Dithiocarbazate-FeIII, -CoIII, -NiII, and -ZnII Complexes: Design, Synthesis, Structure, and Anticancer Evaluation.

Non-platinum-metal complexes show great potential as anticancer agents. Herein, a series of dithiocarbazate non-Pt-metal complexes, including [FeIII(L)2]·Cl·2H2O 1, [CoIII(L)2]·NO3·2.5H2O 2, [NiII(L)2] 3, and [ZnII(L)2] 4, have been designed and evaluated for their efficacy as antineoplastic agents. Among them, complex 2 exhibited higher anticancer efficacy than complexes 1, 3, 4, and cisplatin against several cancer cell lines. Hemolysis assays revealed that complex 2 showed comparable hemolysis with cisplatin. In vivo anticancer evaluations showed that complex 2 could retard tumor xenograft growth effectively with low systemic toxicity. Further studies revealed that complex 2 suppressed cancer cells by triggering multiple mechanisms involving the simultaneous inhibition of mitochondria and glycolytic bioenergetics. Overall, our study provides new insights into the anticancer mechanism of Co complexes, which can be used as a good strategy to overcome the flexibility of cancer cells to chemotherapy adaptation.

Prostate Health Index (phi) and its derivatives predict Gleason score upgrading after radical prostatectomy among patients with low-risk prostate cancer.

To analyze the performance of the Prostate Health Index (phi) and its derivatives for predicting Gleason score (GS) upgrading between prostate biopsy and radical prostatectomy (RP) in the Chinese population, an observational, prospective RP cohort consisting of 351 patients from two medical centers was established from January 2017 to September 2020. Pathological reclassification was determined by the Gleason Grade Group (GG). The area under the receiver operating characteristic curve (AUC) and logistic regression (LR) models were used to evaluate the predictive performance of predictors. In clinically low-risk patients with biopsy GG ≤2, phi (odds ratio [OR] = 1.80, 95% confidence interval [95% CI]: 1.14-2.82, P = 0.01) and its derivative phi density (PHID; OR = 2.34, 95% CI: 1.30-4.20, P = 0.005) were significantly associated with upgrading to GG ≥3 after RP, and the results were confirmed by multivariable analysis. Similar results were observed in patients with biopsy GG of 1 for the prediction of upgrading to RP GG≥2. Compared to the base model (AUC = 0.59), addition of the phi or PHID could provide additional predictive value for GS upgrading in low-risk patients (AUC = 0.69 and 0.71, respectively, both P < 0.05). In conclusion, phi and PHID could predict GS upgrading after RP in clinically low-risk patients.

AMPK activator C24 inhibits hepatic lipogenesis and ameliorates dyslipidemia in HFHC diet-induced animal models.

Dyslipidemia is a chronic metabolic disease characterized by elevated levels of lipids in plasma. Recently, various studies demonstrate that the increased activity of adenosine 5'-monophosphate-activated protein kinase (AMPK) causes health benefits in energy regulation. Thus, great efforts have been made to develop AMPK activators as a metabolic syndrome treatment. In the present study, we investigated the effects of the AMPK activator C24 on dyslipidemia and the potential mechanisms. We showed that C24 (5-40 µM) dose-dependently increased the phosphorylation of AMPKα and acetyl-CoA carboxylase (ACC), and inhibited lipogenesis in HepG2 cells. Using compound C, an AMPK inhibitor, or hepatocytes isolated from liver tissue-specific AMPK knockout AMPKα1α2fl/fl;Alb-cre mice (AMPK LKO), we demonstrated that the lipogenesis inhibition of C24 was dependent on hepatic AMPK activation. In rabbits with high-fat and high-cholesterol diet-induced dyslipidemia, administration of C24 (20, 40, and 60 mg · kg-1· d-1, ig, for 4 weeks) dose-dependently decreased the content of TG, total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) in plasma and played a role in protecting against hepatic dysfunction by decreasing lipid accumulation. A lipid-lowering effect was also observed in high-fat and high-cholesterol diet-fed hamsters. In conclusion, our results demonstrate that the small molecular AMPK activator C24 alleviates hyperlipidemia and represents a promising compound for the development of a lipid-lowering drug.

