Increased Circulating IL-32 Is Associated With Placenta Macrophage-derived IL-32 and Gestational Diabetes Mellitus.

OBJECTIVE: Placenta-derived inflammation plays a vital role in the pathophysiology of gestational diabetes mellitus (GDM). IL-32 is a novel pro-inflammatory cytokine and metabolic regulator involved in the development of metabolic disease. We investigated the effect of IL-32 in GDM. MATERIALS AND METHODS: First-trimester C-reactive protein (CRP) level was monitored in a case-control study of 186 women with GDM and 186 women without. Placental tissue was lysed and analyzed by high-resolution liquid chromatography-tandem mass spectrometry. Circulating level of inflammatory cytokines IL-32, IL-6, and TNF-α were measured by ELISA kits. The expression of placenta-derived macrophages, inflammatory cytokines, and related pathway proteins were assessed by reverse transcriptase-quantitative PCR, western blot, immunohistochemistry, or immunofluorescence. RESULTS: First-trimester CRP level in peripheral blood was closely associated with glucose and insulin resistance index and was an independent correlation with the development of GDM. High-resolution liquid chromatography-tandem mass spectrometry revealed that placenta-derived CRP expression was dramatically elevated in women with GDM. Interestingly, the expression of placenta-derived IL-32 was also increased and located in the macrophages of placental tissue. Meanwhile, the expression of IL-6, TNF-α, and p-p38 were up-regulated in the placental tissues with GDM. Either IL-6 or TNF-α was colocated with IL-32 in the placental tissue. Importantly, circulating IL-32 throughout pregnancy was increased in GDM and was related to placental-derived IL-32 expression, circulating IL-6, and TNF-α, glucose and insulin resistance index. CONCLUSION: Increased circulating IL-32 throughout pregnancy was closely associated with placenta macrophage-derived IL-32 expression and GDM. First trimester IL-32 level in peripheral blood may serve to predict the development of GDM.

PPARG: A Promising Therapeutic Target in Breast Cancer and Regulation by Natural Drugs.

Breast cancer (BC) is the most common type of cancer among females. Peroxisome proliferator-activated receptor gamma (PPARG) can regulate the production of adipocyte-related genes and has anti-inflammatory and anti-tumor effects. Our aim was to investigate PPARG expression, its possible prognostic value, and its effect on immune cell infiltration in BC, and explore the regulatory effects of natural drugs on PPARG to find new ways to treat BC. Using different bioinformatics tools, we extracted and comprehensively analyzed the data from the Cancer Genome Atlas, Genotype-Tissue Expression, and BenCaoZuJian databases to study the potential anti-BC mechanism of PPARG and potential natural drugs targeting it. First, we found that PPARG was downregulated in BC and its expression level correlates with pathological tumor stage (pT-stage) and pathological tumor-node-metastasis stage (pTNM-stage) in BC. PPARG expression was higher in estrogen receptor-positive (ER+) BC than in estrogen receptor-negative (ER-) BC, which tends to indicate a better prognosis. Meanwhile, PPARG exhibited a significant positive correlation with the infiltration of immune cells and correlated with better cumulative survival in BC patients. In addition, PPARG levels were shown to be positively associated with the expression of immune-related genes and immune checkpoints, and ER+ patients had better responses to immune checkpoint blocking. Correlation pathway research revealed that PPARG is strongly associated with pathways, such as angiogenesis, apoptosis, fatty acid biosynthesis, and degradation in ER+ BC. We also found that quercetin is the most promising natural anti-BC drug among natural medicines that upregulate PPARG. Our research showed that PPARG may reduce BC development by regulating the immune microenvironment. Quercetin as PPARG ligands/agonists is a potential natural drug for BC treatment.

Manipulating electromagnetic waves in a cavity-waveguide system with nontrivial and trivial modes.

