Sanguinarine targets BRD4 to suppress cell proliferation and migration in clear cell renal cell carcinoma.

Sanguinarine is an alkaloid with diverse biological activities, nevertheless, whether it can target epigenetic modifiers remains unknown. In this study, sanguinarine was characterized as a strong BRD4 inhibitor with IC50 = 361.3 nM against BRD4 (BD1) and IC50 = 302.7 nM against BRD4 (BD2) that can inactivate BRD4 reversibly. Additional cellular assays suggested that sanguinarine can bind BRD4 in human clear cell renal cell carcinoma (ccRCC) cell line 786-O and inhibit cell growth with IC50 (24 h) = 0.6752 µM and IC50 (48 h) = 0.5959 µM in a BRD4 dependent manner partially. Meanwhile, sanguinarine can inhibit the migration of 786-O cells in vitro and in vivo, and reverse epithelial-mesenchymal transition. Moreover, it can inhibit 786-O cells proliferation in vivo in a BRD4 dependent manner partially. In sum, our study identified BRD4 as a new target of sanguinarine, and sanguinarine may serve as a potential therapeutic agent against ccRCC.

ABT-263 exerts a protective effect on upper urinary tract damage by alleviating neurogenic bladder fibrosis.

This study investigated the mechanism of action of ABT-263 in the treatment of neurogenic bladder fibrosis (NBF)and its protective effects against upper urinary tract damage (UUTD). Sixty 12-week-old Sprague-Dawley (SD) rats were randomly divided into sham, sham + ABT-263 (50 mg/kg), NBF, NBF + ABT-263 (25 mg/kg, oral gavage), and NBF + ABT-263 (50 mg/kg, oral gavage) groups. After cystometry, bladder and kidney tissue samples were collected for hematoxylin and eosin (HE), Masson, and Sirius red staining, and Western Blotting (WB) and qPCR detection. Primary rat bladder fibroblasts were isolated, extracted, and cultured. After co-stimulation with TGF-ß1 (10 ng/mL) and ABT-263 (concentrations of 0, 0.1, 1, 10, and 100 µmol/L) for 24 h, cells were collected. Cell apoptosis was detected using CCK8, WB, immunofluorescence, and annexin/PI assays. Compared with the sham group, there was no significant difference in any physical parameters in the sham + ABT-263 (50 mg/kg) group. Compared with the NBF group, most of the markers involved in fibrosis were improved in the NBF + ABT-263 (25 mg/kg) and NBF + ABT-263 (50 mg/kg) groups, while the NBF + ABT-263 (50 mg/kg) group showed a significant improvement. When the concentration of ABT-263 was increased to 10 µmol/L, the apoptosis rate of primary bladder fibroblasts increased, and the expression of the anti-apoptotic protein BCL-xL began to decrease.ABT-263 plays an important role in relieving NBF and protecting against UUTD, which may be due to the promotion of myofibroblast apoptosis through the mitochondrial apoptosis pathway.

METTL3/N6-methyladenosine/ miR-21-5p promotes obstructive renal fibrosis by regulating inflammation through SPRY1/ERK/NF-κB pathway activation.

Renal fibrosis induced by urinary tract obstruction is a common clinical occurrence; however, effective treatment is lacking, and a deeper understanding of the mechanism of renal fibrosis is needed. Previous studies have revealed that miR-21 impacts liver and lung fibrosis progression by activating the SPRY1/ERK/NF-kB signalling pathway. However, whether miR-21 mediates obstructive renal fibrosis through the same signalling pathway has not been determined. Additionally, studies have shown that N6-methyladenosine (m6 A) modification-dependent primary microRNA (pri-microRNA) processing is essential for maturation of microRNAs, but its role in the maturation of miR-21 in obstructive renal fibrosis has not yet been investigated in detail. To address these issues, we employed a mouse model of unilateral ureteral obstruction (UUO) in which the left ureters were ligated for 3, 7 and 14 days to simulate the fibrotic process. In vitro, human renal proximal tubular epithelial (HK-2) cells were transfected with plasmids containing the corresponding sequence of METTL3, miR-21-5p mimic or miR-21-5p inhibitor. We found that the levels of miR-21-5p and m6 A modification in the UUO model groups increased significantly, and as predicted, the SPRY1/ERK/NF-kB pathway was activated by miR-21-5p, confirming that miR-21-5p plays an important role in obstructive renal fibrosis by enhancing inflammation. METTL3 was found to play a major catalytic role in m6 A modification in UUO mice and drove obstructive renal fibrosis development by promoting miR-21-5p maturation. Our research is the first to demonstrate the role of the METTL3-m6 A-miR-21-5p-SPRY1/ERK/NF-kB axis in obstructive renal fibrosis and provides a deeper understanding of renal fibrosis.

