Pharmacokinetic Interactions Between Tegoprazan and the Combination of Clarithromycin, Amoxicillin and Bismuth in Healthy Chinese Subjects: An Open-Label, Single-Center, Multiple-Dosage, Self-Controlled, Phase I Trial.

BACKGROUND: Tegoprazan is a potassium-competitive acid blocker that inhibits gastric acid and which may be used for eradicating Helicobacter pylori. This study focuses on the pharmacokinetic interaction and safety between tegoprazan and the combination of clarithromycin, amoxicillin and bismuth in healthy Chinese subjects. METHODS: An open-label, three-period, single-center, multiple-dosage, single-sequence, phase I trial was conducted in 22 healthy subjects. In period 1, the subjects took tegoprazan 50 mg twice daily for 7 days, and in period 2 they were administered clarithromycin 500 mg, amoxicillin 1000 mg and bismuth potassium citrate 600 mg twice daily for 7 days (days 14-20). Tegoprazan, clarithromycin, amoxicillin and bismuth potassium citrate were then administered in combination for 7 days (days 21-27) in period 3. Blood samples were collected up to 12 h after the last dose of each period. Safety assessments were performed in each period. RESULTS: The geometric mean ratios (GMRs) [90% confidence interval (CI)] of maximum plasma concentration at steady state (Cmax,ss) and area under the plasma concentration-time curve over the dosing interval (AUCτ) at steady state were 195.93% (175.52-218.71%) and 287.54% (263.28-314.04%) for tegoprazan and 423.23% (382.57-468.22%) and 385.61% (354.62-419.30%) for tegoprazan metabolite M1, respectively. The GMRs (90% CI) of Cmax,ss and AUCτ were 83.69% (77.44-90.45%) and 110.30% (102.74-118.41%) for clarithromycin, 126.25% (114.73-138.93%) and 146.94% (135.33-159.55%) for 14-hydroxyclarithromycin, 75.89% (69.73-82.60%) and 94.34% (87.94-101.20%) for amoxicillin, and 158.43% (125.43-200.11%) and 183.63% (156.42-215.58%) for bismuth, respectively. All reported adverse events were mild. The frequency of adverse events during the coadministration stage was not higher than that during the single- or triple-drug administration stages. CONCLUSION: The plasma exposure of tegoprazan, M1, 14-hydroxyclarithromycin and bismuth was increased after the coadministration of tegoprazan, clarithromycin, amoxicillin and bismuth. The coadministration exhibited favorable safety and tolerability. CLINICAL TRIALS REGISTRATION: CTR20230643.

Effects of Yinzhihuang on Alleviating Cyclosporine A-Induced Cholestatic Liver Injury via Farnesoid X Receptor-Mediated Regulation of Transporters and Enzymes in Vitro and in Vivo.

Yinzhihuang (YZH), a traditional Chinese medicine prescription, was widely used to treat cholestasis. Cholestatic liver injury limited the use of the immunosuppressive drug cyclosporine A (CsA) in preventing organ rejection after solid organ transplantation. Clinical evidences suggested that YZH could enhance bile acids and bilirubin clearance, providing a potential therapeutic strategy against CsA-induced cholestasis. Nevertheless, it remains unclear whether YZH can effectively alleviate CsA-induced cholestatic liver injury, as well as the molecular mechanisms responsible for its hepatoprotective effects. The purpose of the present study was to investigate the hepatoprotective effects of YZH on CsA-induced cholestatic liver injury and explore its molecular mechanisms in vivo and vitro. The results demonstrated that YZH significantly improved the CsA-induced cholestatic liver injury and reduced the level of liver function markers in serum of Sprague-Dawley (SD) rats. Targeted protein and gene analysis indicated that YZH increased bile acids and bilirubin efflux into bile through the regulation of multidrug resistance-associated protein 2 (Mrp2), bile salt export pump (Bsep), sodium taurocholate cotransporting polypeptide (Ntcp) and organic anion transporting polypeptide 2 (Oatp2) transport systems, as well as upstream nuclear receptors farnesoid X receptor (Fxr). Moreover, YZH modulated enzymes involved in bile acids synthesis and bilirubin metabolism including Cyp family 7 subfamily A member 1 (Cyp7a1) and uridine 5'-diphosphate (UDP) glucuronosyltransferase family 1 member A1 (Ugt1a1). Furthermore, the active components geniposidic acid, baicalin and chlorogenic acid exerted regulated metabolic enzymes and transporters in LO2 cells. In conclusion, YZH may prevent CsA-induced cholestasis by regulating the transport systems, metabolic enzymes, and upstream nuclear receptors Fxr to restore bile acid and bilirubin homeostasis. These findings highlight the potential of YZH as a therapeutic intervention for CsA-induced cholestasis and open avenues for further research into its clinical applications.

