Crystal Field-Engineered Cr3+-Doped Gd3(MgxGa5-2xGex)O12 Phosphors for Near-Infrared LEDs and X-ray Imaging Applications.

Inorganic materials doped with chromium (Cr) ions generate remarkable and adjustable broadband near-infrared (NIR) light, offering promising applications in the fields of imaging and night vision technology. However, achieving high efficiency and thermal stability in these broadband NIR phosphors poses a significant challenge for their practical application. Here, we employ crystal field engineering to modulate the NIR characteristics of Cr3+-doped Gd3Ga5O12 (GGG). The Gd3MgxGa5-2xGexO12 (GMGG):7.5% Cr3+ (x = 0, 0.05, 0.15, 0.20, and 0.40) phosphors with NIR emission are developed through the cosubstitution of Mg2+ and Ge4+ for Ga3+ sites. This cosubstitution strategy also effectively reduces the crystal field strength around Cr3+ ions, which results in a significant enhancement of the photoluminescence (PL) full width at half-maximum (fwhm) from 97 to 165 nm, alongside a red shift in the PL peak and an enhancement of the PL intensity up to 2.3 times. Notably, the thermal stability of the PL behaviors is also improved. The developed phosphors demonstrate significant potential in biological tissue penetration and night vision, as well as an exceptional scintillation performance for NIR scintillator imaging. This research paves a new perspective on the development of high-performance NIR technology in light-emitting diodes (LEDs) and X-ray imaging applications.

Visualized Stress-Temperature Sensor with the Zinc Sulfide and Perovskite Glass Ceramics Composite.

The visualized dual-modal stress-temperature sensing refers to the ability of a sensor to provide real-time and visible information about both stress and temperature and has indeed attracted significant interest in various fields. However, the development of convenient methods for achieving this capability remains a challenge. In this work, a dual-modal stress-temperature sensor is successfully fabricated using a ZnS/Cu@CsPbBr1.2I1.8 glass ceramics (GCs)/polydimethylsiloxane (PDMS) (ZCP) composite film. The tunable ML color is achieved by modulating the concentration of CsPbBr1.2I1.8 GCs in the ZCP composite films based on the light conversion process from ZnS/Cu to CsPbBr1.2I1.8 GCs. Additionally, the stress and temperature can be visualized simultaneously by integrating the ML intensity and ML color of the ZCP composite film. This feature allows for the real-time monitoring of automotive tire temperature by embedding the ZCP composite film on the tire surface, enabling a strong and stable response to both stress and temperature changes. Overall, this work offers a convenient, efficient, and repeatable approach for achieving visualized dual-modal stress-temperature sensing in the fields of mechanical engineering, structural health monitoring, and intelligent devices.

Multimode-Responsive Luminescence of Er3+ Single-Activated CaF2 Phosphor for Advanced Information Encryption.

The current optical anticounterfeit strategies that rely on multimode luminescence in response to the photon or thermal stimuli have significant importance in the field of anticounterfeiting and information encryption. However, the dependence on light and heat sources might limit their flexibility in practical applications. In this work, Er3+ single-doped CaF2 phosphors that show multistimuli-responsive luminescence have been successfully prepared. The as-obtained CaF2:Er3+ phosphor exhibits green photoluminescence (PL) and color-tunable up-conversation (UC) luminescence from red to green due to the cross-relaxation of Er3+ ions. Additionally, as-obtained CaF2:Er3+ phosphors also display green mechano-luminescence behavior, which is induced by the contact electrification between the CaF2 particles and PDMS polymers, enabling the phosphor to flexibly respond to mechanical stimuli. Moreover, feasible anticounterfeiting schemes with the capability of multistimuli-responsive and flexible decryption have been constructed, further expanding the application of optical materials in the field of advanced anticounterfeiting and information encryption.

[Expert consensus statement on Kangfu Xiaoyan Suppository in treatment of pelvic inflammatory in clinical practice].