Aquaporin1-3 expression in normal and hydronephrotic kidneys in the human fetus.

BACKGROUND: Decreased expression of the renal aquaporin (AQP) protein family is associated with hydronephrosis in adult humans and animals. However, the expression of AQPs, especially subtypes AQP1-3, which play a core role in the urinary concentration function, in hydronephrotic human fetuses is not clear. The aim of this study is to investigate the expression of the AQP1-3 in normal and hydronephrotic human fetal kidneys. METHODS: Twenty-one normal and six hydronephrotic kidney (HK) samples were harvested from abortive fetuses. Meanwhile, seven normal adult human kidney samples were collected as positive controls. Quantitative real-time PCR, western blotting, and immunohistochemistry were used to analyze the expression of AQP1-3. RESULTS: Both the protein and messenger mRNA expression levels of AQP1-3 increased with gestational age in the normal fetuses, but the levels were significantly lower than those in the adult tissues and significantly higher than those in the hydronephrotic fetuses at the same gestational age. CONCLUSIONS: The increased expression of AQP1-3 with gestational age in the fetal kidney may indicate maturation of the urinary concentrating ability. The lower expression of AQP1-3 in HKs may reflect a maturation obstacle with regard to urinary concentration in human hydronephrotic fetuses.

The relationship between Aquaporin-2 protein levels in amniotic fluid and the fetal kidney in humans.

OBJECTIVES: Aquaporin-2 (AQP2) is an important water channel protein that is expressed in the renal collecting duct and plays a key role in urine concentration and body water homeostasis. It has been demonstrated that the urinary excretion of AQP2 correlates strongly with its expression in the kidney in adult humans and rats. However, there have been no studies on the urinary excretion of AQP2 in human fetuses during development. Fetal urine is the main source of the amniotic fluid; we speculate that the level of AQP2 in the amniotic fluid could reflect the expression level of the AQP2 protein in the fetal kidney. The purpose of the present study was to explore the relationship between AQP2 in the amniotic fluid and that in the fetal kidney. METHODS: In the present study, the concentration of the AQP2 protein in human amniotic fluid was measured by Enzyme-linked immunosorbent assay (ELISA) and its expression level in human fetal kidneys were examined by wastern blot and immunohistochemistry. RESULTS: Both the expression level of AQP2 in the fetal kidney (F = 195.9, P < 0.001) and the concentration of AQP2 in the amniotic fluid increased with gestational age (F = 1098, P < 0.001). Moreover, the concentration of AQP2 in the amniotic fluid was positively correlated with its expression level in the fetal kidney (r = 0.872, P < 0.0001). CONCLUSIONS: Our research indicates that AQP2 levels in the amniotic fluid may be used as a marker for AQP2 expression in the fetal kidney.

The efficacy and safety comparison of surgical treatments for stress urinary incontinence: A network meta-analysis.