The coupled cavity-waveguide approach provides a flexible platform to design integrated photonic devices that are widely applied in optical communications and information processing. Topological photonic crystals that can excite the nontrivial edge state (ES) and corner state (CS) have an unprecedented capability to manipulate electromagnetic (EM) waves, leading to a variety of unusual functionalities that are impossible to achieve with conventional cavity-waveguide systems. In this Letter, two-dimensional photonic crystals consisting of an ES waveguide, a CS cavity, and a trivial cavity are proposed as a means to robustly control the transmission characteristics of electromagnetic waves. As a proof-of-principle example, the analog of electromagnetically induced transparency (EIT) that is tolerated in disorders due to the robustness of the CS is numerically demonstrated. In addition, the analog of multi-EIT is also verified by introducing a trivial cavity with two degenerate orthogonal modes. This unique approach for robustly manipulating EM waves may open an avenue to the design of high-performance filters, modulators, and on-chip processors.

Population pharmacokinetic/pharmacodynamic analysis of PEG-rhGH enhances confidence in exploring dosing schemes with longer intervals.

BACKGROUND AND OBJECTIVES: PEG-rhGH (Jintrolong®, 0.2 mg/kg/week) is approved in China for the treatment of growth hormone deficiency (GHD) in children. Although 0.2 mg/kg/2 weeks PEG-rhGH failed the non-inferiority threshold of 20% compared with 0.2 mg/kg/week PEG-rhGH, it notably increases serum IGF-1 levels and height velocity in a phase IV trial. In the absence of investigation on the relationship between pharmacokinetics and pharmacodynamics, this analysis aimed to build a population pharmacokinetic/pharmacodynamic (PopPK/PD) model to characterize the relationship between serum PEG-rhGH concentration and serum insulin-like growth factor-1 (IGF-1) levels after subcutaneously administration of PEG-rhGH and to explore the possibility of flexible dosing schemes and improve the clinical monitor practice of IGF-1 levels. METHODS: A total of 41 subjects were included for the PopPK analysis, consisting of 30 healthy adults (single dose of 0.1-0.4 mg/kg) and 11 GHD children (multiple doses of 0.2 mg/kg/2 weeks for 26 consecutive weeks). Only GHD children were included for the PopPK/PD analysis. The time courses of serum PEG-rhGH concentrations in healthy adults and GHD children and those of serum IGF-1 levels stimulated by serum PEG-rhGH were well developed with non-linear mixed-effects modeling. RESULTS: Serum PEG-rhGH pharmacokinetics after subcutaneous administration were adequately described by a one-compartment model with a zero-order input into the absorption compartment followed by first-order absorption dictating absorption into the central compartment, with a dual elimination process consisting of a capacity limited process and a non-capacity limited process. Body weight was a significant covariate. The drug effects on IGF-1 levels were adequately described by a turnover model with saturable effect relationship. IGF-1 responses at the various dosing scheme scenarios were simulated, and illustrated that dosing schemes with intervals longer than the approved one week could be promising, which may provide comparable peaks and average IGF-1 levels and IGF-1 SDS to dosing schemes that have been clinically proven to be tolerated and effective. An accurate prediction of the time course of the effect of various dosing schemes may assist the clinical monitoring practice. CONCLUSIONS: This pharmacokinetic/pharmacodynamic analysis suggested that longer intervals or higher dosing strengths (e.g., 0.3 mg/kg/10 days) in children with GHD are promising compared with the approved dosing scheme (0.2 mg/kg/week). Our simulation may assist the clinical monitoring of the PEG-rhGH therapy.

Better detoxifying effect of ripe forsythiae fructus over green forsythiae fructus and the potential mechanisms involving bile acids metabolism and gut microbiota.

Forsythiae Fructus (FF), the fruit of Forsythia suspensa (Thunb.) Vahl. (Lianqiao), is one of the most fundamental herbs in Traditional Chinese Medicines (TCM), mainly due to its heat-clearing and detoxifying effects. There are two types of FF, the greenish fruits that start to ripen (GF) and the yellow fruits that are fully ripe (RF), called "Qingqiao" and "Laoqiao" referred to the Chinese Pharmacopoeia, respectively. It undergoes a complex series of changes during the maturation of FF. However, the clinical uses and preparation of phytopharmaceuticals of FF have not been distinguished to date. Moreover, there is limited information on the study of the difference in pharmacological activity between RF and GF. In this study, a rat model of bile duct ligation (BDL)-induced cholestasis was used to compare the differences in their effects. RF was found to have better results than GF in addressing toxic bile acids (BAs) accumulation and related pathological conditions caused by BDL. The underlying mechanism may be related to the interventions of gut microbiota. The results of the present study suggest that the better detoxifying effect of RF than GF may be indirectly exerted through the regulation of gut microbiota and thus the improvement of BAs metabolism.