Sarsasapogenin improves adipose tissue inflammation and ameliorates insulin resistance in high-fat diet-fed C57BL/6J mice.

Insulin resistance is a major cause of type 2 diabetes and metabolic syndrome. Macrophage infiltration into obese adipose tissue promotes inflammatory responses that contribute to the pathogenesis of insulin resistance. Suppression of adipose tissue inflammatory responses is postulated to increase insulin sensitivity in obese patients and animals. Sarsasapogenin (ZGY) is one of the metabolites of timosaponin AIII in the gut, which has been shown to exert anti-inflammatory action. In this study, we investigated the effects of ZGY treatment on obesity-induced insulin resistance in mice. We showed that pretreatment with ZGY (80 mg·kg-1·d-1, ig, for 18 days) significantly inhibited acute adipose tissue inflammatory responses in LPS-treated mice. In high-fat diet (HFD)-fed obese mice, oral administration of ZGY (80 mg·kg-1·d-1, for 6 weeks) ameliorated insulin resistance and alleviated inflammation in adipose tissues by reducing the infiltration of macrophages. Furthermore, we demonstrated that ZGY not only directly inhibited inflammatory responses in macrophages and adipocytes, but also interrupts the crosstalk between macrophages and adipocytes in vitro, improving adipocyte insulin resistance. The insulin-sensitizing and anti-inflammatory effects of ZGY may result from inactivation of the IKK /NF-κB and JNK inflammatory signaling pathways in adipocytes. Collectively, our findings suggest that ZGY ameliorates insulin resistance and alleviates the adipose inflammatory state in HFD mice, suggesting that ZGY may be a potential agent for the treatment of insulin resistance and obesity-related metabolic diseases.

Diphyllin Improves High-Fat Diet-Induced Obesity in Mice Through Brown and Beige Adipocytes.

Brown adipose tissue (BAT) and beige adipose tissue dissipate metabolic energy and mediate nonshivering thermogenesis, thereby boosting energy expenditure. Increasing the browning of BAT and beige adipose tissue is expected to be a promising strategy for combatting obesity. Through phenotype screening of C3H10-T1/2 mesenchymal stem cells, diphyllin was identified as a promising molecule in promoting brown adipocyte differentiation. In vitro studies revealed that diphyllin promoted C3H10-T1/2 cell and primary brown/beige preadipocyte differentiation and thermogenesis, which resulted increased energy consumption. We synthesized the compound and evaluated its effect on metabolism in vivo. Chronic experiments revealed that mice fed a high-fat diet (HFD) with 100 mg/kg diphyllin had ameliorated oral glucose tolerance and insulin sensitivity and decreased body weight and fat content ratio. Adaptive thermogenesis in HFD-fed mice under cold stimulation and whole-body energy expenditure were augmented after chronic diphyllin treatment. Diphyllin may be involved in regulating the development of brown and beige adipocytes by inhibiting V-ATPase and reducing intracellular autophagy. This study provides new clues for the discovery of anti-obesity molecules from natural products.

Effects of diabetes mellitus and Metformin administration on prostate cancer detection at biopsy among Chinese men: a case-control study.

PURPOSE: To determine the associations among diabetes status, Metformin administration and prostate cancer (PCa) detection at biopsy in Chinese population. METHODS: A case-control study was conducted among a prospectively enrolled prostate biopsy cohort of 518 patients from Jan 2013 to Dec 2014 at our institute. Diabetes status and Metformin administration were determined through medical records and self-report. Different clinical characteristics were registered and compared among different groups. Univariate and multivariate logistic regression analyses were performed to evaluate the effects of diabetes status and Metformin administration on the detection of overall as well as high-grade PCa at biopsy. RESULTS: PCa was detected in 229 (44.2%) men, and high-grade PCa (Gleason score ≥8) was detected in 65 (12.5%) men. Diabetes was observed in 96 men, and 28 of them were administered with Metformin. Both overall and high-grade cancer detection rates were significantly higher in diabetic patients (p<0.001). In multivariate analysis, diabetes status was a risk factor for high-grade cancer detection (OR 7.699, 95%CI 3.483-17.020, p<0.001), but not for total PCa detection (OR 1.774, 95%CI 0.831-3.787, p=0.138). Meanwhile, Metformin administration was proved to be a protective factor for high-grade disease (OR 0.420, 95%CI 0.201-0.879, p=0.021) in multivariate analysis, while no correlation was detected with overall cancer detection (OR 0.786, 95%CI 0.172-3.593, p=0.756). CONCLUSIONS: Diabetes status was positively associated with biopsy-mediated high-grade PCa detection in Chinese population, while the positive association would be partly compromised by Metformin administration.