AIMS: Stress urinary incontinence (SUI) is a common problem worldwide. Mainstream surgical procedures include tension-free vaginal tape (TVT), transobturator tape (TOT), tension-free vaginal tape-obturator (TVT-O), tension-free vaginal tape SECUR (TVT-S), and adjustable single-incision sling (Ajust). The aim of this study was to compare the efficacy and safety of these surgical procedures and assess which surgery is most optimal for SUI by adopting a network meta-analysis (NMA). METHODS: Electronic databases including PubMed, Cochrance Library, and Embase database were researched systematically, until March 21, 2017. The randomized controlled trials (RCTs) that compared the efficacy and safety of TVT, TOT, TVT-O, TVT-S, and Ajust were identified. The studies were included in the analysis when met the predefined inclusion criteria. After demographic and outcome data extraction, a network meta-analysis was conducted with software R 3.3.2 and STATA 14.0. Objective cure rate, subjective cure rate, postoperative complication rate, bladder perforation, tape erosion, urinary retention, and postoperative pain were considered as outcomes, and the outcomes were displayed as odds ratios (ORs) and 95% credible intervals (CrI). The consistency of direct and indirect evidence was assessed by node splitting. The ranks based on probabilities of intervention for the different endpoints were performed. RESULTS: Fourty-five RCTs with 7295 participants were analyzed. The NMA results revealed that, TVT, TOT, and Ajust had a higher objective cure rate than TVT-O and TVT-S (TVT-O: OR = 0.76, 95%CI [0.61, 0.94]; TVT-S: OR = 0.41, 95%CI [0.28, 0.60]). TVT, TOT, and TVT-O had a superior subjective cure rate than TVT-S and Ajust (Ajust: OR = 0.45, 95%CI [0.20, 0.91]; TVT-S: OR = 0.29, 95%CI [0.15, 0.56]). With TVT as the reference, TVT-S had a statistically lower postoperative complication rate (TVT-S: OR = 0.39, 95%CI [0.16, 0.89]). TVT-O, TVT-S, and TOT had a significantly lower bladder perforation rate (TOT: OR = 0.076, 95%CI [0.0060, 0.37]; TVT-O: OR = 4.1e-17, 95%CI [6.1e-48, 0.0032]; TVT-S: OR = 3.8e-17, 95%CI [1.8e-48, 0.0052]). There were no obvious differences between the five treatments for tape erosion. TVT-O exhibited a less postoperative retention (TVT-O: OR = 0.35, 95%CI [0.16, 0.74]). Probabilities of ranking results indicated that TOT was the treatment with best ranking in efficacy and a relatively high safety. CONCLUSIONS: Our study recommend TOT as the optimal regimen for SUI with high efficacy and moderate safety when compared with TVT, TVT-O, TVT-S, and Ajust interventions. However, with the limitation of our study, additional high-quality studies are needed to further evaluate the outcomes.

Study on the relationship between net primary productivity and site quality in Japanese larch plantations in mountainous areas of eastern Liaoning.

Plantation forests enhance carbon storage in terrestrial ecosystems in China. Larix kaempferi (Lamb.) Carrière (Lamb.) (Larix olgensis Henry) is the main species for afforestation in the eastern Liaoning Province. Therefore, it is important to understand the correlation between the site class and carbon sink potential of Larix kaempferi plantations in Liaoning Province for afforestation and carbon sink in this area. The model was fitted using three classical theoretical growth equations: the Richards model, the Korf model, and the Hossfeld model. This study used the forest resource inventory data for management in Liaoning Province in 2011 to build six dynamic height-age models for a Larix kaempferi plantation in Dandong City regardless of base-age. The optimal model derived by the generalized algebraic difference approach (GADA) method was compared with the model derived by the algebraic difference approach (ADA) method. The superiority of GADA was demonstrated by comparison. The Levenberg-Marquardt algorithm was used to fit the model. The statistical and biological characteristics were considered synthetically when comparing the models. The best model was screened out by statistical analysis and graphic analysis. The results show that the differential height-age model derived from Richards equation can well explain the growth process of Larix kaempferi in Dandong City, Liaoning Province under different conditions. The site index model based on Richards equation and derived by GADA was used to calculate the site class of a Larix kaempferi plantation in Dandong City. The net primary productivity (NPP) value from the past ten years was extracted from the MOD17A3HGF data set. Spearman correlation analysis and Kendall correlation analysis were used to show that there is a significant positive correlation between NPP value and site class of Larix kaempferi plantation in Dandong City. Among them, the highest growth occurred in 2016; NPP increased by about 3.914 gC/m2/year for every two increases in height-age grade; the lowest increase in NPP was in 2014; NPP increased by about 2.113 gC/m2/year for every two increases in height-age grade; and for every two increases in height-age grade in the recent ten years, the average NPP value increased by about 2.731 gC/m2/year.

Prevalence, risk factors, psychological effects of children and adolescents with lower urinary tract symptoms: a large population-based study.