"Rim-Differentiated" Pillar[6]arenes.

A "rim-differentiated" pillar[6]arene (RD-P[6]) was obtained successfully, with the assistance of a dimeric silver trifluoroacetate template, among eight different constitutional isomers in a direct and regioselective manner. The solid-state conformation of this macrocycle could switch from the 1,3,5-alternate to a truly rim-differentiated one upon guest inclusion. This highly symmetric RD-P[6] not only hosts metal-containing molecules inside its cavity, but also can form a pillar[6]arene-C60 adduct through co-crystallization on account of donor-acceptor interactions. The development of synthetic strategies to desymmetrize pillararenes offers new opportunities for engineering complex molecular architectures and organic electronic materials.

Decreased Monocyte Count Is Associated With Gestational Diabetes Mellitus Development, Macrosomia, and Inflammation.

CONTEXT: The immune system plays a central role in the pathophysiology of gestational diabetes mellitus (GDM). Monocytes, the main innate immune cells, are especially important in the maintenance of a normal pregnancy. OBJECTIVE: Here, we investigated the potential effect of monocytes in GDM. METHODS: Monocyte count was monitored throughout pregnancy in 214 women with GDM and 926 women without in a case-control and cohort study. Circulating levels of inflammatory cytokines, placenta-derived macrophages, and their products were measured. RESULTS: Throughout pregnancy, monocyte count was significantly decreased in women with GDM, and was closely associated with glucose level, insulin resistance, and newborn weight. First-trimester monocyte count outperformed that of the second and third trimester as a risk factor and diagnostic predictor of GDM and macrosomia both in the case-control and cohort study. In addition, our cohort study showed that as first-trimester monocyte count decreased, GDM and macrosomia incidence, glucose level, and newborn weight increased in a stepwise manner. Risk of GDM started to decrease rapidly when first-trimester monocyte count exceeded 0.48 × 109/L. Notably, CD206 and interleukin 10 (IL-10) were significantly lower, whereas CD80, CD86, tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6) were higher both in GDM placental tissue and peripheral blood. First-trimester monocyte count was positively related to IL-10 and CD206, but negatively related to CD80, CD86, TNF-α, and IL-6. CONCLUSION: Decreased monocyte count throughout pregnancy was closely associated with the development of GDM, macrosomia, and the chronic inflammatory state of GDM. First-trimester monocyte count has great potential as an early diagnostic marker of GDM.

Alterations in CD8+ Tregs, CD56+ Natural Killer Cells and IL-10 Are Associated With Invasiveness of Nonfunctioning Pituitary Adenomas (NFPAs).

Invasive nonfunctioning pituitary adenomas (NFPAs) grow rapidly and the mechanisms are unclear. Among many complex mechanisms, the role of immunity in the development of NFPAs has not been fully explored. Here, we analyzed the clinical features 146 NFPA patients who underwent trans-sphenoidal surgery or craniotomy and examined the effects of immune tolerance in invasiveness of NFPA patients using fluorescence-activated cell sorting and immunohistochemical methods. We found patients with invasive NFPAs had more visual deficits and defective fields, higher tumor size, and lower white blood cell count compared with patients with noninvasive NFPAs. Additionally, compared with patients with noninvasive NFPAs, patients with invasive NFPAs had conspicuously lower CD3-CD56+ natural killer (NK) cells and significantly higher levels of CD3+CD8+CD28-T cells (CD8+ Tregs) and interleukin-10 (IL-10) in peripheral blood. Moreover, patients with invasive NFPAs had lower infiltrated CD56+ cells, less infiltrated CD28+ cells, and significantly greater IL-10 expression. These results demonstrated that low CD56+ cells infiltration and CD28+ cells infiltration, as well as high IL-10 expression in pituitary tumor tissues, were related with increased invasiveness of NFPAs. Levels of CD3-CD56+ NK cells, CD8+ Tregs and IL-10 in the peripheral blood could be feasible diagnostic markers for invasive NFPAs.