Antidepressant Shugan Jieyu Capsule Alters Gut Microbiota and Intestinal Microbiome Function in Rats With Chronic Unpredictable Mild Stress -Induced Depression.

Shugan Jieyu Capsule (SG) has been widely used in China to treat mild to moderate depression. Hypericum perforatum L. (St John's Wort, SJW) is the main ingredient of SG and has been used as herbal medicine to treat depression in western countries. However, it is known that SJW has low bioavailability and does not easily get through the blood-brain barrier. Therefore, how SG plays an antidepressant effect in the central nervous system (CNS) remains an urgent problem to be solved. Mounting research has described the relationship between antidepressants and intestinal microbiota to illuminate antidepressive mechanisms in the CNS. We aimed to investigate the effects of therapy with SG on the function of gut microbiota and intestinal microbiota in rats with chronic unpredictable mild stress (CUMS)-induced depression. The psychophysiological state and the hypothalamic-pituitary-adrenal axis function of rats are evaluated through behavioral experiments, corticosterone levels, serotonin levels, and adrenal index measurements. 16S rDNA amplicon sequencing is used to test the changes in gut microbiota and make functional predictions of genes. With treatment of SG, the depression-like behaviors of CUMS-induced rats were reversed; the corticosterone levels and the adrenal index decreased significantly; the level of serotonin increased significantly; and the alpha and beta diversity analysis of microbiota showed an increase in the richness and uniformity of the flora were increased. SG regulated the relative abundance of Actinobacteria, Erysipelotrichaceae, Bifidobacteriaceae, Atopobiaceae, Dubosiella, and Bifidobacterium; Linear discriminant analysis effect size analysis demonstrated that Lactobacillaceae (family level), Lactobacillus (genus level), Lactobacillales (order level), Bacilli (class level), and Lactobacillus-reuteri (species level) were biomarkers in the SG group samples, and also likely to modulate metabolic pathways, such as those involved in carbohydrate metabolism, amino acid metabolism, and signal transduction. These data clearly illustrated the effect of SG on gut microbiome, thus laying the foundation for uncovering more insights on the therapeutic function of the traditional Chinese antidepressants. The potential of SG on mechanisms of antidepression to alter gut microbiota and intestinal microbiome function exposed to CUMS can be explored.

Effect of capsaicin on breast cancer resistance protein (BCRP/Abcg2) and pharmacokinetics of probe substrates in rats.

Breast cancer resistance protein (BCRP/Abcg2 in human, Bcrp/Abcg2 in rat), a member of the ATP-binding cassette (ABC) transporter family, acts as an efflux pump for xenobiotics, with ability to transport various drugs out of cells. Capsaicin may have the potential to modulate the function of Bcrp transport. This study was to evaluate the effects of capsaicin on the pharmacokinetics of sulfasalazine, a Bcrp substrate, in rats and investigate the mechanism of this food-drug interaction.The rats were pre-treated with 5% carboxymethylcellulose sodium (vehicle), capsaicin (3, 8, 25 mg/kg) and cyclosporine A (10 mg/kg) by gastric gavage for 7 days. On day 7, blood, liver and intestine samples were collected after sulfasalazine administered. Liquid chromatography tandem mass spectrometry (LC-MS/MS) was used to study the effects of capsaicin on the pharmacokinetics of sulfasalazine in rats. RT-PCR and western blotting were used to study the mechanism in biomolecules in rats, respectively.Compared with vehicle group, AUC0-∞ of sulfasalazine in rats were increased by 1.5-folds, 1.6-folds and 1.7-folds in 3, 8 and 25 mg/kg/d capsaicin pre-treated groups. At the same time, the CL/F in rats were decreased by 33%, 38% and 42% in the three groups. In addition, we found Bcrp mRNA levels and protein expressions in rat livers and intestines were decreased in 3, 8 and 25 mg/kg/d capsaicin-treated groups.Our study demonstrated that long-term ingestion of capsaicin significantly enhanced the AUC of sulfasalazine involved down-regulate Bcrp gene and protein expression in rat liver and intestine.