Background: Lower urinary tract symptoms (LUTS) are clinically frequent and seriously affect the psychological and mental health of children and adolescents. However, most studies on LUTS and its influence on the psychological behavior and mental health have focused on adults. This study aimed to investigate LUTS prevalence and associated factors in children and adolescents and explore its impact on psychological behavior. Materials and methods: From October 2019 to November 2021, an epidemiological LUTS survey was carried out on 6,077 children aged 6-15 years old in 12 primary and secondary schools in China by using anonymous questionnaires. Results: A total of 5,500 valid questionnaires were collected, and the total prevalence of four representative symptoms of LUTS: urgency, frequency, daytime urinary incontinence, and nocturnal enuresis was 19.46%, 14.55%, 9.75%, and 8.4%, respectively. The prevalence decreased with age, which decreased rapidly in children aged 6-12 years old. The incidence of LUTS in those who did not continue to use disposable diapers (DD) and began to perform elimination communication (EC) after the age of 1 was significantly higher than that of those who stopped using DD and started EC before 1 year of age (P < 0.05). There were significant differences in the occurrence of LUTS without toiled training (TT) (P < 0.05). The prevalence of LUTS in males was significantly higher than in females (P < 0.05). LUTS in children and adolescents with constipation was significantly higher compared to those without constipation (P < 0.05). The detection rate of abnormal psychological behavior in the LUTS group was 44.6%, which was significantly higher than that in the no LUTS group (21.4%, P < 0.05). The scores of emotional symptoms, conduct problems, hyperactivity, and peer communication problems were significantly higher in the LUTS group than the control group. Conclusions: In Mainland China, the prevalence of LUTS in children and adolescents is high. Continued use of DD after 1 year of age, history of urinary tract infection, lack of TT, and constipation were risk factors for LUTS. EC before 1 year of age is a protective factor for LUTS. The prevalence of psychological behavioral abnormalities is high in children and adolescents with LUTS, which needs to be more concerned.

The value of home-uroflowmetry in evaluation of voiding function in children with overactive bladder.

INTRODUCTION: Overactive bladder (OAB) in children is clinically common and seriously affects the physical and mental health of children. The voiding frequency (VF) is an important basis for the diagnosis of OAB. The emergence of home-uroflowmetry (HUF) has allowed the patients to record the VF while recording the uroflowmetry at home, and the voiding at home can show the real voiding situation. However, the use of HUF to assess OAB in children and its clinical significance has not been reported in the literature. Thus, this study investigate the value of HUF in evaluation of voiding function in children with OAB and survey the VF of healthy children in Mainland China. MATERIALS AND METHODS: From May 2021 to July 2023, 52 children with OAB aged 7-10 years, 48 age-matched volunteers (control group) accepted HUF. Daytime VF and nighttime VF, voided volume (VV) per time, 24-h voided volume (24h-VV), maximum flow rate (Qmax), voiding time (VT), and uroflow pattern were recorded and compute corrected maximum urine flow rate (cQmax). VF in 600 health pupils (7-10 years) from five primary schools in Henan Province China were selected for questionnaire survey by cross-sectional survey and multi-stage sampling methods. RESULTS: 52 children with OAB and 48 healthy children completed the available 48-h HUF recordings. 24-hour, daytime, and nighttime VF, and cQmax were higher in the OAB group than in the control group (P < 0.05). However, average VV, Qmax, and VT were lower in the OAB group than in the control group (P < 0.05). There was no significant difference in 24h-VV between two groups (P > 0.05). A total of 502 questionnaires qualified for statistical analysis, and the 24h-VF was 6.3 ± 0.95 times, daytime VF was 5.6 ± 0.89 times, and nighttime VF was 0.7 ± 0.59 times. There was no significant difference in the comparison of 24-h, daytime, and nighttime VF between boys and girls and in the comparison of VF by age (P > 0.05). Compared with the results of the questionnaire, the difference of VF in HUF control group was not statistically significant (P > 0.05). CONCLUSIONS: The VF in children is similar to that of adults and the HUF is a useful tool with the ability to more realistically record changes in voiding function in children with OAB.

Activation of the TGF-ß1/Smads/α-SMA pathway is related to histological and functional changes in children with neurogenic bladder.