Phi-based risk calculators performed better in the prediction of prostate cancer in the Chinese population.

Risk prediction models including the Prostate Health Index (phi) for prostate cancer have been well established and evaluated in the Western population. The aim of this study is to build phi-based risk calculators in a prostate biopsy population and evaluate their performance in predicting prostate cancer (PCa) and high-grade PCa (Gleason score ≥7) in the Chinese population. We developed risk calculators based on 635 men who underwent initial prostate biopsy. Then, we validated the performance of prostate-specific antigen (PSA), phi, and the risk calculators in an additional observational cohort of 1045 men. We observed that the phi-based risk calculators (risk calculators 2 and 4) outperformed the PSA-based risk calculator for predicting PCa and high-grade PCa in the training cohort. In the validation study, the area under the receiver operating characteristic curve (AUC) for risk calculators 2 and 4 reached 0.91 and 0.92, respectively, for predicting PCa and high-grade PCa, respectively; the AUC values were better than those for risk calculator 1 (PSA-based model with an AUC of 0.81 and 0.82, respectively) (all P < 0.001). Such superiority was also observed in the stratified population with PSA ranging from 2.0 ng ml-1to 10.0 ng ml-1. Decision curves confirmed that a considerable proportion of unnecessary biopsies could be avoided while applying phi-based risk calculators. In this study, we showed that, compared to risk calculators without phi, phi-based risk calculators exhibited superior discrimination and calibration for PCa in the Chinese biopsy population. Applying these risk calculators also considerably reduced the number of unnecessary biopsies for PCa.

Differential expressions of integrin-linked kinase, ß-parvin and cofilin 1 in high-fat diet induced prostate cancer progression in a transgenic mouse model.

High-fat diet induced obesity was associated with more aggressive prostate cancer. Recent research has demonstrated that integrin-linked kinase (ILK), ß-parvin and downstream cofilin 1 jointly affected cancer progression. Meanwhile, these proteins were also involved in energy metabolism. Therefore, the present study was conducted to investigate the potential function of ILK, ß-parvin and cofilin 1 in the high-fat diet-induced progression of prostate cancer. Transgenic mice with prostate cancer were employed, fed with different diets and sacrificed at 20 and 28 weeks. Tumor differentiation, extracapsular extension and metastasis were compared between the groups. Expression levels of ILK, ß-parvin and cofilin 1 in prostate were evaluated by immunohistochemical analysis and determined by an immunoreactivity score. Public databases were applied for analysis and validation. It was detected that high-fat diet feeding promoted cancer progression in transgenic mice with prostate cancer, with increased expressions of ß-parvin (P=0.038) and cofilin 1 (P=0.018). Higher expressions of ILK, ß-parvin and cofilin 1 were also associated with poorer cancer differentiation. Additionally, higher mRNA levels of CFL1 were correlated with a worse disease-free survival in patients of certain subgroups from The Cancer Genome Atlas database. Further studies were warranted in discussing the potential roles of ILK, ß-parvin and cofilin 1 in high-fat diet feeding induced progression of prostate cancer.

High-fat diet-induced adipokine and cytokine alterations promote the progression of prostate cancer in vivo and in vitro.