Preparation of Biodegradable Polymeric Nanocapsules for Treatment of Malignant Tumor Using Coaxial Capillary Microfluidic Device.

Objective: Nanocapsules play a role in the targeted delivery of chemotherapy drugs. However, the traditional technology for preparation of nanocapsules is relatively complex with poor controllability, leading to large differences batch to batch. This study aimed to evaluate the quality of drugs-loaded nanocapsules (Drugs-NCs) fabricated by coaxial capillary microfluidic device, and inhibitory effect on malignant tumors. Materials and Methods: In this study, oxaliplatin, irinotecan, and 5-fluorouracil were selected as chemotherapy drugs, and Drugs-NCs were prepared by coaxial glass capillary microfluidic device. Next, transmission electron microscope was utilized to characterize surface morphology and particle size distribution of Drugs-NCs. Then, high performance liquid chromatography was used to determine the drug loading and encapsulation efficiency. Dialysis method was performed to measure the drug release of Drugs-NCs in vitro. To study the effects of Drugs + NCs on tumor growth in vivo, BALB/c (nu/nu) nude mice were used in vivo experiments. Results: The Drugs-NCs were spherical and uniform in size (103.4 nm). Besides, the encapsulation efficiencies of oxaliplatin, irinotecan, and 5-fluorouracil were 97.0%, 95.7%, and 15.6%, respectively. Moreover, drugs encapsulated in the nanocapsules released less and was pH-dependent, with more rapid release being observed at pH 5.5 group compared with pH 7.4 group. MTT assay and in vivo experiments indicated the inhibitory effect of Drugs-NCs on malignant tumors. Conclusion: The prepared nanocapsules had potential tumor targeting. Furthermore, coaxial capillary microfluidic device could be used as a promising microfluidic technology to fabricate multiple Drug-NCs.

Prediction of Atorvastatin Pharmacokinetics in High-Fat Diet and Low-Dose Streptozotocin-Induced Diabetic Rats Using a Semiphysiologically Based Pharmacokinetic Model Involving Both Enzymes and Transporters.

Atorvastatin is a substrate of cytochrome P450 3a (CYP3a), organic anion-transporting polypeptides (OATPs), breast cancer-resistance protein (BCRP), and P-glycoprotein (P-gp). We aimed to develop a semiphysiologically based pharmacokinetic (semi-PBPK) model involving both enzyme and transporters for predicting the contributions of altered function and expression of CYP3a and transporters to atorvastatin transport in diabetic rats by combining high-fat diet feeding and low-dose streptozotocin injection. Atorvastatin metabolism and transport parameters comes from in situ intestinal perfusion, primary hepatocytes, and intestinal or hepatic microsomes. We estimated the expressions and functions of these proteins and their contributions. Diabetes increased the expression of hepatic CYP3a, OATP1b2, and P-gp but decreased the expression of intestinal CYP3a, OATP1a5, and P-gp. The expression and function of intestinal BCRP were significantly decreased in 10-day diabetic rats but increased in 22-day diabetic rats. Based on alterations in CYP3a and transporters by diabetes, the developed semi-PBPK model was successfully used to predict atorvastatin pharmacokinetics after oral and intravenous doses to rats. Contributions to oral atorvastatin PK were intestinal OATP1a5 < intestinal P-gp < intestinal CYP3a < hepatic CYP3a < hepatic OATP1b2 < intestinal BRCP. Contributions of decreased expression and function of intestinal CYP3a and P-gp by diabetes to oral atorvastatin plasma exposure were almost attenuated by increased expression and function of hepatic CYP3a and OATP1b2. Opposite alterations in oral plasma atorvastatin exposure in 10- and 22-day diabetic rats may be explained by altered intestinal BCRP. In conclusion, the altered atorvastatin pharmacokinetics by diabetes was the synergistic effects of altered intestinal or hepatic CYP3a and transporters and could be predicted using the developed semi-PBPK.