This research is to investigate the expression of the TGF-ß1/Smads/α-SMA pathway and its effect on bladder histology and function in children with neurogenic bladder (NB). The bladder specimens from 10 children with NB and 8 children with vesicoureteral junction obstruction were collected into the NB and control groups. The expression of TGF-ß1, Smad2, Smad3, Smad4, Smad6, α-SMA, fibronectin, collagen I and collagen III in bladder tissues was detected. In addition, the histological characteristics of the bladder were evaluated. A preoperative urodynamic study was performed on all children with NB. We analysed the correlations among the expression of the marker protein a-SMA in myofibroblasts, effector cells of the pathway, and bladder function parameters. Compared with those in the control group, the expression of TGF-ß1, Smad2, Smad3, Smad4, α-SMA, fibronectin, collagen I and collagen III was significantly increased in the NB group, while the expression of Smad6 was decreased (p < 0.01). HE and Masson staining in the NB group showed increased collagen levels and hypertrophy of smooth muscle cells. Children with NB had a low bladder volume ratio (BVR), low compliance (△C) and high maximum bladder pressure, low maximum flow rate, large postvoid residual volume, low bladder contraction index and low bladder voiding efficiency. The expression of α-SMA was negatively correlated with the BVR (r = - 0.7066, P = 0.0223) and △C (r = - 0.6516, P = 0.0412). We conclude that the TGF-ß1/Smads/α-SMA pathway is activated in the bladder tissue of children with NB and may be involved in the processes causing histological and functional changes.

Molecular Mechanism of SARS-CoVs Orf6 Targeting the Rae1-Nup98 Complex to Compete With mRNA Nuclear Export.

The accessory protein Orf6 is uniquely expressed in sarbecoviruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is an ongoing pandemic. SARS-CoV-2 Orf6 antagonizes host interferon signaling by inhibition of mRNA nuclear export through its interactions with the ribonucleic acid export 1 (Rae1)-nucleoporin 98 (Nup98) complex. Here, we confirmed the direct tight binding of Orf6 to the Rae1-Nup98 complex, which competitively inhibits RNA binding. We determined the crystal structures of both SARS-CoV-2 and SARS-CoV-1 Orf6 C-termini in complex with the Rae1-Nup98 heterodimer. In each structure, SARS-CoV Orf6 occupies the same potential mRNA-binding groove of the Rae1-Nup98 complex, comparable to the previously reported structures of other viral proteins complexed with Rae1-Nup98, indicating that the Rae1-Nup98 complex is a common target for different viruses to impair the nuclear export pathway. Structural analysis and biochemical studies highlight the critical role of the highly conserved methionine (M58) of SARS-CoVs Orf6. Altogether our data unravel a mechanistic understanding of SARS-CoVs Orf6 targeting the mRNA-binding site of the Rae1-Nup98 complex to compete with the nuclear export of host mRNA, which further emphasizes that Orf6 is a critical virulence factor of SARS-CoVs.

Global Characterization of Immune Infiltration in Clear Cell Renal Cell Carcinoma.

BACKGROUND: Immunotherapy has revolutionized the treatment of clear cell renal cell carcinoma (ccRCC). However, the therapy is constrained by drug resistance. Therefore, further characterization of immune infiltration in ccRCC is needed to improve its efficacy. METHODS: Here, we adopted the CIBERSORT method to analyze the level of 22 immune cells, and analyzed the correlation of immune cells and clinical parameters in ccRCC in The Cancer Genome Atlas. We used consensus clustering to cluster ccRCC and identified differently expressed genes (DEGs) between hot and cold tumors using the "Limma" package, and then performed enrichment analysis of DEGs. Finally, we constructed and validated a Cox regression model using the "survival", "glmnet", and "survivalROC" packages, implemented in R. RESULTS: Regulatory T cells upregulated in tumor tissue increased during tumor progression, and correlated with poor overall survival in ccRCC. Consensus clustering identified four clusters of ccRCC. To elucidate the underlying mechanisms of immune cell infiltration, we subdivided these four clusters into two major types, immune hot and cold, and identified DEGs between them. The results revealed different transcription profiles in the two tumor types, with hot tumors being enriched in immune-related signaling, whereas cold tumors were enriched in extracellular matrix remodeling and the phosphatidylinositol 3-kinase-AKT (PI3K/AKT) pathway. We further identified hub genes and prognostic-related genes from the DEGs, and constructed a Cox regression model for predicting the overall survival of patients with ccRCC. The areas under the receiver operating characteristics curve for the risk model for the training, testing, and external Zhengzhou validation cohorts were 0.834, 0.733, and 0.812, respectively. Notably, gene sets in the prediction model could also predict the overall survival of patients receiving immunotherapy. CONCLUSION: These findings provide a comprehensive characterization of immune infiltration in ccRCC, while the constructed model can be used effectively to predict the overall survival of ccRCC patients.

