 16.6 ± 6.5%, respectively. We observed that maternal, but not paternal, obesity was associated with a greater increase in children's PBF during the follow-up. An adjusted mean difference in annual increase of PBF was 0.41% [95% confidence interval (CI): 0.01%, 0.84%] for children with obese mothers, compared with those with normal-weight mothers. Both maternal and paternal obesity was associated with a greater increase in their children's BMI and WC (p trend<0.01 for both); however, the associations were stronger in mother-children pairs than those in father-children pairs. CONCLUSIONS: Maternal obesity was associated with a greater increase in PBF in Chinese school-aged children.

Body mass index, waist circumference, body fat mass, and risk of developing hypertension in normal-weight children and adolescents.

BACKGROUND AND AIMS: We prospectively examined the association between three adiposity indices, including body mass index (BMI), waist circumference (WC), and percentage of body fat (PBF), and risk of hypertension in normal-weight Chinese children. METHODS AND RESULTS: The current study included 1526 (713 boys and 813 girls) normal-weight Chinese children (age 6-14 years old), who were free of hypertension at baseline (2014). Heights, body weight, WC, and PBF (estimated by bioelectrical impedance analysis) were measured at the baseline. Blood pressure was repeatedly measured in 2014, 2015 and 2016. Hypertension was defined as either high systolic blood pressure and/or high diastolic blood pressure, according to age- and sex-specific 95th percentile for Chinese children. We used Cox proportional hazards model to calculate the association between exposures and hypertension. We identified 88 incident hypertension cases during two years of follow up. High BMI was associated with high risk of developing hypertension after adjusting for potential confounders. The adjusted hazard ratio for hypertension was 2.88 (95% CI: 1.24, 6.69) comparing two extreme BMI quartiles. Each SD increase of BMI (≈1.85 kg/m2) was associated with a 32% higher likelihood to developing hypertension (Hazard ratio = 1.32; 95% CI: 1.003, 1.73). In contrast, we did not find significant associations between WC or PBF and higher hypertension risk (p-trend >0.2 for both). CONCLUSION: High BMI, but not WC and PBF, was associated with high risk of hypertension in normal-weight Chinese children.

[Interaction of DAXX and human papillomavirus type 16 E2 protein].

The aim of the study was to explore the interactions of human papilloma virus 16 (HPV16) E2 protein and Daxx. The location or co-localization of PML and E2 with Daxx in Caski cells was observed by indirect immunofluorescence test. The interaction of E2 and Daxx was analyzed by co-immunoprecipitation, Western-blot and yeast-two hybrid assay. In Caski cells the fluorescence of Daxx or PML was mainly distributed in the cytoplasm or nucleus, respectively, and in the align image their signals did not overlapped. However, when the red signal of HPV16 E2 and the green signal of Daxx in cyto- plasm of Caski cells were merged, the yellow signals appeared. The yeast co-transformed with pGBKT7/Daxx and pGADT7/E2 or pGADT7/E2 TAD can grow onto SD/-Trp-Leu-His and SD/-Trp-Leu-His-Ade plates. So Daxx wasn't co-located with PML but with HPV16 E2 mainly in the cytoplasm of Caski cells. On the base of the results one can propose that HPV16 E2, in particularly its transcription-activity domain (TAD), interacts with Daxx.

The Relationship between Body Mass Index and Incident Diabetes Mellitus in Chinese Aged Population: A Cohort Study.

OBJECTIVES: Previous studies reported that overweight older adults had a lower mortality after cardiovascular diseases attack, indicating being thinner might not always be better. However, there is an ongoing debate about what is the optimal range of body mass index (BMI) for the aged population. We aimed to evaluate the value of BMI for the prediction of incident diabetes mellitus (DM) in the Chinese elderly population. METHODS: A total number of 6,911 Chinese elderly people (4,110 men and 2,801 women, aged 71 ± 6.0 years) were included in this cohort study. BMI was measured at baseline (Jan 1, 2014, to Dec 31, 2014). All the participants were further classified into six groups: <18.5 kg/m2, 18.5 to <22.5 kg/m2, 22.5 to <25.0 kg/m2, 25.0 to <27.5 kg/m2, 27.5 to <30.0 kg/m2, and ≥30.0 kg/m2. Fasting blood glucose (FBG) and glycated hemoglobin A1c (HbA1c) were annually measured during follow-up (Jan 1, 2015-May 31, 2019). DM was confirmed if either FBG ≥ 7.0 mmol/L or HbA1c ≥ 6.5%. We used the Cox proportional hazard regression model to evaluate the association between BMI and the prediction of incident DM. RESULTS: Comparing individuals with a BMI range of 18.5 to <22.5 kg/m2 (reference), the hazard ratio for incident DM was 2.13 (95% CI: 1.54~2.95), 2.14 (95% CI: 1.53~3.00), 3.17 (95% CI: 2.19~4.59), 3.15 (95% CI: 1.94~5.09), and 3.14 (95% CI: 1.94~5.09) for the group with a BMI range of 22.5 to <25.0 kg/m2, 25.0 to <27.5 kg/m2, 27.5 to <30.0 kg/m2, and ≥30.0 kg/m2 after adjusting for baseline age, sex, blood pressure, lipid profiles, and eGFR (P trend < 0.001), after adjusting for the abovementioned confounders. The association tended to be closer in men and young participants, compared with their counterparts. CONCLUSIONS: High BMI was associated with a high risk of developing DM in the Chinese aged population. Thus, it is optimal for the aged population to maintain their body weight within a reasonable range to prevent chronic diseases.