The protective effect of hypericin on postpartum depression rat model by inhibiting the NLRP3 inflammasome activation and regulating glucocorticoid metabolism.

BACKGROUND: St John's Wort (Hypericum perforatum, SJW) is widely used to treat postpartum depression (PPD) because of its high safety. Hypericin (HY) is the main effective component of SJW. The physiological roles of NLRP3 inflammasome activation and glucocorticoid metabolism are closely linked to depression. But, it remains elusive whether HY relieve PPD through targeting NLRP3 inflammasome activation or other mechanism. This study aimed to clarify the therapeutic effects of HY on PPD model rats and its underlying mechanisms in vivo. METHODS: hormone-simulated pregnancy model was used, and behavioral tests was used to assess depressive state. Inflammatory factors in serum were tested by Enzyme-linked immunosorbent assay. RESULTS: Changes in the classic behavioral tests reflected that HY could alleviate the symptoms of PPD as effective as fluoxetine (FLU). Both of HY and FLU could significantly inhibit the protein expression of NLRP3, caspase-1 in hypothalamus and decrease the levels of inflammatory factors (IL-6, IL-1ß, TNF - α) in serum. For hormone level determination, HY can not only significantly reduce the level of CORT, but also reverse the activity of 11ß - HSD2 enzyme, which is different from FLU. LIMITATIONS: More experiments will be needed to verify the target of HY. CONCLUSION: All those data suggest that HY can effectively relieve PPD by reversing glucocorticoid metabolism, increasing ER expression, and then relieve neuroinflammation.

Quantitation of six steroid hormones by ultra-performance liquid chromatography-tandem mass spectrometry in plasma and prefrontal cortex samples from rats with chronic unpredictable mild stress-induced depression.

Steroid hormones such as glucocorticoids and their metabolites are closely related to mental diseases and neuroendocrine diseases. Quantitative analysis of these substances will help in understanding their roles in related research fields. In this study, an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed to detect the concentration of corticosterone (CORT) and its metabolites, progesterone (PROG) and testosterone in rat plasma and prefrontal cortex (PFC), and was applied to investigate the changes in hormones in rats with depression induced by chronic unpredictable mild stress (CUMS). The method was shown to be linear in the quantitation range for all analytes. Intra- and inter-day accuracy and precision were between 80% and 120%. Furthermore, we found that the level of CORT in plasma and PFC increased, whereas that of 11-dehydrocorticosterone (11-DHCORT) as well as the ratio of 11-DHCORT and CORT declined in rats with CUMS-induced depression. The trends of these changes in central PFC and peripheral plasma were consistent. In conclusion, this study successfully established an UPLC-MS/MS method for simultaneous measurement of CORT and its metabolites, PROG and testosterone in rat plasma and PFC, and applied it to rats with depression. The method could be further applied to the research of depression and diseases related to these steroid hormones.

Erectile Dysfunction Is Associated With Excessive Growth Hormone Levels in Male Patients With Acromegaly.

Objective: To determine the risk factors for erectile dysfunction (ED) in male patients with acromegaly and to prospectively investigate the short-term changes of erectile function after surgery or medical treatment. Methods: Sixty-three male patients were subjected to nocturnal penile tumescence and rigidity (NPTR) test for the evaluation of erectile function. The measurement of serum nitric oxide (NO) was also performed. Twenty-seven patients were re-evaluated by NPTR after surgery or long-term somatostatin analogues (SSA) treatment. Results: Twenty-two patients (34.9%) had ED. Patients with ED showed higher random GH (17.89 [10.97-44.19] µg/L vs 11.63 [4.31-28.80] µg/L, p = 0.020) and GH nadir (GHn) (10.80 [6.69-38.30] µg/L vs 8.76 [3.62-18.19] µg/L, p = 0.044) during oral glucose tolerance test (OGTT). The NO levels of ED patients were lower than non-ED patients (9.15 [5.58-22.48] µmol/L vs 16.50 [12.33-31.78] µmol/L, p = 0.012). After treatment, patients who present improvement in erectile function showed lower post-GHn (0.07 [0.03-0.12] ng/ml vs 1.32 [0.09-3.60] ng/ml, p = 0.048) and post-IGF-1 index (1.03 ± 0.38 vs 1.66 ± 0.95, p = 0.049). The multivariate analysis indicated post-GHn was still associated with the improvement of erectile function after correction of other covariates (OR: 0.059, 95% CI: 0.003-1.043, p = 0.053). Conclusions: Excessive GH is related to ED in male patients with acromegaly. GH normalization after treatment is beneficial for short-term erectile function recovery.