Apigenin Nanoparticle Attenuates Renal Ischemia/Reperfusion Inflammatory Injury by Regulation of miR-140-5p/CXCL12/NF-κB Signaling Pathway.

Apigenin as a natural flavonoid product has been proved previously to play a renoprotective effect during ischemia/reperfusion injury (IRI), but the particular mechanisms involving the positive effects of apigenin remain totally unclear. The study investigated apigenin's roles and underlying biological mechanisms in IR-induced acute kidney injury (AKI). Thirty-six mice received a right nephrectomy and clamping of the left renal artery for 30 minutes, and then perfusion for 24 h. Apigenin was loaded onto a biodegradable polymer carrier (nanoparticle) to enhance its bioavailability. Mice were subjected to intraperitoneally injection with apigenin (5, 10 or 20 mg/kg) for 24 h before surgery. For in vitro experiments, mouse renal tubular epithelial cells (mRTECs) and miR-140-5p mimic/inhibitor transfected mRTECs were subjected to hypoxia/reoxygenation in the presence or absence of apigenin. In vitro, we uncovered that hypoxia/reoxygenation stimulation caused inflammatory injury in mRTECs. Apigenin reduced the hypoxia/reoxygenation-induced cell inflammatory injury and NF- B p65 nuclear translocation from cytoplasm and activation. Moreover, apigenin reduced hypoxia/reoxygenationtriggered miR-140-5p down-regulation. What's more, the luciferase reporter system revealed that miR-140-5p negatively regulates CXCL12, which is its direct target of action. CXCL12 exhibited an inhibitory effect on the apigenin-induced inactivation of NF- B signaling pathway. Furthermore, we observed that apigenin pretreatment attenuated the IR-triggered up-regulation of serum creatinine and blood urea nitrogen, elevation of pro-inflammatory cytokines secretion and tubular cell apoptosis, enhancement of CXCL12 and decline of miR-140-5p in vivo. Our studies show that apigenin protects against IR-triggered renal cell inflammatory injury in vivo and in vitro by miR-140-5p up-regulation and CXCL12 downregulation via quenching the NF- B pathway activation. Apigenin may be an encouraging therapeutic agent for patients with IR-associated kidney injury.

[Bioinformatic analysis of immune-related lncRNA based on TCGA database in patients with prostate cancer].

Objective To investigate the clinical significance of immune-related long non-coding RNAs (lncRNAs) and their potential role in guiding the treatment of prostate cancer. Methods lncRNAs of prostate cancer were obtained from TCGA database. The immune-related gene sets were downloaded from Molecular Signatures Database. Gene-lncRNA co-expression was confirmed by Pearson correlation analysis, and univariate Cox regression and selected operator regression (Lasso) were performed to identify important and immune-related lncRNAs. "gglot package" and "survival package" of R software were used to evaluate the correlation between the lncRNAs and clinical characteristics and the prognostic value of the lncRNAs. lnc2RNA database was used to analyze the difference of lncRNAs between normal prostate tissue and prostate cancer tissue. Starbase and David database were used to determine the predict function of lncRNAs in prostate cancer. Results AL162586.1, AC138028.4, SLC25A25-AS1, AC002553.1, AC004816.1, LINC00641 and AC027796.4 were key immune-related lncRNAs, and their expression was positively associated with N stage; the expression levels of AL162586.1 and SLC25A25-AS1 increased with higher T stage. The expression levels of SLC25A25-AS1 and LINC00641 were significantly different in tumor tissues from that of normal tissues. The GO enrichment showed that SLC25A25-AS1 was mainly distributed in membrane, had negative regulation of mRNA splicing via spliceosome and by a nucleotide binding. KEGG pathway enrichment showed that targeted genes were mainly involved in spliceosome pathway. Conclusion lncRNA has become a new research direction in prostate cancer and SLC25A25-AS1 may affect the prognosis of patients through splicing pathway.