Correlation between long strand non-coding RNA GASS expression and prognosis of cervical cancer patients.

OBJECTIVE: Cervical cancer is the second popular female specific malignant tumors. Long-strand non-coding RNA (lncRNA) GAS5 (Growth Arrest Specific 5) participates in pathological processes of various malignant tumors. This study aimed at investigating the correlation between lncRNA GAS5 expression and prognosis of cervical cancer patients. PATIENTS AND METHODS: Cancer tissues were collected from 48 cervical cancer patients. GAS5 expression in cervical cancer cells was determined by qRT-PCR and in situ hybridization (ISH). The correlation between GAS5 expression and pathological parameters of patients was analyzed. Cervical cancer cell line HeLa was used as the in vitro model, RNA interference approach was adopted to suppress lnc-RNA GAS5 expression. MTT assay was employed to analyze cell proliferation potency. Transwell assay was conducted to analyze the cell migration potency, and tumor cell invasion was measured. RESULTS: qRT-PCR and ISH results showed that GAS5 expression in cervical cancer tissues was significantly inhibited compared to that in adjacent tissues (p<0.05). GAS5 expression was correlated with FIGO stage and metastatic tumor parameters of cervical cancer patients (p<0.01). RNA interference data showed that the down-regulation of GAS5 significantly enhanced cell proliferation and invasion potency (p<0.05). CONCLUSIONS: GAS5 is down-regulated in cervical cancer cells, and this is probably related to patient clinical stage and tumor invasion or metastasis. The regulatory role of GAS5 on cell proliferation provides the academic basis for the future therapy of cervical cancer.

Decreased HoxD10 Expression Promotes a Proliferative and Aggressive Phenotype in Prostate Cancer.

HoxD10 gene plays a critical role in cell proliferation in the process of tumor development. However, the protein expression level and the function of HoxD10 in prostate cancer remain unknown. Using tissue microarray, we demonstrate that the protein expression of HoxD10 is commonly decreased in prostate cancer tissues (n = 92) compared to adjacent benign prostate tissues (n = 77). Functionally, knockdown of HoxD10 resulted in significant promotion of prostate cancer cell proliferation. Moreover, knockdown of HoxD10 strikingly stimulated prostate tumor growth in a mouse xenograft model. We also found a significant association between decreased immunohistochemical staining of HoxD10 expression and higher Gleason score (P = 0.031) and advanced clinical pathological stage (P = 0.011). An analysis of the Taylor database revealed that decreased HoxD10 expression predicted worse biochemical recurrence (BCR)-free survival of PCa patients (P = 0.005) and the multivariate analyses further supported that HoxD10 might be an independent predictor for BCR-free survival (P = 0.027). Collectively, our data suggest that the loss of HoxD10 function is common and may thus result in a progressive phenotype in PCa. HoxD10 may function as a biomarker that differentiates patients with BCR disease from the ones that are not after radical prostatectomy, implicating its potential as a therapeutic target.

Inhibition of the activity of the luteinizing hormone-releasing hormone (LH-RH) by analogues with variations at positions 2, 3, and 6 and the carboxyl terminus.

In the isolated rat pituitary assay, [Thr2,Leu3]-LH-RH, [Leu2,Ala3,D-Ala6]-LH-RH, and des-Gly10-[Abu2,Ala3,D-Ala6]-LH-RH ethylamide inhibited the LH release due to 0.3 ng/mL of added LH-RH at a 10 microgram/mL dosage. Under these same assay conditions, des-Gly10-[Ile2,Ala3,D-Ala6]-LH-RH ethylamide was about one-tenth as active, and no inhibition was observed by [Leu2,Ser3]-LH-RH or [Leu2,Asn3]-LH-RH at a 100 microgram/mL dosage. The corresponding results from FSH inhibition assays, in vitro, are also reported.