Kangfu Xiaoyan Suppository is widely used in the treatment of gynecological inflammatory diseases. Long-term clinical application and a certain amount of research evidences show that Kangfu Xiaoyan Suppository can alleviate the clinical symptoms of pelvic inflammatory diseases,reduce the recurrence rate,and relieve sequelae,with a better safety and economic characteristics. As a type of nationally protected traditional Chinese medicine and type B medicine included in medical insurance,it has been selected as a Chinese patent medicine for rectal administration. It was included in the Guidelines for diagnosis and treatment of common gynecological diseases of traditional Chinese medicine published by the Chinese Academy of Traditional Chinese Medicine in 2012,the Pelvic inflammatory diseases diagnosis and treatment guidelines issued by the Infectious Diseases Collaborative Group of the Obstetrics and Gynecology Branch of the Chinese Medical Association in 2014,and the group standard of Single use of traditional Chinese medicine/combined antibiot guidelines for clinical practice-pelvic inflammatory diseases of the Chinese Academy of Traditional Chinese Medicine in 2017. To further enhance clinicians' understanding of the drug and better guide its rational clinical use,experts from the field of gynecology of traditional Chinese and Western medicine were invited to develop and compile this expert consensus. This consensus takes full account of clinical evidences and expert clinical experience,and form recommendations for clinical problems based on evidences and consensus recommendations for clinical problems without evidence by nominal grouping method. The expert consensus is mainly formed in the consideration of six factors: quality of evidence,economy,efficacy,adverse reactions,patient acceptability and others. Based on clinical research evidences and expert experience,this consensus provides a preliminary reference for the clinical use of the drug in a concise and clear format. However,evidence-based support is still required in a large number of high-quality studies,and this consensus will be revised in the future according to new clinical problems and the update of evidence-based evidence in practical application.

Effect of Acupuncture and Clomiphene in Chinese Women With Polycystic Ovary Syndrome: A Randomized Clinical Trial.

Importance: Acupuncture is used to induce ovulation in some women with polycystic ovary syndrome, without supporting clinical evidence. Objective: To assess whether active acupuncture, either alone or combined with clomiphene, increases the likelihood of live births among women with polycystic ovary syndrome. Design, Setting, and Participants: A double-blind (clomiphene vs placebo), single-blind (active vs control acupuncture) factorial trial was conducted at 21 sites (27 hospitals) in mainland China between July 6, 2012, and November 18, 2014, with 10 months of pregnancy follow-up until October 7, 2015. Chinese women with polycystic ovary syndrome were randomized in a 1:1:1:1 ratio to 4 groups. Interventions: Active or control acupuncture administered twice a week for 30 minutes per treatment and clomiphene or placebo administered for 5 days per cycle, for up to 4 cycles. The active acupuncture group received deep needle insertion with combined manual and low-frequency electrical stimulation; the control acupuncture group received superficial needle insertion, no manual stimulation, and mock electricity. Main Outcomes and Measures: The primary outcome was live birth. Secondary outcomes included adverse events. Results: Among the 1000 randomized women (mean [SD] age, 27.9 [3.3] years; mean [SD] body mass index, 24.2 [4.3]), 250 were randomized to each group; a total of 926 women (92.6%) completed the trial. Live births occurred in 69 of 235 women (29.4%) in the active acupuncture plus clomiphene group, 66 of 236 (28.0%) in the control acupuncture plus clomiphene group, 31 of 223 (13.9%) in the active acupuncture plus placebo group, and 39 of 232 (16.8%) in the control acupuncture plus placebo group. There was no significant interaction between active acupuncture and clomiphene (P = .39), so main effects were evaluated. The live birth rate was significantly higher in the women treated with clomiphene than with placebo (135 of 471 [28.7%] vs 70 of 455 [15.4%], respectively; difference, 13.3%; 95% CI, 8.0% to 18.5%) and not significantly different between women treated with active vs control acupuncture (100 of 458 [21.8%] vs 105 of 468 [22.4%], respectively; difference, -0.6%; 95% CI, -5.9% to 4.7%). Diarrhea and bruising were more common in patients receiving active acupuncture than control acupuncture (diarrhea: 25 of 500 [5.0%] vs 8 of 500 [1.6%], respectively; difference, 3.4%; 95% CI, 1.2% to 5.6%; bruising: 37 of 500 [7.4%] vs 9 of 500 [1.8%], respectively; difference, 5.6%; 95% CI, 3.0% to 8.2%). Conclusions and Relevance: Among Chinese women with polycystic ovary syndrome, the use of acupuncture with or without clomiphene, compared with control acupuncture and placebo, did not increase live births. This finding does not support acupuncture as an infertility treatment in such women. Trial Registration: clinicaltrials.gov Identifier: NCT01573858.

Serum metabolomics study of polycystic ovary syndrome based on liquid chromatography-mass spectrometry.