PRMT1 is a novel molecular therapeutic target for clear cell renal cell carcinoma.

Background and Objective: Epigenetic alterations are common events in clear cell renal cell carcinoma (ccRCC), and protein arginine methyltransferase 1 (PRMT1) is an important epigenetic regulator in cancers. However, its role in ccRCC remains unclear. Methods: We investigated PRMT1 expression level and its correlations to clinicopathological factors and prognosis in ccRCC patients based on ccRCC tissue microarrays (TMAs). Genetic knockdown and pharmacological inhibition using a novel PRMT1 inhibitor DCPT1061 were performed to investigate the functional role of PRMT1 in ccRCC proliferation. Besides, we confirmed the antitumor effect of PRMT1 inhibitor DCPT1061 in ccRCC cell-derived tumor xenograft (CDX) models as well as patient-derived tumor xenograft (PDX) models. Results: We found PRMT1 expression was remarkably upregulated in tumor tissues and associated with poor pathologic characters and outcomes of ccRCC patients. Furthermore, genetic knockdown and pharmacological inhibition of PRMT1 by a novel potent inhibitor DCPT1061 dramatically induced G1 cell cycle arrest and suppressed ccRCC cell growth. Mechanistically, RNA sequencing and further validation identified Lipocalin2 (LCN2), a secreted glycoprotein implicated in tumorigenesis, as a crucial regulator of ccRCC growth and functional downstream effector of PRMT1. Epigenetic silencing of LCN2 autocrine secretion by PRMT1 deficiency decreased downstream p-AKT, leading to reduced p-RB and cell growth arrest through the neutrophil gelatinase associated lipocalin receptor (NGALR). Moreover, PRMT1 inhibition by DCPT1061 not only inhibited tumor growth but also sensitized ccRCC to sunitinib treatment in vivo by attenuating sunitinib-induced upregulation of LCN2-AKT-RB signaling. Conclusion: Taken together, our study revealed a PRMT1-dependent epigenetic mechanism in the control of ccRCC tumor growth and drug resistance, indicating PRMT1 may serve as a promising target for therapeutic intervention in ccRCC patients.

Uropathogenic Escherichia coli Infection Compromises the Blood-Testis Barrier by Disturbing mTORC1-mTORC2 Balance.

The structural and functional destruction of the blood-testis barrier (BTB) following uropathogenic E. coli (UPEC) infection may be a critical component of the pathologic progress of orchitis. Recent findings indicate that the mammalian target of the rapamycin (mTOR)-signaling pathway is implicated in the regulation of BTB assembly and restructuring. To explore the mechanisms underlying BTB damage induced by UPEC infection, we analyzed BTB integrity and the involvement of the mTOR-signaling pathway using in vivo and in vitro UPEC-infection models. We initially confirmed that soluble virulent factors secreted from UPEC trigger a stress response in Sertoli cells and disturb adjacent cell junctions via down-regulation of junctional proteins, including occludin, zonula occludens-1 (ZO-1), F-actin, connexin-43 (CX-43), ß-catenin, and N-cadherin. The BTB was ultimately disrupted in UPEC-infected rat testes, and blood samples from UPEC-induced orchitis in these animals were positive for anti-sperm antibodies. Furthermore, we herein also demonstrated that mTOR complex 1 (mTORC1) over-activation and mTORC2 suppression contributed to the disturbance in the balance between BTB "opening" and "closing." More importantly, rapamycin (a specific mTORC1 inhibitor) significantly restored the expression of cell-junction proteins and exerted a protective effect on the BTB during UPEC infection. We further confirmed that short-term treatment with rapamycin did not aggravate spermatogenic degeneration in infected rats. Collectively, this study showed an association between abnormal activation of the mTOR-signaling pathway and BTB impairment during UPEC-induced orchitis, which may provide new insights into a potential treatment strategy for testicular infection.