Nonapeptide ethylamide inhibitors of the luteinizing hormone-releasing hormone (LH-RH) having a D-alanyl residue in position 6 and variations at positions 2 and 3.

A series of ten analogues, of structure des-Gly10-[amino acid2, amino acid3,D-Ala6]-LH-RH ethylamide, was synthesized by solid-phase methods. L-Aromatic and alkylamino acids were substituted into position 2 and alkylamino acids into position 3. Highest in vitro inhibition of LH-RH action was obtained with analogues having aromatic residues in position 2. Des-Gly10-[Trp2,Leu3,D-Ala6]-LH-RH ethylamide inhibited the action of 0.6 ng/mL of LH-RH, in an isolated pituitary assay, at a dosage as low as 1 microgram/mL, and the corresponding Phe2 analogue inhibited the effect of 0.3 ng of LH-RH at 0.1 microgram/mL. The Trp2 analogue inhibited ovulation in rats at the dosage of 1.5 mg per rat.

Inhibitory analogues of the luteinizing hormone-releasing hormone having D-aromatic residues in positions 2 and 6 and variation in position 3.

A single sc injection of 750 microgram/rat of [D-Phe2,Pro3,D-Phe6]-LH-RH on proestrus completely inhibited ovulation in 4-day cycling rats. Ovulation was inhibited partially at 375 microgram/rat. At the 720 microgram/rat dosage, analogues of LH-RH with D-Phe in positions 2 and 6, and with Sar, Arg, or Hyp in position 3, resulted in partial inhibitors and an inactive analogue with Thr substitution. In the same assay, analogues with D-Phe in position 2 and D-Trp in position 6 were partial inhibitors when D-Phe, Met, or Val were in position 3 and inactive with Ile substitution.

Inhibitors of the luteinizing hormone-releasing hormone based upon modifications in the 2, 3, and 6 positions.

[Leu2,Leu3,D-Ala6]-LH-RH (less than Glu-Leu-Leu-Ser-Tyr-D-Ala-Leu-Arg-Pro-Gly-[NH2) and [Val2,Leu3,D-Ala6]-LH-RH completely inhibited the release of LH and FSH induced by 0.3 ng/ml of medium of LH-RH on isolated rat pituitaries, at a dosage of 10 mug. [Leu2,Val3,D-Ala6]-LH-RH and [Val2,Val3,D-Ala6]-LH-RH also completely inhibited this response but were one-tenth as active as [Leu2,Leu3,D-Ala6]-LH-RH. All of the analogs were devoid of agonist activities. The incorporation of the D-Ala residue in position 6 into the [Leu2,Leu3]-LH-RH sequence, therefore, increased the inhibition potency as much as tenfold.

Structural requirements in positions 1, 2, 3, and 6 of the luteinizing hormone-releasing hormone (LH-RH) for antiovulatory activity.

Sixteen analogues of the luteinizing hormone-releasing hormone (LH-RH) were synthesized by the solid-phase method. In new and surprising relationships, it was found that the substitution of D-Trp into position 3 of [D- less than Glu1,D-Phe2,amino acid3,D-Phe6]-LH-RH significantly enhanced the antiovulatory potency, but substitution by Pro, N-Me-Phe,N-Me-Leu, or L-Trp reduced antiovulatory activity. The substitution of L- less than Glu in position 1 of [D-Phe2,Pro3,D-Phe6]-LH-RH by cyclohexylcarbonyl (Chc), benzoyl (Bz), Ac, Hyp, Ac-Met, hydrogen, Pro, and D- less than Glu residues, and the substitution of D-Phe in position 2 by D-Trp, D-His, D-Phg, and L-Phe residues resulted in analogues with no antiovulatory activity at 750 microgram/rat. Structural requirements for the design of inhibitors of higher potency have been discussed.

The agouti-related protein decapeptide (Yc[CRFFNAFC]Y) possesses agonist activity at the murine melanocortin-1 receptor.

Agouti-related protein (AGRP) is a naturally occurring antagonist of the brain melanocortin receptors (MC3R and MC4R) and is physiologically implicated as participating in feeding behavior and energy homeostasis. The human AGRP decapeptide Yc[CRFFNAFC]Y has been previously reported as binding to the human MC3 and MC4 receptors and antagonizing the MC4 receptor. We have synthesized this decapeptide and pharmacologically characterized it at the murine melanocortin receptors and found it to possess MC4R antagonist activity (pA(2) = 6.8) and, unexpectedly, MC1R agonist activity (EC(50) = 2.89 microM). This study characterizes the first AGRP-based peptide agonist at the melanocortin receptors.

Quantitative light microscopic autoradiographic localization of binding sites labelled with [3H]vasopressin antagonist d(CH2)5Tyr(Me)VP in the rat brain, pituitary and kidney.