Polycystic ovary syndrome (PCOS) is a complex, heterogeneous disorder, which produces in 5-10% reproductive age women. In this study, a nontargeted metabolomics approach based on ultra high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry is used to investigate serum metabolic characteristics of PCOS. PCOS women and healthy control can be clustered into two distinct groups based on multivariate statistical analysis. Significant increase in the levels of unsaturated free fatty acids, fatty acid amides, sulfated steroids, glycated amino acid and the decrease in levels of lysophosphatidylcholines, lysophosphatidylethanolamines, etc., were found. These metabolites showed abnormalities of lipid- and androgen-metabolism, increase of stearoyl-CoA desaturase (SCD) activity and accumulation of advanced glycation end-products in PCOS patients. On the basis of the binary logistic regression model, free fatty acid (FFA) 18:1/FFA 18:0, FFA 20:3, dihydrotestosterone sulfate, glycated phenylalanine, and uridine were combined as a diagnostic biomarker. The area under the curve (AUC) of combinational biomarker was 0.839 in 131 discovery phase samples and 0.874 in 109 validation phase samples. The findings of our study offer a new insight to understand the pathogenesis mechanism, and the discriminating metabolites may provide a prospect for PCOS diagnosis.

Maternal androgen excess reduces placental and fetal weights, increases placental steroidogenesis, and leads to long-term health effects in their female offspring.

Here, we tested the hypothesis that excess maternal androgen in late pregnancy reduces placental and fetal growth, increases placental steroidogenesis, and adversely affects glucose and lipid metabolism in adult female offspring. Pregnant Wistar rats were randomly assigned to treatment with testosterone (daily injections of 5 mg of free testosterone from gestational days 16 to 19) or vehicle alone. In experiment 1, fetal and placental weights, circulating maternal testosterone, estradiol, and corticosterone levels, and placental protein expression and distribution of estrogen receptor-α and -ß, androgen receptor, and 17ß-hydroxysteroid dehydrogenase 2 were determined. In experiment 2, birth weights, postnatal growth rates, circulating testosterone, estradiol, and corticosterone levels, insulin sensitivity, adipocyte size, lipid profiles, and the presence of nonalcoholic fatty liver were assessed in female adult offspring. Treatment with testosterone reduced placental and fetal weights and increased placental expression of all four proteins. The offspring of testosterone-treated dams were born with intrauterine growth restriction; however, at 6 wk of age there was no difference in body weight between the offspring of testosterone- and control-treated rats. At 10-11 wk of age, the offspring of the testosterone-treated dams had less fat mass and smaller adipocyte size than those born to control rats and had no difference in insulin sensitivity. Circulating triglyceride levels were higher in the offspring of testosterone-treated dams, and they developed nonalcoholic fatty liver as adults. We demonstrate for the first time that prenatal testosterone exposure alters placental steroidogenesis and leads to dysregulation of lipid metabolism in their adult female offspring.

High-affinity VEGF antagonists by oligomerization of a minimal sequence VEGF-binding domain.

Vascular endothelial growth factor (VEGF) neutralizing antagonists including antibodies or receptor extracellular domain Fc fusions have been applied clinically to control angiogenesis in cancer, wet age-related macular degeneration, and edema. We report here the generation of high-affinity VEGF-binding domains by chemical linkage of the second domain of the VEGF receptor Flt-1 (D2) in several configurations. Recombinant D2 was expressed with a 13 a.a. C-terminal tag, including a C-terminal cysteine to enable its dimerization by disulfide bond formation or by attachment to divalent PEGs and oligomerization by coupling to multivalent PEGs. Disulfide-linked dimers produced by Cu(2+) oxidation of the free-thiol form of the protein demonstrated picomolar affinity for VEGF in solution, comparable to that of a D2-Fc fusion (sFLT01) and ~50-fold higher than monomeric D2, suggesting the 26 a.a. tag length between the two D2 domains permits simultaneous interaction of both faces of the VEGF homodimer. Extending the separation between the D2 domains by short PEG spacers from 0.35 kD to 5 kD produced a modest ~2-fold increase in affinity over the disulfide, thus defining the optimal distance between the two D2 domains for maximum affinity. By surface plasmon resonance (SPR), a larger (~5-fold) increase in affinity was observed by conjugation of the D2 monomer to the termini of 4-arm PEG, and yielding a product with a larger hydrodynamic radius than sFLT01. The higher affinity displayed by these D2 PEG tetramers than either D2 dimer or sFLT01 was largely a consequence of a slower rate of dissociation, suggesting the simultaneous binding by these tetramers to neighboring surface-bound VEGF. Finally, disulfide-linked D2 dimers showed a greater resistance to autocatalytic fragmentation than sFLT01 under elevated temperature stress, indicating such minimum-sequence constructs may be better suited for sustained-release formulations. Therefore, these constructs represent novel Fc-independent VEGF antagonists with ultrahigh affinity, high stability, and a range of hydrodynamic radii for application to multiple therapeutic targets.