GESTATIONAL WEIGHT GAIN AS AN INDEPENDENT RISK FACTOR FOR MACROSOMIA IN WOMEN WITH INTERMEDIATE STATE GESTATIONAL BLOOD GLUCOSE.

Objective: Macrosomia is closely associated with gestational diabetes mellitus (GDM) but its relationship with maternal intermediate state gestational blood glucose (ISGBG; normal fasting blood glucose and 7.8 mmol/L <1 hour blood glucose [BG] <10 mmol/L or 6.7 mmol/L <2 hour BG <8.5 mmol/L) is unclear. Here, we analyzed the clinical characteristics and pregnancy outcomes and explored risk factors for macrosomia in women with ISGBG. Methods: A total of 847 women with normal glucose tolerance gestation, 330 with ISGBG, and 99 with GDM were included. Maternal and fetal clinical data were collected and 3-point BG following oral glucose tolerance test, fasting insulin, glycated hemoglobin, and blood lipids profile were measured. Results: The incidence rate of macrosomia among the neonates of women with ISGBG was as high as 10.9%. In the ISGBG group, prepregnancy body mass index (BMI), gestational weight gain (GWG) and the proportion of women with excessive GWG (eGWG) were significantly higher in women with macrosomia compared with those who delivered a normal weight neonate. In women with ISGBG, neonate weight was positively correlated with maternal prepregnancy weight (r = 0.183, P<.01), prepregnancy BMI (r = 0.135, P<.01), and GWG (r = 0.255, P<.01), and negatively correlated with high-density lipoprotein cholesterol (r = -0.172, P<.01). Nonetheless, only eGWG was an independent risk factor (odds ratio = 3.18, 95% confidence interval = 1.26 to 7.88, P<.05) for macrosomia. The risk of macrosomia in pregnant women with prepregnancy BMI <25 kg/m2 or BMI ≥25 kg/m2 and eGWG was 3.39 and 3.27 times, respectively. Conclusion: The incidence rate of macrosomia is increased in women with ISGBG and eGWG is the strongest independent risk factor. In order to reduce the risk for macrosomia, timely lifestyle intervention to promote appropriate weight gain during pregnancy deserves evaluation. Abbreviations: AUC = area under the curve; BG = blood glucose; 1 hour BG = 1 hour blood glucose after OGTT; 2 hour BG = 2 hour blood glucose after OGTT; BMI = body mass index; CI = confidence interval; eGWG = excessive gestational weight gain; FBG = fasting blood glucose; FINS = fasting insulin; GDM = gestational diabetes mellitus; HbA1c = glycated hemoglobin; HDL-C = high-density lipoprotein cholesterol; HOMA-IR = homeostasis model assessment of insulin resistance index; ISGBG = intermediate state gestation blood glucose; LDL-C = low-density lipoprotein cholesterol; Ln = natural logarithm; MLBW = mature low birth weight; NGTG = normal glucose tolerance gestation; OGTT = oral glucose tolerance test; OR = odds ratio; SD = standard deviation.

Characteristics of ß-oxidative and reductive metabolism on the acyl side chain of cinnamic acid and its analogues in rats.

Cinnamic acid and its analogues (pyragrel and ozagrel) undergo chain-shortened (ß-oxidative) and reductive metabolism on acyl side chain. In this study, we characterized the ß-oxidative and reductive metabolism on acyl side chain of cinnamic acid and its analogues using primary rat hepatocytes, hepatic mitochondrial, and microsomal systems. A compartmental model including parent compounds and metabolites was developed to characterize in vivo ß-oxidative and reductive metabolism following an intravenous dose of parent compounds to rats. The fitted total in vivo clearance values were further compared with the in vitro values predicted by the well-stirred model. We showed that hepatic microsomal CYP450s did not catalyze ß-oxidative or reductive metabolism of the three compounds. Similar to ß-oxidation of fatty acids, ß-oxidative metabolism on their acyl side chain occurred mainly in mitochondria, which was highly dependent on ATP, CoA and NAD+. Fatty acids and NADH inhibited the ß-oxidative metabolism. Reductive metabolism occurred in both mitochondria and microsomes. Reduction in mitochondria was ATP-, CoA-, and NAD(P)H-dependent and reversible, which was suppressed by enoyl reductase inhibitor triclosan. Reduction in microsomes was ATP-, CoA-, and NADPH-dependent but little affected by triclosan. Both plasma concentrations of ß-oxidative metabolites and reductive metabolites were successfully fitted using the compartmental model. The estimated total in vivo clearance values were consistent with those predicted from hepatocytes and organelles, implicating significance of in vitro kinetics. These findings demonstrate the roles of hepatic mitochondria and microsomes in ß-oxidative and reductive metabolism on acyl side chain of cinnamic acid and its analogues along with their metabolic characteristics.