Purified black tea theaflavins and theaflavins/catechin supplements did not affect serum lipids in healthy individuals with mildly to moderately elevated cholesterol concentrations.

BACKGROUND: Ingestion of tea flavonoids found in both green and black tea is linked to cardiovascular health benefits such as lowering serum lipids. Evidence for a cholesterol-lowering benefit of green or black tea consumption from human intervention studies is, however, conflicting and active components responsible for the effect have not yet been clearly identified. AIM OF THE STUDY: In a randomized, double-blind, placebo-controlled, parallel design study the effects of ingesting a purified black tea theaflavins (TFs) powder alone or in combination with catechin (TFs/catechins) on lowering serum total (TC) and LDL-cholesterol (LDL-c) were assessed. METHODS: In total, 102 mildly to moderately hypercholesterolemic (TC and LDL-c: 5.70 +/- 0.74 and 3.97 +/- 0.61 mmol/L, respectively) subjects (67 men and 35 women) were randomly assigned to consume once daily one capsule of one of the 3 treatments: TFs (providing 77.5 mg), TFs/catechins (providing 75.0 mg TFs plus 150.0 mg catechins and 195.0 mg of other polyphenols), or placebo (cellulose). RESULTS: Serum TC and LDL-c concentrations did not differ significantly among the 3 treatments as assessed at 4, 8, and 11 weeks using analysis of covariance (p = 0.1187 and p = 0.1063, respectively). Although changes over time from baseline to week 11 were significant for TC and LDL-c (p = 0.0311 and p = 0.0269, respectively), this decrease over time was seen in the TFs and placebo groups. CONCLUSION: In this human intervention study, no statistically significant LDL-c lowering effect was seen with either TFs alone or the TFs/catechins combination as compared to placebo. Based on these findings it cannot be concluded that tea flavonoids such as theaflavins and catechins are responsible for a putative cholesterol-lowering effect of black tea, at least not with the daily dose applied in the present study.

[Effects of testosterone substitution on metabolic syndrome-related factors in hypogonadal males: a meta-analysis].

OBJECTIVE: To conduct a meta-analysis on the effects of testosterone on the related factors of metabolic syndrome in hypogonadal males. METHODS: Based on the principles and methods of Cochrane systematic reviews, we searched the PubMed (1980 to August 2009), Embase (1980 to August 2009), the Cochrane Central Register of Controlled Trials and CNKI (1995 to August 2009) , and handsearched some relevant journals and conference proceedings as well. We also identified randomized controlled trials addressing the use of testosterone for the treatment of hypogonadism, screened the retrieved studies according to the predefined inclusion and exclusion criteria, evaluated the quality of the included studies, and performed a meta-analysis on the results of homogeneous studies using the Cochrane Collaboration's RevMan 5.0 software. RESULTS: Six randomized controlled trials were included. The results of analysis indicated that testosterone substitution could significantly ameliorate fasting blood glucose, total cholesterol and insulin resistance in hypogonadism patients, and it could also reduce LDL, HDL, triglyceride and systolic blood pressure, though with no significant difference from the controls. However, there was insufficient evidence to show the effects of testosterone on waist circumference, waist-hip ratio and diastolic blood pressure. CONCLUSION: Existing clinical evidence has demonstrated the positive effects of testosterone substitution on the improvement of insulin resistance, blood glucose and lipids, but due to the heterogeneity and high risk of bias in the included studies, the evidence might be insufficient to give full support to the demonstration. Further large-scale trials are required to define the metabolic effects of testosterone in the treatment of hypogonadism.

Sex Differences in Kidney Function and Metabolism Assessed Using Hyperpolarized [1-13C]Pyruvate Interleaved Spectroscopy and Nonspecific Imaging.