Apatinib-loaded CalliSpheres Beads for embolization in a rabbit VX2 liver tumor: characterization in vitro, pharmacokinetics and tumor response in vivo.

Apatinib mesylate is an oral antiangiogenic agent that can inhibit activation of vascular endothelial growth factor receptor-2 tyrosine kinase. However, its therapeutic use in liver cancer is restricted due to severe systemic toxicity. Our work aimed to construct apatinib-loaded CalliSpheres Beads (CBAPA) and investigate its application in transarterial chemoembolization (TACE) of liver cancer. The established stock solution containing 20, 40 or 60 mg apatinib were fully mixed with 100-300 µm CalliSpheres Beads (CB) for 2 hours, respectively. The highest loading efficiency at 30 min after combination in 20 mg group (maximum 70.7%). Further, apatinib can be steadily released from CBAPA in vitro release test. For pharmacokinetics and tumor response in vivo, sixty New Zealand white rabbits with VX2 liver tumor were assigned into four groups: sham (NS) group, apatinib solution alone (APA) group, CB group and CBAPA group. Apatinib was measured in plasma and liver tissue by high performance liquid chromatography-tandem mass spectrometry. Compared to APA group, the administration of apatinib by TACE with CBAPA resulted in low systemic concentration. In addition, intratumoural apatinib concentration was higher than adjacent hepatic parenchyma in the CBAPA group. Compared to other three groups, CBAPA group achieved lower tumor growth rate and improved survival time. In conclusion, these findings provide a basis for the potential application of apatinib-loaded CalliSpheres Beads in liver cancer.

Effects of cyclosporin A on the pharmacokinetics and toxicities of irinotecan mediated by UGT1A1 in vitro and in vivo.

Irinotecan (CPT-11) is a broad spectrum agent for the treatment of solid tumor malignancies, despite severe diarrhea is limiting its widespread usage. The local effects of SN-38 in the small intestine were considered to be responsible for the irinotecan-induced delayed diarrhea. It was proposed that cyclosporin A (CsA) inhibiting biliary excretion could attenuate this side effect, but in fact, it could not improve the therapeutic index of irinotecan. At present, most studies focused on the inhibition of bile excretion by cyclosporin A through the transporters MRP2 and MDR1 and its effect the irinotecan treatment in vivo. However, UDP glucuronyltransferase-1 polypeptide A1 (UGT1A1) was related to a significantly altered disposition of irinotecan and its metabolites, and was therefore associated with irinotecan-induced toxicity. This study focused on UGT1A1-mediated conversion of SN-38 to SN-38G, and systematically investigated the CsA-irinotecan interactions in vitro and in vivo. After treatment with 10 mg·kg-1 CsA for 7 days, the bile excretion of irinotecan and its metabolites decreased and AUC0-∞ increased significantly. The AUC0-∞ (SN-38G)/AUC0-∞ (SN-38) was significantly reduced when compared with that in vehicle-treated rats. In the liver microsome incubation system, the IC50 of CsA for UGT1A1 enzyme was 9.4 µM. Furthermore, the UGT1A1 mRNA and protein expression levels were significantly reduced. The present study indicated that CsA treatment could enhance the systemic exposure and toxicity of SN-38 by inhibiting the UGT1A1 enzyme. The inhibition of UGT1A1 enzyme might be a critical factor in the failure of CsA improving irinotecan's treatment index.

Population pharmacokinetic analysis of tacrolimus in Chinese cardiac transplant recipients.

Objective: Usage of tacrolimus is complicated by its narrow therapeutic index and wide between- and within-subject pharmacokinetic variability. We aimed to obtain more information regarding the influence of various covariates on the disposition of tacrolimus in the early phase after cardiac transplantation using a population pharmacokinetic method, and provide information for the individualisation of drug dosing in the clinical setting. Methods: Routine therapeutic drug monitoring concentrations (897 observations) were retrospectively collected from 146 hospitalised patients. One compartment model with first-order absorption (absorption rate constant Ka was fixed as 4.48/hour) was employed to establish the population pharmacokinetic model using a non-linear mixed-effects modelling approach. Various demographic parameters, postoperative day and concomitant medications influencing drug clearance and distribution volume were investigated in this study. Bootstrap and prediction-corrected visual predictive check were employed to validate the final model. With the goal of tacrolimus trough concentrations within the therapeutic window, simulation was performed. Results: Pharmacokinetic parameter population typical estimates for clearance (CL/F) and apparent distribution volume (V/F) were 14.23 L/hour and 760.80 L, respectively. Postoperative day and co-administration of Wuzhi capsules were identified as important factors affecting CL/F. Total body weight was significantly associated with the V/F. Results of model evaluation indicated a good stable and precise performance of the final model. Based on the simulation results, a simple-touse dosage regimen table to guide clinicians with drug dosing was created. Conclusion: The final population model could provide information for the individualised dosing of tacrolimus for cardiac transplant recipients.