Increase in P-glycoprotein levels in the blood-brain barrier of partial portal vein ligation /chronic hyperammonemia rats is medicated by ammonia/reactive oxygen species/ERK1/2 activation: In vitro and in vivo studies.

Liver failure altered P-glycoprotein (P-gp) function and expression at blood-brain barrier (BBB), partly owing to hyperammonemia. We aimed to examine the effects of partial portal vein ligation (PVL) plus chronic hyperammonemia (CHA) on P-gp function and expression at rat BBB. Experimental rats included sham-operation (SH), PVL, CHA and PVL+CHA. The PVL+CHA rats were developed by ammonia-containing diet for 2 weeks after operation. The brain-to-plasma concentration ratios (Kp) and apparent unidirectional influx constants (Kin) of rhodamine123 and sodium fluorescein were measured to assess function of P-gp and BBB integrity, respectively. Human cerebral microvascular endothelial cells (HCMEC/D3) were used to assess effects of ammonia on P-gp expression and function. It was found that PVL+CHA significantly decreased Kp and Kin of rhodamine123 without affecting brain distribution of fluorescein. The P-gp expressions in membrane protein in cortex and hippocampus were significantly increased in CHA and PVL +CHA rats, especially in PVL + CHA rats, while remarkably increased phosphorylated ERK1/2 was only found in PVL +CHA rats. Expressions of tight junction proteins claudin-5 and occluding in rat brain remained unchanged. In vitro data showed that NH4Cl increased reactive oxygen species, membrane expression and function of P-gp as well as phosphorylated ERK1/2 levels in HCMEC/D3. The NH4Cl-induced alterations were reversed by reactive oxygen species scavenger N-acetylcysteine and ERK1/2 inhibitor U0126. In conclusion, PVL+CHA increased function and membrane translocation of P-gp at rat BBB partly via ammonia. Reactive oxygen species/ERK1/2 pathway activation may be one of the reasons that ammonia upregulated P-gp expression and function at BBB.

Predicted contributions of cytochrome P450s to drug metabolism in human liver microsomes using relative activity factor were dependent on probes.

Contributions of cytochrome P450 (CYP450) isoforms to drug metabolism are often predicted using relative activity factor (RAF) method, assuming RAF values were independent of probe. We aimed to report probe-dependent characteristic of RAF values using CYP3A4 or CYP2C9 probes. Metabolism of four CYP3A4 probes (testosterone, midazolam, verapamil and atorvastatin) and three CYP2C9 probes (tolbutamide, diclofenac and S-warfarin) in human liver microsomes (HLM) and cDNA-expressed recombinant CYP450 (Rec-CYP450) systems were characterized and RAFCL value was estimated as ratio of probe intrinsic clearance in HLM to that in Rec-CYP450. CYP450i contributions to metabolic reaction of a probe were predicted using other probes and compared with data from specific inhibitions. Contributions of CYP3A4 and CYP2C9 to metabolism of deoxypodophyllotoxin and nateglinide were also predicted. RAF values were dependent on probes, leading to probe-dependently predicted contributions. Predicted contributions of CYP3A4 to formations of 6ß-hydroxytestosterone, 1'-hydroxymidazolam, norverapamil, ortho-hydroxyatorvastatin and para-hydroxyatorvastatin using other probes were 47.46-219.46%, 21.62-98.87%, 186.49-462.44%, 21.87-101.15% and 53.62-247.97%, respectively. Predicted contributions of CYP3A4 and CYP2C9 to nateglinide metabolism were 8.18-37.84% and 36.08-94.04%, separately. In conclusion, CYP450i contribution to drug metabolism in HLM estimated using RAF approach were probe-dependent. Therefore, contribution of each isoform must be confirmed by multiple probes.