Tai Chi for Overweight/Obese Adolescents and Young Women with Polycystic Ovary Syndrome: A Randomized Controlled Pilot Trial.

Background: Exercise is one of the recommended interventions for polycystic ovary syndrome (PCOS), and current evidence has shown that Tai chi may have favorable effects. The objective of this randomized controlled pilot trial was to study the feasibility and potential effects of Tai chi for overweight/obese adolescents and young women with PCOS, so a future definitive randomized controlled trial (RCT) can be well designed and implemented. Materials and Methods: This study recruited 50 patients who were randomly assigned to two groups (Tai chi and self-monitored exercise) at a ratio of 3 : 2. The intervention lasted for 3 months, and the feasibility and effectiveness outcomes were measured. Results: A total of 42 patients completed the study, including 24 in the Tai chi group and 18 in the control group. Compared with the self-monitored exercise group, there was a significantly decreased body mass index (BMI) in the Tai chi group adjusted for baseline BMI. The testosterone level and lipid profile were also decreased compared to controls; the same tendency was also observed for the homeostasis model assessment of insulin resistance (HOMA-IR), but the difference did not achieve statistical significance. Twenty-four (out of 30, 80%) patients in the Tai chi group and 18 (out of 20, 90%) patients in the self-monitored exercise group completed the data collection. A total of 36 exercise sessions were held in both groups. Patients in the Tai chi group took a mean of 34.0 ± 2.21 classes (93.06%), and those in the self-monitored exercise group engaged in 32 ± 3.06 exercise sessions (88.27%) out of the 36 required exercise sessions. Conclusions: The present pilot study was feasible to deliver; there was a decrease in BMI, testosterone level, and lipid profile for PCOS patients in the Tai chi group at 3 months. In a future definitive trial, lower recruitment rate and outcome measurements lead to poor patient acceptance such as the 5-time point oral glucose tolerance test need to be considered and one fixed type of aerobic exercise and supervision from the investigator for the control group are also needed. Trial registration: ClinicalTrials.gov, NCT02608554.

HDAC5 inhibits ovarian angiogenesis in dehydroepiandrosterone-induced mouse model of polycystic ovary syndrome.

INTRODUCTION: Abnormal ovarian angiogenesis is a common feature of polycystic ovary syndrome (PCOS), a typical endocrine disorder affecting women of reproductive age. Histone deacetylase 5 (HDAC5) has been documented as a suppressor of angiogenesis. The aim of this study was to explore the effect of HDAC5 on ovarian angiogenesis in a PCOS mouse model. MATERIAL AND METHODS: PCOS was induced in female C57BL/6 mice by 20-day administration of dehydroepiandrosterone (DHEA). HDAC5 was over-expressed in PCOS mice by corresponding adenovirus injection. In total, 120 mice were used in this study. Western-blotting, real-time PCR, hematoxylin and eosin staining, enzyme-linked immunosorbent assay (ELISA), immunohistochemical staining, flow cytometry, and co-immunoprecipitation were respectively used to evaluate the effect of HDAC5 on PCOS mice. RESULTS: PCOS ovaries showed a compensatory increase in HDAC5 expression, while HDAC5 over-expression alleviated abnormalities in ovarian morphology and serum hormone levels after PCOS modeling. HDAC5 inhibited ovarian angiogenesis in PCOS mice by regulating angiogenesis-related factors, such as VEGFA, platelet-derived growth factors B and D (PDGFB/D), and angiopoietins 1 and 2 (ANGPT1/2) and CD31. HDAC5 over-expression decreased levels of reactive oxygen species (ROS) and malondialdehyde, while promoting activities of catalase and superoxide dismutase in ovaries of PCOS mice, suggesting its suppressive effects on oxidative stress, an inducer of uncontrolled angiogenesis. Moreover, HDAC5 suppressed activation of angiogenesis-related HIF-1α/VEGFA/VEGFR2 signaling in PCOS ovaries partly via inhibiting VEGFR2 acetylation. CONCLUSIONS: This study reveals the protective role of HDAC5 in PCOS by inhibiting ovarian angiogenesis and provides a molecular candidate for PCOS therapy in the future.