Long Noncoding RNA HUPCOS Promotes Follicular Fluid Androgen Excess in PCOS Patients via Aromatase Inhibition.

CONTEXT: Androgen excess is a key feature of polycystic ovary syndrome (PCOS), but the underlying molecular mechanism remains unclear. OBJECTIVE: To determine the role and mechanism of novel long noncoding RNA (lncRNA) highly up-regulated in PCOS (HUPCOS) in the androgen excess of PCOS patients. DESIGN: The lncRNA expression profile in granulosa cells derived from PCOS and non-PCOS women were analyzed by using microarray assay. Human granulosa cell line KGN was used for mechanism investigation. SETTING: This was a university-based study. PATIENTS: Thirty-eight PCOS and 38 control patients were recruited: 8 PCOS and 8 control samples used for microarray discovery, the remaining 30 PCOS cases and 30 controls for quantitative RT-PCR validation. MAIN OUTCOME MEASURES: The aberrant expression lncRNA profile of PCOS patients was measured using microarray. The relationship of HUPCOS and follicular fluid testosterone was measured. Aromatase expression were analyzed after HUPCOS downregulation. HUPCOS interaction protein was confirmed by RNA pull-down. RESULTS: The significantly elevated lncRNA in PCOS granulosa cells was named HUPCOS, which was positively correlated with follicular fluid testosterone of PCOS patients. HUPCOS downregulation increased aromatase expression and promoted conversion of androgen to estrogen. RNA-binding protein with multiple splicing (RBPMS) was the most likely protein that combined with HUPCOS. CONCLUSIONS: Our findings suggested that HUPCOS mediated androgen excess in follicular fluid of PCOS patients by suppressing aromatase expression via interaction with RBPMS.

CXCL1-LCN2 paracrine axis promotes progression of prostate cancer via the Src activation and epithelial-mesenchymal transition.

BACKGROUND: Mechanisms driving the progression of castration-resistant prostate cancer are believed to relate substantially to the tumor microenvironment. However, the cross-talks between tumor epithelial cell, stromal cells, and immune cells are yet to be fully elucidated. The present study aims to determine the role of chemokine and neutrophil derived cytokine paracrine axis in mediating the interaction between tumor cells, stromal myofibroblasts, and neutrophils in the tumor microenvironment of prostate cancer. METHODS: To identify myofibroblasts and neutrophil derived specific proteins affecting progression of prostate cancer, bioinformatics analyses were firstly performed in independent human prostate cancer gene expression data sets from the GEO data bank. Expression of stromal myofibroblasts secretory chemokine CXCL1 and neutrophil derived cytokine LCN2 was evaluated in prostate tissues via immunohistochemistry assay. We further investigated the effect of CXCL1 and LCN2 on prostate cancer using in vivo and in vitro models, and explored the underlying signal transduction pathways. RESULTS: A CXCL1-LCN2 paracrine network was confirmed in prostate cancer tissue samples, which was correlated with the biochemical recurrence of prostate cancer. Of note, CXCL1-LCN2 axis activates Src signaling, triggers the epithelial-mesenchymal transition (EMT), consequently promotes the migration of prostate cancer cells, leading to enhanced tumor metastasis. CONCLUSIONS: Our findings may provide enhanced insight into the interactions of carcinoma-stromal cells and immune cells linked to prostate cancer progression, wherein CXCL1-LCN2 axis is a key contributor to prostate cancer cells migration. These data indicate tumor microenvironment and Src signaling pathway may be potential therapeutic targets of prostate cancer treatment.

Development of an underivatized LC-MS/MS method for quantitation of 14 neurotransmitters in rat hippocampus, plasma and urine: Application to CUMS induced depression rats.