High-fat diet (HFD) -induced obesity is associated with more aggressive and lethal prostate cancer (PCa) in males, although the exact underlying mechanisms remain unclear. In the present study, transgenic adenocarcinoma of mouse prostate (TRAMP) models fed on an HFD (40% fat) or a control diet (CD; 16% fat) were generated, and cancer differentiation, local invasion and metastasis were compared at 20, 24 and 28 weeks. Mouse sera from each group were collected, and adipokines and cytokines were measured using multiplex immunoassays. HFD-sera and CD-sera were additionally processed into conditioned media (2.5% mixed sera), and in vitro studies were conducted to determine the proliferation, migration and invasion of cancer cells when conditioned media were used for culture. In TRAMP mice, HFD feeding increased body weight and adipose tissue deposition, and promoted the progression of PCa, specifically with regard to poorer differentiation, increased local invasion and metastasis rate. Sera from HFD-fed TRAMP mice contained increased levels of leptin, and a time-dependent increasing trend in the levels of CC chemokine ligand (CCL)3, CCL4, CCL5 and CXC chemokine ligand (CXCL)10 was observed. However, no alterations were detected in the levels of adiponectin, interleukin (IL)-4, IL-5, IL-6, IL-12p70, interferon-γ, tumor necrosis factor-α, CCL2, CCL7, CCL11, CXCL1 and CXCL2. In vitro studies determined that HFD-sera-conditioned medium promoted proliferation, migration and invasion of DU145 cells, as compared with CD-sera-conditioned medium and serum-free medium. In conclusion, the results of the present study suggested that the circulating adipokine and cytokine alterations in response to excess adipose tissue deposition induced by HFD feeding contributed to PCa progression.

Evaluation of PSA-age volume score in predicting prostate cancer in Chinese population.

This study was performed to evaluate prostate-specific antigen-age volume (PSA-AV) scores in predicting prostate cancer (PCa) in a Chinese biopsy population. A total of 2355 men who underwent initial prostate biopsy from January 2006 to November 2015 in Huashan Hospital were recruited in the current study. The PSA-AV scores were calculated and assessed together with PSA and PSA density (PSAD) retrospectively. Among 2133 patients included in the analysis, 947 (44.4%) were diagnosed with PCa. The mean age, PSA, and positive rates of digital rectal examination result and transrectal ultrasound result were statistically higher in men diagnosed with PCa (all P < 0.05). The values of area under the receiver operating characteristic curves (AUCs) of PSAD and PSA-AV were 0.864 and 0.851, respectively, in predicting PCa in the entire population, both performed better than PSA (AUC = 0.805; P < 0.05). The superiority of PSAD and PSA-AV was more obvious in subgroup with PSA ranging from 2.0 ng ml-1 to 20.0 ng ml-1. A PSA-AV score of 400 had a sensitivity and specificity of 93.7% and 40.0%, respectively. In conclusion, the PSA-AV score performed equally with PSAD and was better than PSA in predicting PCa. This indicated that PSA-AV score could be a useful tool for predicting PCa in Chinese population.

Prognostic factors in Chinese patients with prostate cancer receiving primary androgen deprivation therapy: validation of Japan Cancer of the Prostate Risk Assessment (J-CAPRA) score and impacts of pre-existing obesity and diabetes mellitus.

PURPOSE: Our aim was to determine the prognostic factors in Chinese patients with prostate cancer receiving primary androgen deprivation therapy (PADT), validate the Japan Cancer of the Prostate Risk Assessment (J-CAPRA) score, and investigate the impacts of pre-existing obesity and diabetes mellitus (DM). METHODS: The study enrolled Chinese patients diagnosed with prostatic adenocarcinoma and treated with bilateral orchiectomy as PADT at Huashan Hospital, Fudan University (Shanghai, China), from January 2003 to December 2015. The overall survival (OS) and prognostic value of J-CAPRA score, pre-existing obesity, DM, and various clinicopathological variables were analyzed. RESULTS: Of the 435 patients enrolled, 174 (40.0%) deaths occurred during follow-up; 3- and 5-year OS were 74.0 and 58.9%, respectively. Multivariate analysis identified that higher Gleason score and metastasis were both correlated with worse OS and that higher J-CAPRA score was correlated with worse OS [hazard ratio (HR) 1.110, 95% confidence interval (CI) 1.035-1.190, P = 0.003). Different risk categories based on J-CAPRA score showed good stratification in OS (log-rank P = 0.015). In subgroup analysis, pre-existing obesity as a protective factor in younger patients (age ≤ 65, HR 0.271, 95% CI 0.075-0.980, P = 0.046) and pre-existing DM as a risk factor in older patients (> 75, HR 1.854, 95% CI 1.026-3.351, P = 0.041) for OS were recognized, and the prediction accuracy of J-CAPRA was elevated after incorporating pre-existing obesity and DM. CONCLUSIONS: The J-CAPRA score presented with good OS differentiation among Chinese patients under PADT. Younger patients (age ≤ 65) had better OS with pre-existing obesity, while older patients (age > 75) had worse OS with pre-existing DM.