Cryptotanshinone reverses reproductive and metabolic disturbances in prenatally androgenized rats via regulation of ovarian signaling mechanisms and androgen synthesis.

This trial explores 1) prenatally androgenized (PNA) rats as a model of polycystic ovary syndrome (PCOS) and 2) reproductive and metabolic effects of cryptotanshinone in PNA ovaries. On days 16-18 of pregnancy, 10 rats were injected with testosterone propionate (PNA mothers) and 10 with sesame oil (control mothers). At age 3 mo, 12 female offspring from each group were randomly assigned to receive saline and 12 cryptotanshinone treatment during 2 wk. Before treatment, compared with the 24 controls, the 24 PNA rats had 1) disrupted estrous cycles, 2) higher 17-hydroxyprogesterone (P = 0.030), androstenedione (P = 0.016), testosterone and insulin (P values = 0.000), and glucose (P = 0.047) levels, and 3) higher areas under the curve (AUC) for glucose (AUC-Glu, P = 0.025) and homeostatic model assessment for insulin resistance (HOMA-IR, P = 0.008). After treatment, compared with vehicle-treated PNA rats, cryptotanshinone-treated PNA rats had 1) improved estrous cycles (P = 0.045), 2) reduced 17-hydroxyprogesterone (P = 0.041), androstenedione (P = 0.038), testosterone (P = 0.003), glucose (P = 0.036), and insulin (P = 0.041) levels, and 3) lower AUC-Glu (P = 0.045) and HOMA-IR (P = 0.024). Western blot showed that cryptotanshinone reversed the altered protein expressions of insulin receptor substrate-1 and -2, phosphatidylinositol 3-kinase p85α, glucose transporter-4, ERK-1, and 17α-hydroxylase within PNA ovaries. We conclude that PNA model rats exhibit reproductive and metabolic phenotypes of human PCOS and that regulation of key molecules in insulin signaling and androgen synthesis within PNA ovaries may explain cryptotanshinone's therapeutic effects.

A retro-inverso α-melanocyte stimulating hormone analog with MC1R-binding selectivity.

α-melanocyte stimulating hormone (α-MSH) is a tridecapeptide fragment of pro-opiomelanocortin (POMC) with broad effects on appetite, skin pigmentation, hormonal regulation, and potential roles in both inflammation and autoimmunity. The use of this peptide as an anti-inflammatory agent is limited by its low selectivity between the melanocortin receptors, susceptibility to proteolytic degradation, and rapid clearance from circulation. A retro-inverso (RI) sequence of α-MSH was characterized for receptor activity and resistance to protease. This peptide demonstrated surprisingly high selectivity for binding the melanocortin receptor 1 (MC1R). However, RI-α-MSH exhibited a diminished binding affinity for MC1R compared to α-MSH. Mapping of the residues critical for agonist activity, receptor binding, and selectivity by alanine scanning, identified the same critical core tetrapeptide required for the native peptide. Modest improvements in affinity were obtained by conservative changes employing non-natural amino acids and substitution of the C-terminal sequence with a portion of a MC1R ligand peptide previously identified by phage display. Recombination of these elements yielded a peptide with an identical K(i) as α-MSH at MC1R and a lower EC(50) in Mel-624 melanoma cells. A number of other structural modifications of the RI peptide were found to differ in effect from those reported for the L-form α-MSH, suggesting a significantly altered interaction with the MC1R.

[Impact of Cryptotanshinone on the reproductivity and metabolism of male mice with Akt2 deletion].