Sensitive and comprehensive measurement of systemic metabolites of tryptophan, phenylalanine and glutamate metabolism in biological samples is effective for understanding the pathogenesis of depression and other neurological diseases. Therefore, this study developed an underivatized liquid chromatography tandem mass spectrometry (LC-MS/MS) method for simultaneous monitoring the 3 components of glutamate metabolism in rat hippocampus and 11 components of tryptophan and phenylalanine metabolism in rat hippocampus, plasma and urine, and applied it to investigate their changes in rats induced by chronic unpredictable mild stress (CUMS). The investigated analytes are as follows: tryptophan, serotonin, 5-hydroxyindoleacetic acid, kynurenine, kynurenic acid, xanthurenic acid, 3-hydroxyanthranilic acid, quinolinic acid, phenylalanine, tyrosine, tyramine, glutamate, glutamine and gamma-aminobutyric acid. The method was verified to be sensitive and effective with satisfactory linearity, accuracies in the range of 78.2%-120.4%, and precisions less than 17.8% for all identified analytes. A series of significant changes in CUMS-induced rats can be detected: tryptophan, serotonin and tyrosine levels decreased and quinolinic acid increased in both hippocampus and plasma. In addition, the kynurenine/tryptophan ratios increased in hippocampus and plasma, the kynurenic acid/quinolinic acid ratios of plasma and urine were significantly reduced. These findings demonstrated that the CUMS procedure could lead to the central and peripheral imbalances of tryptophan and phenylalanine metabolism. In conclusion, a LC-MS/MS method for simultaneous measurement of several neurotransmitters in rat hippocampus, plasma and urine was developed and successfully applied to investigation of the central and peripheral changes in CUMS-induced rats. The method would be expected to provide applicability to the study of the mechanisms of depression and other related diseases associated with these neurotransmitters.

17ß-Estradiol promotes endometrial cancer proliferation and invasion through IL-6 pathway.

Accumulating evidence revealed that the leading risk factor of endometrial cancer is exposure to endogenous and exogenous estrogens, while the exact mechanism underlying estrogen contribution to endometrial cancer progression has not been elucidated clearly. Interleukin (IL)-6 has been verified to be critical for tumor progression in several human cancers. In this study, we provided evidence that 17ß-estradiol (E2) could significantly promote endometrial cancer cells viability, migration and invasion through activation of IL-6 pathway, which involved in its downstream pathway and target genes (p-Stat3, Bcl-2, Mcl-1, cyclin D1 and MMP2). Meanwhile, utilization of IL-6-neutralizing antibody could partially attenuate the increased cancer growth and invasion abilities in Ishikawa and RL95-2 endometrial cancer cell lines and an orthotopic endometrial cancer model. We established a causative link between estrogen and IL-6 signaling activation in the development of endometrial cancer. The molecular mechanism defined in this study provided the evidence that E2 promotes endometrial carcinoma progression via activating the IL-6 pathway, indicating that interruption of IL-6 might be an essential therapeutic strategy in estrogen-dependent endometrial cancer.

HIGHER GROWTH HORMONE LEVELS ARE ASSOCIATED WITH ERECTILE DYSFUNCTION IN MALE PATIENTS WITH ACROMEGALY.

Objective: To investigate in vivo correlates of erectile dysfunction (ED) in male patients with acromegaly. Methods: Fifty-one male patients with acromegaly were assessed by the International Index of Erectile Function-5 and Acromegaly Quality of Life (Acro-QoL) questionnaires. The measurement of serum nitric oxide (NO) were performed in patients and age-matched nonacromegalic controls. Results: Among 51 patients analyzed, 32 (62.7%) had ED. Patients with ED showed lower Acro-QoL scores regarding global (69.8 ± 17.7 versus 79.4 ± 11.2; P = .035) and personal relationship dimensions (59.6 ± 22.1 versus 76.8 ± 17.6; P = .012) than non-ED patients. ED patients were older (44.5 ± 11.2 years versus 33.2 ± 8.5 years; P = .04) and showed higher growth hormone (GH) levels (15.5 µg/L [interquartile range of 9.5 to 34.5 µg/L] versus 5.9 µg/L [interquartile range of 3.4 to 13.9 µg/L]; P = .001) compared to non-ED patients. The cutoff values for identifying ED were 7.9 µg/L for random GH and 5.3 µg/L for GH nadir after oral administration of 75 g of glucose. There was no significant difference in total testosterone levels between the two groups (6.36 ± 4.24 nmol/L versus 9.54 ± 5.50 nmol/L; P = .299). The NO levels in patients with acromegaly were significantly lower than those in nonacromegalic controls (8.77 ± 1.78 µmol/L versus 19.19 ± 5.02 µmol/L, respectively; P = .049). Furthermore, the NO levels were even lower in ED patients than those in non-ED patients (5.14 ± 0.98 µmol/L versus 12.09 ± 3.44 µmol/L; P = .027). Conclusion: Our study showed that ED is prevalent in male acromegalic patients and may be associated with systemic endothelial dysfunction induced by excessive GH. Further studies investigating the mechanism of GH and ED are required. Abbreviations: Acro-QoL = Acromegaly Quality of Life; ED = erectile dysfunction; FSH = follicle-stimulating hormone; GH = growth hormone; IGF-1 = insulin-like growth factor 1; IIEF-5 = international index of erection function-5; LH = luteinizing hormone; MRI = magnetic resonance imaging; NO = nitric oxide; OGTT = oral glucose tolerance test; QoL = quality of life; ROC = receiver operating characteristic.