Aldosterone induces inflammatory cytokines in penile corpus cavernosum by activating the NF-κB pathway.

Emerging evidence indicates that aldosterone and mineralocorticoid receptors (MRs) are associated with the pathogenesis of erectile dysfunction. However, the molecular mechanisms remain largely unknown. In this study, freshly isolated penile corpus cavernosum tissue from rats was treated with aldosterone, with or without MRs inhibitors. Nuclear factor (NF)-kappa B (NF-κB) activity was evaluated by real-time quantitative PCR, luciferase assay, and immunoblot. The results demonstrated that mRNA levels of the NF-κB target genes, including inhibitor of NF-κB alpha (IκB-α), NF-κB1, tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6), were higher after aldosterone treatment. Accordingly, phosphorylation of p65/RelA, IκB-α, and inhibitor of NF-κB kinase-ß was markedly increased by aldosterone. Furthermore, knockdown of MRs prevented activation of the NF-κB canonical pathway by aldosterone. Consistent with this finding, ectopic overexpression of MRs enhanced the transcriptional activation of NF-κB by aldosterone. More importantly, the MRs antagonist, spironolactone blocked aldosterone-mediated activation of the canonical NF-κB pathway. In conclusion, aldosterone has an inflammatory effect in the corpus cavernosum penis, inducing NF-κB activation via an MRs-dependent pathway, which may be prevented by selective MRs antagonists. These data reveal the possible role of aldosterone in erectile dysfunction as well as its potential as a novel pharmacologic target for treatment.

Genetic polymorphisms in leptin, adiponectin and their receptors affect risk and aggressiveness of prostate cancer: evidence from a meta-analysis and pooled-review.

Leptin and adiponectin signaling was associated with development and progression of various cancers. The present study aimed to clarify the role of genetic variants in leptin, adiponectin and their receptors in prostate cancer. After comprehensive search and manuscript scanning, a total of 49 genetic variants were enrolled and examined for their relations to cancer risk and aggressiveness. In the meta-analysis, LEP rs7799039 (allele contrast: OR 1.133, 95%CI 1.024-1.254), ADIPOQ rs2241766 (allele contrast: OR 1.201, 95%CI 1.015-1.422) and ADIPOR1 rs10920531 (allele contrast: OR 1.184, 95%CI 1.075-1.305) variants were identified to be correlated with increased risk of prostate cancer. On the contrary, LEPR rs1137101 (allele contrast: OR 0.843, 95%CI 0.730-0.973) and ADIPOR1 rs2232853 (allele contrast: OR 0.638, 95%CI 0.535-0.760) variants were associated with decreased risk of prostate cancer. From the pooled-review, we additionally recognized eight variants associated with cancer risk and another eight variants associated with cancer aggressiveness, respectively. These observations indicated important roles of leptin, adiponectin and their receptors in the development and progression of prostate cancer. The identified polymorphisms might assist in developing better risk-assessment tools, as well as generating novel targeted therapies, especially for obese cancer patients with impaired leptin and adiponectin signaling.

The Huashan risk calculators performed better in prediction of prostate cancer in Chinese population: a training study followed by a validation study.