OBJECTIVE: To investigate the impact of protein kinase B (Akt2) allele deletion on testicular reproductive function, and to discuss the regulatory effect of Cryptotanshinone on the reproductivity of male mice with Akt2 allele deletion and its molecular mechanism. METHODS: Fifteen Akt2 +/+ male mice were randomly divided into Groups A (baseline control, n = 7) and B (stimulation, n = 8), and another 29 Akt2 -/- male mice into C (baseline control, n = 7), D (stimulation, n = 8), E (solvent, n = 7) and F (Cryptotanshinone, n = 7). Groups B and D underwent human chorionic gonadotropin (HCG) stimulation tests at 5 IU / 20 g, while A and C received physiological saline, all for 4 hours; Group F were given gastric lavage of Cryptotanshinone, while E solvent only, at 600 mg/kg twice a day for 8 weeks, both subjected to oral glucose tolerance tests (OGTT) at 2 g/kg before and after the treatment. The body and bilateral testis weights were obtained, the serum testosterone (T) level measured, and the expressions of testicular steroid hormone synthesis and glycometabolism-related genes determined by RT-PCR. RESULTS: OGTT showed that the level of blood glucose was significantly higher in Groups C and D than in A and B ([10.38 +/- 1.42] and [10.96 +/- 1.81] mmol/L vs [7.92 +/- 0.63] and [8.32 +/- 0.44] mmol/L, P < 0.05), but had no significant differences at different time points in E and F (P > 0.05). The testis weight was remarkably higher in Groups C and D than in A and B ([0.17 +/- 0.01] and [0.17 +/- 0.01] g vs [0.15 +/- 0.01] and [0.15 +/- 0.02] g, P < 0.05), but exhibited no obvious difference in E and F, nor were there any significant differences in body weight among different groups (P > 0.05). The serum T level was markedly higher in Group C than in A ([9.08 +/- 1.59] nmol/L vs [6.42 +/- 0.95] nmol/L, P < 0.05), but evidently lower in F than in E ([5.94 +/- 0.49] nmol/L vs [8.18 +/- 1.44] nmol/L, P < 0.05). The baseline expression levels of Cyp11, Cyp17, 3B-HSD, Star, Gsk3beta, Erk-1, and MCM2 mRNA were significantly higher in Group C than in A (P < 0.05). After HCG stimulation, the expressions of Cyp11, Cyp17, 3B-HSD, and Star mRNA were remarkably increased in B and D, but with no obvious difference between the two groups (P > 0.05), while the expressions of Cyp11, Cyp17, 3B-HSD, Star, Gsk3beta, Erk-1, and MCM2 mRNA markedly decreased in F as compared with E (P < 0.05). CONCLUSION: Akt2 gene deletion may affect glycometabolism and testicular function, and cause abnormal glycometabolism and androgen secretion in male mice, whose molecular mechanism is associated with the elevated expressions of the key glycometabolic molecules and of the key enzymes for androgen synthesis. Cryptotanshinone can reduce the levels of androgens by down-regulating the expressions of the key enzymes for androgen synthesis.

How to Screen and Prevent Metabolic Syndrome in Patients of PCOS Early: Implications From Metabolomics.

Background: Polycystic ovary syndrome (PCOS) is a complex reproductive endocrine disorder. And metabolic syndrome (MS) is an important bridge for PCOS patients to develop other diseases, such as diabetes and coronary heart disease. Our aim was to study the potential metabolic characteristics of PCOS-MS and identify sensitive biomarkers so as to provide targets for clinical screening, diagnosis, and treatment. Methods: In this study, 44 PCOS patients with MS, 34 PCOS patients without MS, and 32 healthy controls were studied. Plasma samples of subjects were tested by ultraperformance liquid chromatography (UPLC) system combined with LTQ-orbi-trap mass spectrometry. The changes of metabolic characteristics from PCOS to PCOS-MS were systematically analyzed. Correlations between differential metabolites and clinical characteristics of PCOS-MS were assessed. Differential metabolites with high correlation were further evaluated by the receiver operating characteristic (ROC) curve to identify their sensitivity as screening indicators. Results: There were significant differences in general characteristics, reproductive hormone, and metabolic parameters in the PCOS-MS group when compared with the PCOS group and healthy controls. We found 40 differential metabolites which were involved in 23 pathways when compared with the PCOS group. The metabolic network further reflected the metabolic environment, including the interaction between metabolic pathways, modules, enzymes, reactions, and metabolites. In the correlation analysis, there were 11 differential metabolites whose correlation coefficient with clinical parameters was greater than 0.4, which were expected to be taken as biomarkers for clinical diagnosis. Besides, these 11 differential metabolites were assessed by ROC, and the areas under curve (AUCs) were all greater than 0.7, with a good sensitivity. Furthermore, combinational metabolic biomarkers, such as glutamic acid + leucine + phenylalanine and carnitine C 4: 0 + carnitine C18:1 + carnitine C5:0 were expected to be sensitive combinational biomarkers in clinical practice. Conclusion: Our study provides a new insight to understand the pathogenesis mechanism, and the discriminating metabolites may help screen high-risk of MS in patients with PCOS and provide sensitive biomarkers for clinical diagnosis.

Site-Specific Antibody Conjugation to Engineered Double Cysteine Residues.