IL-6 promotes endometrial cancer cells invasion and migration through signal transducers and activators of transcription 3 signaling pathway.

Interleukin (IL)-6 is the most well-known traditional activator of activating signal transducers and activators of transcription 3 (Stat3). They have been proved to promote cancer progression in several human cancers. However, their exact roles in endometrial cancer have not been elucidated clearly. In this study, we aimed to investigate the role of IL-6/Stat3 signaling pathway in human endometrial cancer cells invasion and migration. We demonstrated that Stat3 is activated in endometrial cancer cell lines. To investigate the role of Stat3 in endometrial cancer invasive capacity, we used Stat3 inhibitor Stattic and found that Stattic significantly inhibited the migration and invasion of endometrial cancer cells elevated by IL-6. Furthermore, we showed that Stat3 inhibitor significantly decreased the expression of MMP2 enhanced by IL-6, indicating that IL-6 promoted endometrial cancer invasion and migration by Stat3-induced MMP2 upregulation. Taken together, our findings indicate that targeting IL-6/Stat3 pathway might be a potentially effective therapeutic strategy for treating endometrial cancer.

Primary malignant melanotic melanoma and hypomelanotic melanoma of the female urethra: case series and a review of the literature in China.

The incidence of primary malignant melanoma (MM) of female urethra is extremely low, leading to paucity of recommendations on management. The objectives of our study were to gain more insight into the clinical features, diagnosis, treatment, and prognosis of this rare type of tumor. We carried out a retrospective analysis of all four cases who underwent an operation in our hospital since 1980. Moreover, other 32 cases of MM that have been reported in Chinese papers were also included for further review. The age of the patients ranged from 38 to 81 years. A mass in the urethral meatus and hematuria are common presentations. The final diagnosis depends on histopathological examination. After surgery alone or combined with chemotherapy/radiotherapy/immunotherapy, all cases were followed for 1-151 months, whereas only one lived for more than 4 years after receiving the diagnosis. A timely and accurate diagnosis of MM is critical, especially for hypomelanotic and amelanotic cases. Immunohistochemical staining and electron microscopy are necessary for a precise diagnosis in some cases. Extensive resection, early chemotherapy, and immunotherapy may help to improve survival.

IDO and TDO as a potential therapeutic target in different types of depression.

Depression is highly prevalent worldwide and a leading cause of disabilty. However, the medications currently available to treat depression fail to adequately relieve depressive symptoms for a large number of patients. Research into the aberrant overactivation of the kynurenine pathway and the production of various active metabolites has brought new insight into the progression of depression. IDO and TDO are the first and rate-limiting enzymes in the kynurenine pathway and regulate the production of active metabolites. There is substantial evidence that TDO and IDO enzyme are activated during depression, and therefore, IDO and TDO inhibitors have been identified as ideal therapeutic targets for depressive disorder. Hence, this review will focus on the kynurenine branch of tryptophan metabolism and describe the role of IDO and TDO in the pathology of depression. In addition, this review will compare the relative imbalance between KYNA and neurotoxic kynurenine metabolites in different psychiatric disorders. Finally, this review is also directed toward assessing whether IDO and TDO are potential therapeutic target in depression associated with other diseases such as diabetes and/or cancer, as well as the development of potent IDO and TDO inhibitors.