Association of High Prolactin Level on Postoperative Day 1 and Tumor Invasion with Female Gonadal Dysfunction After Trans-Sphenoidal Surgery of Pituitary Adenomas.

BACKGROUND The aim of this study was to evaluate the risk factors of gonadal dysfunction among Chinese women of reproductive age with pituitary adenomas (PAs) after trans-sphenoidal surgery. MATERIAL AND METHODS We retrospectively evaluated 317 women (16-44 years old) who underwent gonadal function and hormone testing before and after trans-sphenoidal surgery for PAs during 2003-2012. Gonadal function was assessed on the basis of menstrual status. RESULTS Three women were excluded because of pre-existing gynecological diseases. Before trans-sphenoidal surgery, 34 (10.7%) women were eugonadal and 283 (89.3%) women had gonadal dysfunction. After trans-sphenoidal surgery, 130/189 (68.7%) women with follow-up menstruation data were eugonadal, and 59/189 (31.2%) women exhibited gonadal dysfunction. In addition, 67.4% women of reproductive age with PAs and gonadal dysfunction were restored by trans-sphenoidal surgery (P<0.01). Postoperative gonadal dysfunction was independently associated with high prolactin level at day 1 after trans-sphenoidal surgery (odds ratio (OR)=1.024; 95% confidence interval (CI)=1.005-1.043; P=0.012) and tumor invasion (OR=5.752; 95%CI=1.618-20.447; P<0.01). Based on the receiver operating characteristic (ROC) curve, prediction of gonadal dysfunction in women of reproductive age after trans-sphenoidal surgery for PAs using prolactin >46.82 µg/L on postoperative day 1 had sensitivity of 88%, specificity of 95%, positive predictive value of 98%, and negative predictive value of 76%, and an area under the ROC curve of 0.701. CONCLUSIONS Gonadal dysfunction is very common in Chinese women of reproductive age with PAs and can be effectively restored by trans-sphenoidal surgery. Prolactin >46.82 µg/L at 1 day after trans-sphenoidal surgery and tumor invasion can predict postoperative gonadal dysfunction in these patients.

Ameliorative effect of berberine coated bio-active nanoparticles in acetaminophen induced hepato-renal damage in diabetic rats.

The current investigation was performed for the detailed analysis of protective effect of biofabricate berberine coated nano­silver ameliorate (BBR-AgNPs) on acetaminophen (APAP) induced hepato-renal damages in diabetic rats by blood biochemistry, tissue biochemistry, histopathological and immunohistochemical analysis. The spherical shaped BBR-AgNPs were synthesized by the Biofabrication technique and its physico-chemical characterizations done by different spectroscopic (UV-vis spectrophotometer, XRD spectroscopy, FTIR spectroscopy EDAX & DLS analyses) and microscopic (FE-SEM) techniques. The diabetic developed rats were administrated with APAP (2.0 g/5 mL/kg) and scrutinize its hepato-renal injuries. The synthesized BBR-AgNPs (75 mg/kg p.o) was administrated orally to the APAP-induced diabetic rats. The result of biochemical markers and lipid peroxidation were significantly (P ˂ 0.05) increased in APAP-induced diabetic rats but decreased the level of antioxidants (P ˂ 0.05), which results obtained in liver and kidney compared to the control group. Immunohistochemical studies result showed that the APAP-induced diabetic rats expressed a high immunoreactivity of nuclear transcription factor (NF-kB). Whereas, the acetaminophen-induced diabetic rats were treated with BBR-AgNPs renovated the changes in the above parameters analyzed. The results of the study clearly indicated that the BBR-AgNPs possess the antioxidant properties as well as anti-diabetic effects, furthermore, the acetaminophen-induced liver and kidney damage was probably inhibited by the inhibition of proinflammatory factor & NF-kB factors.