Metabolic sex differences have recently been shown to be particularly important in tailoring treatment strategies. Sex has a major effect on fat turnover rates and plasma lipid delivery in the body. Differences in kidney structure and transporters between male and female animals have been found. Here we investigated sex-specific renal pyruvate metabolic flux and whole-kidney functional status in age-matched healthy Wistar rats. Blood oxygenation level-dependent and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) were used to assess functional status. Hyperpolarized [1-13C]pyruvate was used to assess the metabolic differences between male and female rats. Female rats had a 41% ± 3% and 41% ± 5% lower absolute body and kidney weight, respectively, than age-matched male rats. No difference was seen between age-matched male and female rats in the kidney-to-body weight ratio. A 56% ± 11% lower lactate production per mL/100 mL/min was found in female rats than in age-matched male rats measured by hyperpolarized magnetic resonance and DCE MRI. Female rats had a 33% ± 11% higher glomerular filtration rate than age-matched male rats measured by DCE MRI. A similar renal oxygen tension (T2*) was found between age-matched male and female rats as shown by blood oxygenation level-dependent MRI. The results were largely independent of the pyruvate volume and the difference in body weight. This study shows an existing metabolic difference between kidneys in age-matched male and female rats, which indicates that sex differences need to be considered when performing animal experiments.

CDC27 Promotes Tumor Progression and Affects PD-L1 Expression in T-Cell Lymphoblastic Lymphoma.

T-lymphoblastic lymphoma (T-LBL) is a rare hematological malignancy with highly aggressive, unique clinical manifestations, and poor prognosis. Cell division cycle 27 (CDC27) was previously reported to be a significant subunit of the anaphase-promoting complex/cyclosome. However, the specific functions and relevant mechanisms of CDC27 in T-LBL remain unknown. Through immunohistochemistry staining, we identified that CDC27 was overexpressed in T-LBL tissues and related to tumor progression and poor survival. Functional experiments demonstrated that CDC27 promoted proliferation in vivo and in vitro. Further experiment suggested the role of CDC27 in facilitating G1/S transition and promoting the expression of Cyclin D1 and CDK4. Then the effect of CDC27 in inhibiting apoptosis was also identified. Furthermore, we found a positive correlation between the expression of CDC27 and Programmed death ligand-1 (PD-L1) by immunohistochemistry staining. The interaction between CDC27 and PD-L1 was also proved by western blot, luciferase gene reporter assay and immunofluorescence. Taken together, our results showed that CDC27 contributes to T-LBL progression and there is a positive correlation between PD-L1 and CDC27, which offers novel perspectives for future studies on targeting CDC27 in T-LBL.

Corrigendum: CDC27 Promotes Tumor Progression and Affects PD-L1 Expression in T-Cell Lymphoblastic Lymphoma.

[This corrects the article DOI: 10.3389/fonc.2020.00488.].

SCF/c-kit signaling pathway participates in ICC damage in neurogenic bladder.

Neurogenic bladder (NB) is a type of double renal dysfunction caused by nerve lesions. The interstitial cells of Cajal (ICC) damage are involved in bladder dysfunction. The aim of this study is to investigate the effect of stem cell factor (SCF)/c-kit signaling pathway on ICC damage in NB model rats. Maximum cystometric capacity (MCC), bladder leak point pressures (BLPP), and bladder compliance (BC) were measured in sham-operated and NB model rats. Immunofluorescent staining for c-kit was performed to determine ICC count in rat bladder trigone. The morphology and ultrastructure changes of ICCs were observed under an electron microscope. The mRNA levels of c-kit and SCF in bladder tissues were determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The protein levels of c-kit, SCF, p-JAK, p-STAT1, and p-STAT3 in bladder tissues were determined by western blot. ICC proliferation was detected by CCK-8 assay. NB resulted in changes in ultrastructure changes of ICCs and a decrease in the number of ICCs and in expression of c-kit, SCF, p-JAK, p-STAT1, and p-STAT3 in NB tissues. Inhibition of SCF/c-kit signaling pathway suppressed ICC proliferation by inhibiting JAK/STAT3 pathway. Moreover, inhibition of SCF/c-kit signaling pathway impaired the SCF-induced attenuation of ICC damage in NB model rats. Collectively, our data indicate that SCF/c-kit signaling pathway participates in ICC damage in NB.