The performances of the Prostate Cancer Prevention Trial (PCPT) risk calculator and other risk calculators for prostate cancer (PCa) prediction in Chinese populations were poorly understood. We performed this study to build risk calculators (Huashan risk calculators) based on Chinese population and validated the performance of prostate-specific antigen (PSA), PCPT risk calculator, and Huashan risk calculators in a validation cohort. We built Huashan risk calculators based on data from 1059 men who underwent initial prostate biopsy from January 2006 to December 2010 in a training cohort. Then, we validated the performance of PSA, PCPT risk calculator, and Huashan risk calculators in an observational validation study from January 2011 to December 2014. All necessary clinical information were collected before the biopsy. The results showed that Huashan risk calculators 1 and 2 outperformed the PCPT risk calculator for predicting PCa in both entire training cohort and stratified population (with PSA from 2.0 ng ml-1 to 20.0 ng m). In the validation study, Huashan risk calculator 1 still outperformed the PCPT risk calculator in the entire validation cohort (0.849 vs 0.779 in area under the receiver operating characteristic curve [AUC] and stratified population. A considerable reduction of unnecessary biopsies (approximately 30%) was also observed when the Huashan risk calculators were used. Thus, we believe that the Huashan risk calculators (especially Huashan risk calculator 1) may have added value for predicting PCa in Chinese population. However, these results still needed further evaluation in larger populations.

Performance of the Prostate Health Index in predicting prostate biopsy outcomes among men with a negative digital rectal examination and transrectal ultrasonography.

The [-2]proPSA (p2PSA) and its derivatives, the p2PSA-to-free PSA ratio (%p2PSA), and the Prostate Health Index (PHI) have greatly improved discrimination between men with and without prostate cancer (PCa) in prostate biopsies. However, little is known about their performance in cases where a digital rectal examination (DRE) and transrectal ultrasonography (TRUS) are negative. A prospective cohort of 261 consecutive patients in China with negative DRE and TRUS were recruited and underwent prostate biopsies. A serum sample had collected before the biopsy was used to measure various PSA derivatives, including total prostate-specific antigen (tPSA), free PSA, and p2PSA. For each patient, the free-to-total PSA ratio (%fPSA), PSA density (PSAD), p2PSA-to-free PSA ratio (%p2PSA), and PHI were calculated. Discriminative performance was assessed using the area under the receiver operating characteristic curve (AUC) and the biopsy rate at 91% sensitivity. The AUC scores within the entire cohort with respect to age, tPSA, %fPSA, PSAD, p2PSA, %p2PSA, and PHI were 0.598, 0.751, 0.646, 0.789, 0.814, 0.808, and 0.853, respectively. PHI was the best predictor of prostate biopsy results, especially in patients with a tPSA of 10.1-20 ng ml-1 . Compared with other markers, at a sensitivity of 91%, PHI was the most useful for determining which men did not need to undergo biopsy, thereby avoiding unnecessary procedures. The use of PHI could improve the accuracy of PCa detection by predicting prostate biopsy outcomes among men with a negative DRE and TRUS in China.

Body mass index is associated with higher Gleason score and biochemical recurrence risk following radical prostatectomy in Chinese men: a retrospective cohort study and meta-analysis.

BACKGROUND: The aim of the study is to investigate whether body mass index (BMI) affected pathological characteristics and biochemical recurrence (BCR) of prostate cancer after radical prostatectomy in Chinese men. METHODS: Medical records of 211 Chinese patients who underwent radical prostatectomy between 2006 and 2014 were retrospectively reviewed, with follow-up time of 24.5 ± 27.0 months. Multivariate logistic and Cox regression analyses were applied to address the impact of BMI on adverse pathological outcomes and BCR following prostatectomy. A meta-analysis of published studies from MEDLINE or EMBASE was conducted to determine the relationship between BMI and BCR following prostatectomy among Asian populations. RESULTS: Higher BMI was positively correlated with higher biopsy Gleason score (odds ratios (OR) 1.163, 95 % confidence interval (CI) 1.023-1.322, P = 0.021) and pathological Gleason score (OR 1.220, 95 % CI 1.056-1.410, P = 0.007) in multivariate analysis. BCR was detected in 48 patients (22.7 %). Multivariate Cox proportional hazards analysis revealed that higher BMI (hazard ratio (HR) 1.145, 95 % CI 1.029-1.273, P = 0.013) and prostate-specific antigen (HR 1.659, 95 % CI 1.102-2.497, P = 0.015) levels were independent predictors of BCR. The meta-analysis enrolled eight Asian studies of 4145 patients treated by radical prostatectomy. Based on random-effects approach, a 5 kg/m(2) increase in BMI was correlated with 28 % higher risk of BCR (HR 1.22, 95 % CI 0.86-1.72) without statistical significance. CONCLUSIONS: The present study suggested that higher BMI was an independent risk factor for a higher Gleason score, as well as an independent predictor of BCR after radical prostatectomy in Chinese patients. Meta-analysis of Asian studies also indicated that obese patients, although without statistical significance, might be more likely to suffer from BCR.