Contribution of Hepatic Retinaldehyde Dehydrogenase Induction to Impairment of Glucose Metabolism by High-Fat-Diet Feeding in C57BL/6J Mice.

Obesity and insulin resistance are associated with overexpression of retinaldehyde dehydrogenase 1 (RALDH1). We aimed to investigate the roles of hepatic RALDH1 induction in glucose metabolism impairment using mice fed with high-fat-diet (HFD). Mice were fed with HFD for 8 weeks and treated with RALDH inhibitor citral for another 4 weeks. Oral glucose tolerance test (OGTT), pyruvate tolerance test (PTT) and insulin tolerance test were performed. Expressions of phosphoenolpyruvate carboxykinase 1 (PCK1), glucokinase (GCK) and RALDH1 were measured. Therapeutic effects of citral were also documented in diabetic rats. Effects of retinaldehyde on PCK1 and GCK expressions were examined in rat primary hepatocytes and HepG2 cells. The results showed that HFD mice were characterized by hyperlipidaemia and insulin resistance, accompanied by significantly increased RALDH1 activity and expression. Citral (10 and 50 mg/kg) ameliorated HFD-induced hyperlipidaemia and insulin resistance, as demonstrated by the improved fasting glucose, insulin levels and lipid profiles. OGTT and PTT demonstrated that citral reversed HFD-induced glucose disposal impairment and glucose production enhancement. Citral also reversed the increased PCK1 expression and decreased GCK expression by HFD. Citral therapeutic effects were reconfirmed in diabetic rats. In vitro data indicated that retinaldehyde had the strongest PCK1 induction in primary hepatocytes of diabetic rats compared with HFD rats and control rats, in line with the increased RALDH1 expression. Citral reversed the retinaldehyde-induced PCK1 expression in primary rat hepatocytes and HepG2 cells. In conclusion, RALDH1 induction impaired glucose metabolism partly via modulating PCK1 and GCK expressions. Citral improved glucose metabolism through inhibiting RALDH activity.

Correction: Transplantation of HGF gene-engineered skeletal myoblasts improve infarction recovery in a rat myocardial ischemia model.

[This corrects the article DOI: 10.1371/journal.pone.0175807.].

Atorvastatin impaired glucose metabolism in C2C12 cells partly via inhibiting cholesterol-dependent glucose transporter 4 translocation.

Skeletal muscle accounts for approximately 75% of glucose disposal in body and statins impair glucose metabolism. We aimed to investigate the effect of atorvastatin on glucose metabolism in C2C12 cells. Glucose metabolism and expression of glucose transporter 4 (GLUT4) and hexokinase II (HXKII) were measured following incubation with atorvastatin or pravastatin. Roles of cholesterol in atorvastatin-induced glucose metabolism impairment were investigated via adding cholesterol or mevalonic acid and confirmed by cholesterol depletion with methyl-ß-cyclodextrin. Hypercholesterolemia mice induced by high fat diet (HFD) feeding, orally received atorvastatin (6 and 12 mg/kg) or pravastatin (12 mg/kg) for 22 days. Results showed that atorvastatin not pravastatin concentration-dependently impaired glucose consumption, glucose uptake and GLUT4 membrane translocation in C2C12 cells without affecting expression of HXKII or total GLUT4 protein. The atorvastatin-induced alterations were reversed by cholesterol or mevalonic acid. Cholesterol depletion exerted similar impact to atorvastatin, which could be alleviated by cholesterol supplement. Glucose consumption or GLUT4 translocation was positively associated with cellular cholesterol levels. In HFD mice, atorvastatin not pravastatin significantly increased blood glucose levels following glucose or insulin dose and decreased expression of membrane not total GLUT4 protein in muscle. Glucose exposure following glucose or insulin dose was negatively correlated to muscular free cholesterol concentration. Expression of membrane GLUT4 protein was positively related to free cholesterol in muscle. In conclusion, atorvastatin impaired glucose utilization in muscle cells partly via inhibiting GLUT4 membrane translocation due to inhibition of cholesterol synthesis by atorvastatin, at least, partly contributing to glucose intolerance in HFD mice.