Site-specific antibody conjugations generate homogeneous antibody-drug conjugates with high therapeutic index. However, there are limited examples for producing the site-specific conjugates with a drug-to-antibody ratio (DAR) greater than two, especially using engineered cysteines. Based on available Fc structures, we designed and introduced free cysteine residues into various antibody CH2 and CH3 regions to explore and expand this technology. The mutants were generated using site-directed mutagenesis with good yield and properties. Conjugation efficiency and selectivity were screened using PEGylation. The top single cysteine mutants were then selected and combined as double cysteine mutants for expression and further investigation. Thirty-six out of thirty-eight double cysteine mutants display comparable expression with low aggregation similar to the wild-type antibody. PEGylation screening identified seventeen double cysteine mutants with good conjugatability and high selectivity. PEGylation was demonstrated to be a valuable and efficient approach for quickly screening mutants for high selectivity as well as conjugation efficiency. Our work demonstrated the feasibility of generating antibody conjugates with a DAR greater than 3.4 and high site-selectivity using THIOMABTM method. The top single or double cysteine mutants identified can potentially be applied to site-specific antibody conjugation of cytotoxin or other therapeutic agents as a next generation conjugation strategy.

[Study on the apoptosis inducing effect of pseudolaric acid B on cervical carcinoma cell line HeLa cells].

OBJECTIVE: To investigate the biological effect and mechanism of action of pseudolaric acid B (PAB) on the cultured human HeLa cells in vitro. METHODS: MTT and flow cytometric assays were used to detect the cells proliferation inhibitory rate and apoptosis of HeLa cell in exposure to PAB; the morphological changes of apoptosis were observed with electron microscope; and the expressions of p53/bcl-2/bax mRNA were detected by RT-PCR. RESULTS: (1) HeLa cell proliferation was inhibited by PAB in a dose-dependent manner, the IC50 being about 10 micromol/L; (2) flow cytometry showed that the distribution of HeLa cell cycle was changed time-dependently by 10 micromol/L PAB-treatment, showing decrease of G0/G1 phase cell percentage and increase of G2/M phase cell percentage; (3) the bax mRNA expression elevated and bcl-2 protein expression decreased markedly after being treated by 10 micromol/L PAB for 12 h, 24 h, and 48 h; while the expression of p53 mRNA could not be detected. CONCLUSION: PAB can inhibit the proliferation and induce the apoptosis of Hela cells in vitro, and its molecular mechanism may be associated with up-regulating bax mRNA expression and down-regulating bcl-2 mRNA expression.

[Disorder of Tiangui (kidney essence) and reproductive dysfunction in patients with polycystic ovary syndrome].

Traditional Chinese medicine (TCM) usually views polycystic ovary syndrome (PCOS) as a menstrual disease or infertility disease. Reproductive dysfunction in PCOS is characterized by ovarian androgen excess and disturbance of follicular development, and its main clinical manifestations include delayed menstruation, scant menstruation, amenorrhea or infertility. Insulin resistance is a key pathological mechanism of PCOS. "Tiangui" (kidney essence) as a sex-stimulating essence in female in TCM theory, is essential to the menstruation and pregnancy of women. The disturbance of Tiangui (including time, status and rhythm) would result in female reproductive problems. Current studies of Tiangui indicate that ovary is the target organ of PCOS treatment, and its functional characteristics are consistent with the properties of Tiangui in time frame, state form and rhythm cycle. It is then concluded that ovarian dysfunction in PCOS can be expressed as disorder of Tiangui.

Elevated maternal androgen is associated with dysfunctional placenta and lipid disorder in newborns of mothers with polycystic ovary syndrome.

OBJECTIVE: To investigate the placental morphology alterations and identify the clinical characteristics of women with polycystic ovary syndrome (PCOS) and their newborns. Pregnant women with PCOS (n = 12) and pregnant women without PCOS (n = 11) were recruited. Then, the placenta, maternal blood and cord blood were collected after delivery. DESIGN: Clinical observational study. SETTING: Not applicable. PATIENT(S): In the present study, pregnant women with PCOS and healthy pregnant women were recruited from the clinic of the Department of Obstetrics and Gynecology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, China, between February 2015 and October 2015. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): A proteomic analysis was performed on the placenta in women with PCOS and healthy women. RESULT(S): The maternal testosterone, androstenedione, dehydroepiandrosterone sulfate, free androgen index, cholesterol, apolipoprotein B, and apolipoprotein B/apolipoprotein A-I levels were significantly higher in the PCOS group than in the control group, and the offspring in the PCOS group had higher dehydroepiandrosterone sulfate, high-density lipoprotein, and cholesterol levels, when compared with the control group. The placenta in the PCOS group demonstrated infarction, calcification, and a greater intervillous space, when compared with the control group. A higher level of estrogen receptor-ß protein was observed in the placenta of women with PCOS, when compared with women without PCOS. A total of 258 proteins in the placenta were identified to be significantly different, when the PCOS and control groups were compared, and fibronectin 1 exhibited the closest relationship with other differential proteins. CONCLUSION(S): The overexposure to hyperandrogenism and hyperlipidemia affects the functions of the placenta, which are associated with the development of metabolic disorders in newborns.