2-(3-Benzoylthioureido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid ameliorates metabolic disorders in high-fat diet-fed mice.

AIM: Sterol-regulatory element binding proteins (SREBPs) are major transcription factors that regulate liver lipid biosynthesis. In this article we reported a novel synthetic compound 2-(3-benzoylthioureido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (ZJ001) that inhibited the SREBP-1c pathway, and effectively reduced hepatic lipid accumulation in diet-induced obesity (DIO) mice. METHODS: A luciferase reporter driven by an SRE-containing promoter transfected into HepG2 cells was used to discover the compound. Two approaches were used to evaluate the lipid-lowering effects of ZJ001: (1) diet-induced obesity (DIO) mice that were treated with ZJ001 (15 mg·kg(-1)·d(-1), po) for 7 weeks; and (2) HepG2 cells and primary hepatocytes used as in vitro models. RESULTS: ZJ001 (10, 20 µmol/L) dose-dependently inhibited the activity of SRE-containing promoter. ZJ001 administration ameliorated lipid metabolism and improved glucose tolerance in DIO mice, accompanied by significantly reduced mRNA levels of SREBP-1C and SREBP-2, and their downstream genes. In HepG2 cells and insulin-treated hepatocytes, ZJ001 (10-40 µmol/L) dose-dependently inhibited lipid synthesis, and reduced mRNA levels of SREBP-1C and SREBP-2, and their downstream genes. Furthermore, ZJ001 dose-dependently increased the phosphorylation of AMPK and regulatory-associated protein of mTOR (Raptor), and suppressed the phosphorylation of mTOR in insulin-treated hepatocytes. Moreover, ZJ001 increased the ADP/ATP ratio in insulin-treated hepatocytes. CONCLUSION: ZJ001 exerts multiple beneficial effects in diet-induced obesity mice. Its lipid-lowering effects may result from the suppression of mTORC1, which regulates SREBP-1c transcription. The results suggest that the SREBP-1c pathway may be a potential therapeutic target for the treatment of lipid metabolic disorders.

Higher body mass index increases the risk for biopsy-mediated detection of prostate cancer in Chinese men.

OBJECTIVE: To investigate the relationship between body mass index (BMI) and prostate cancer (PCa) risk at biopsy in Chinese men. PATIENTS AND METHODS: We retrospectively reviewed the records of 1,807 consecutive men who underwent initial multicore (≥10) prostate biopsy under transrectal ultrasound guidance between Dec 2004 and Feb 2014. BMI was categorised based on the Asian classification of obesity as follows: <18.5 (underweight), 18.5-22.9 (normal weight), 23-24.9 (overweight), 25-29.9 (moderately obese), and ≥30 kg/m2 (severely obese). The odds ratios (OR) of each BMI category for risk of PCa and high-grade prostate cancer (HGPCa, Gleason score ≥4+3) detection were estimated in crude, age-adjusted and multivariate-adjusted models. Prevalence ratios and accuracies of PSA predicted PCa were also estimated across BMI groups. RESULTS: In total, PCa was detected by biopsy in 750 (45.4%) men, and HGPCa was detected in 419 (25.4%) men. Compared with men of normal weight, underweight men and obese men were older and had higher prostate specific antigen levels. The risk of overall PCa detection via biopsy presented an obvious U-shaped relationship with BMI in crude analysis. Overall, 50.0%, 37.4%, 45.6% 54.4% and 74.1% of the men in the underweight, normal weight, overweight, moderately obese and severely obese groups, respectively, were diagnosed with PCa via biopsy. In multivariate analysis, obesity was significantly correlated with a higher risk of PCa detection (OR = 1.17, 95%CI 1.10-1.25, P<0.001). However, higher BMI was not correlated with HGPCa detection (OR = 1.03, 95%CI 0.97-1.09, P = 0.29). There were no significant differences in the accuracy of using PSA to predict PCa or HGPCa detection across different BMI categories. CONCLUSION: Obesity was associated with higher risk of PCa detection in the present Chinese biopsy population. No significant association was detected between obesity and HGPCa.