Binding sites for the vasopressin (VP) antagonist d(CH2)5Tyr(Me)VP, were located in various brain areas (e.g. the lateral septum, amygdala, choroid plexus and nucleus of the solitary tract) using light microscopic autoradiography. A number of areas (e.g. suprachiasmatic and arcuate nucleus, pineal gland) which previously showed no VP binding were labelled in the present study. The olfactory nucleus and ventromedial hypothalamic nucleus were not labelled. It therefore appears that d(CH2)5Tyr(Me)VP is capable of discriminating between VP and oxytocin binding sites and a more sensitive means of detecting VP binding sites than VP alone.

Are the pharmacological effects of L-prolyl-L-leucyl-glycinamide (PLG) mediated through specific receptor mechanisms?

In an attempt to delineate the mechanism subserving the demonstrated central effects of the tripeptide, L-prolyl-L-leucyl-glycinamide (PLG) in mammals including humans, we developed a radioligand binding assay to characterize the binding of 3H-PLG to rat brain membranes. Equilibrium binding studies indicated that PLG binds to rat striatum with high affinity (KD = 4.69 +/- 0.50 nM), saturability (Bmax = 9.20 +/- 0.30 fmoles mg-1 protein) and reversibility. Kinetic data yielded a KD = 1.42 +/- 0.21 nM for rat striatum. Regional distribution profile of specific 3H-PLG binding revealed that the striatum has the highest density of PLG binding sites, followed by the hypothalamus and the cerebral cortex. Analogues of PLG compete for specific PLG binding in rat striatum with potencies parallelling their in vivo activities in behavioural systems. Our results support the existence of a unique class of putative peptide receptor sites specific for PLG mediating a spectrum of pharmacological effects.

Vasopressin metabolite, AVP4-9, binding sites in brain: distribution distinct from that of parent peptide.

Binding sites for the vasopressin metabolite peptide, (AVP4-9), were detected in the rat brain. These binding sites were present in the hilus of the hippocampal formation, superior and inferior colliculus, pontine reticular nuclei, brainstem nuclei, lateral mammillary nucleus, choroid plexus and subfornical organ. The distribution of AVP4-9 binding sites was distinct from that of the parent peptide (1-3). This distinction was apparent in both the regional and intra-regional distribution.

Synthesis of tritium labeled Ac-[Nle4, D-Phe7]-alpha-MSH4-11-NH2: a superpotent melanotropin with prolonged biological activity.

Ac-[Nle4, D-Phe7]-alpha-MSH4-11-NH2 an octapeptide, is a melanotropin analogue (Ac-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-NH2), which is a superpotent agonist of frog and lizard skin melanocytes and mouse S 91 (Cloudman) melanoma cells. This melanotropin possesses ultraprolonged activity on melanocytes, both in vitro and in vivo, and the peptide is resistant to inactivation by serum enzymes. The tritium-labeled congener was prepared by direct incorporation of [3H]-labeled norleucine into the peptide. The melanotropic activity of the labeled peptide is identical to the unlabeled analogue. This labeled peptide should be useful for studies on the localization and characterization of melanotropin receptors.

A high affinity, highly selective ligand for the delta opioid receptor: [3H]-[D-Pen2, pCl-Phe4, d-Pen5]enkephalin.

Binding characteristics of a new, conformationally constrained, halogenated enkephalin analogue, [3H]-[D-penicillamine2, pCl-Phe4, D-penicillamine5]enkephalin ([3H]pCl-DPDPE), were determined using homogenized rat brain tissue. Saturation binding studies at 25 degrees C determined a dissociation constant (Kd) of 328 +/- 27.pM and a receptor density (Bmax) of 87.2 +/- 4.2 fmol/mg protein. Kinetic studies demonstrated biphasic association for [3H]pCl-DPDPE, with association rate constants of 5.05 x 10(8) +/- 2.5 x 10(8) and 0.147 +/- 10(8) +/- 0.014 x 10(8) M-1 min-1. Dissociation was monophasic with a dissociation rate constant of 2.96 x 10(-3) +/- 0.25 x 10(-3) min-1. The average Kd values determined by these kinetic studies were 8.4 +/- 2.7 pM and 201 +/- 4 pM. Competitive inhibition studies demonstrated that [3H]pCl-DPDPE has excellent selectively for the delta opioid receptor. [3H]pCl-DPDPE binding was inhibited by low concentrations of ligands selective for delta opioid receptor relative to the concentrations required by ligands selective for mu and kappa sites. These data show that [3H]pCl-DPDPE is a highly selective, high affinity ligand which should be useful in characterizing the delta opioid receptor.