[Insulin resistance enhanced the response of the ovary].

OBJECTIVE: To search for the role of impaired insulin signaling in the ovary reproductive failure and abnormal metabolic profiles in the AKT2- mouse. METHODS: Adult, female 129/C57BL/6 (AKT2-) mice were used in these studies. Littermate wide types C57BL/6J (AKT2+), as well as mutant genotypes (AKT2-). The ovaries were abstained from 6 AKT2+ type mice as wall as 6 mutant genotypes, which was used for insulin stimulated glucose uptake study. By ovary transplantation on the day of 12 weeks, three genotypic mice were constructed with body AKT2+ and ovary AKT2+ in Group A, body AKT2+ and ovary AKT2- in Group B, body AKT2- and ovary AKT2+ in Group C. The vaginal smear was done to evaluate the recovery and cyclicity of transplanted ovaries with mutant or intact AKT2. Before execution, every group was randomly separated into basal and stimulated groups in which the mice were injected recombination FSH (0.75 IU/g), and then AKT2, GSK3beta, ERK-1, CYP17 and CYP19 were determined by RT-PCR in the ovaries, and the serum were reserved for the assay of HDL-C, CHO, TG, 17-OHP progesterone, E(2), T, and LH. The weight of each mouse, their ovary and their fat pads and the estrus cycle, were also recorded. RESULTS: (1) The weight of fat pads beside ovaries and fold inguen in C group were significant higher than the other groups. (2) The level of 17-OHP progesterone in B group was higher than A or C group both in basal and FSH-stimulated groups. (3) In the basal group the expression of ERK-1 and CYP17 were enhanced. Moreover in FSH-d stimulated group, the expression of ERK-1, CYP17, CYP19 and GSK3B in B group were higher as compared with the other groups. CONCLUSION: (1) IR existed in the ovary of AKT2- type, and the mice with AKT2-type ovary had delayed cycle, PCO and high level of 17-OHP, which were similar with PCOS. (2) Metabolic dysfunction in the AKT2- mice has close relationship with whole body condition, but not defective insulin signal within ovaries. (3) Defects of insulin activity in the metabolic pathway could induce the increased expression of ERK-1 and mitogenic potential indicating the cross-talk between two pathways of insulin signaling within ovarian cells. Consequently, ovarian hyperovarianism was induced in the defective ovaries, which contribute to the enhanced response to gonadotropin and synthesis of steroid hormone.

Auricular points acupressure for insulin resistance in overweight/obese women with polycystic ovary syndrome: protocol for a randomised controlled pilot trial.

INTRODUCTION: Approximately 5%-20% of reproductive women suffer from polycystic ovary syndrome (PCOS). Auricular points acupressure (AA) may serve as alternative management for PCOS for its benefits in both physical and psychological well-being. However, the effects of AA for insulin resistance (IR) in overweight/obese PCOS women have not been confirmed. METHODS AND ANALYSIS: The present study is designed as a randomised, placebo-controlled pilot trial to evaluate the effectiveness and safety of AA in treating IR in women with PCOS. A total of 60 eligible PCOS subjects will be randomised into an intervention group (AA group) and a control group (sham AA group) in a ratio of 1:1. Magnetic beads will be taped to the auricular points by the same senior acupuncture specialist from the First Affiliated Hospital, Heilongjiang University of Chinese Medicine. The treatment will last for 12 weeks. Primary outcome measure will be changes in homeostasis model assessment of IR between baseline and after 3 months of AA/sham AA treatment. Secondary outcomes include hormonal profile, weight, waist/hip circumference, body mass index, blood pressure, Ferriman-Gallwey score, acne and the assessment of health-related quality of life. Outcome measures are collected at baseline and the end of treatment visit. ETHICS AND DISSEMINATION: The protocol has been approved by the ethics committee of the First Affiliated Hospital of Heilongjiang University of Chinese Medicine (HZYLLKY201800301). Written informed consent will be obtained from all participants. The results will be disseminated through peer-reviewed journals for publications. TRIAL REGISTRATION NUMBER: NCT03546595; Pre-results.