Proinflammatory cytokines in prostate cancer development and progression promoted by high-fat diet.

BACKGROUND: We aimed to examine whether proinflammatory cytokines participated in prostate cancer (PCa) development and progression promoted by high-fat diet (HFD). METHODS: TRAMP (transgenic adenocarcinoma mouse prostate) mice were randomly divided into two groups: normal diet group and HFD group. Mortality rate and tumor formation rate were examined. TRAMP mice were sacrificed and sampled on the 20th, 24th, and 28th week, respectively. Levels of proinflammatory cytokines, including IL-1α, IL-1ß, IL-6, and TNF-α, were tested by FlowCytomix. Prostate tissue of TRAMP mice was used for histology study. RESULTS: A total of 13 deaths of TRAMP mice were observed, among which 3 (8.33%) were from the normal diet group and 10 (27.78%) from the HFD group. The mortality rate of TRAMP mice from HFD group was significantly higher than that of normal diet group (P = 0.032). Tumor formation rate at 20th week of age of HFD group was significantly higher than that of normal diet group (P = 0.045). Proinflammatory cytokines levels, including IL-1α, IL-1ß, IL-6, and TNF-α, were significantly higher in HFD TRAMP mice. CONCLUSIONS: HFD could promote TRAMP mouse PCa development and progression with elevated proinflammatory cytokines levels. Proinflammatory cytokines could contribute to PCa development and progression promoted by HFD.

Genetic polymorphism of interleukin-1A (IL-1A), IL-1B, and IL-1 receptor antagonist (IL-1RN) and prostate cancer risk.

PURPOSE: We aimed to investigate the associations between polymorphisms of interleukin-1A (IL-1A), IL-1B, and IL-1 receptor antagonist (IL-1RN) and prostate cancer (PCa) risk. MATERIALS AND METHODS: A comprehensive search for articles of MEDLINE and EMBASE databases and bibliographies of retrieved articles published up to August 3, 2014 was performed. Methodological quality assessment of the trials was based on a standard quality scoring system. The meta-analysis was performed using STATA 12.0. RESULTS: We included 9 studies (1 study for IL-1A, 5 studies for IL-1B, and 3 studies for IL-1RN), and significant association was found between polymorphisms of IL-1B-511 (rs16944) as well as IL-1B-31 (rs1143627) and PCa risk. IL-1B-511 (rs16944) polymorphism was significantly associated with PCa risk in homozygote and recessive models, as well as allele contrast (TT vs CC: OR, 0.74; 95%CI, 0.58-0.94; P=0.012; TT vs TC+CC; OR, 0.79; 95%CI, 0.63-0.98; P=0.033; T vs C: OR, 0.86; 95%CI, 0.77-0.96; P=0.008). The association between IL-1B-31 (rs1143627) polymorphism and PCa risk was weakly significant under a heterozygote model (OR, 1.35; 95%CI, 1.00-1.80; P=0.047). CONCLUSIONS: Sequence variants in IL-1B-511 (rs16944) and IL-1B-31 (rs1143627) are significantly associated with PCa risk, which provides additional novel evidence that proinflammatory cytokines and inflammation play an important role in the etiology of PCa.