Anthocyanin Consumption and Risk of Colorectal Cancer: A Meta-Analysis of Observational Studies.

This meta-analysis aimed to summarize the association between anthocyanin consumption and the risk of colorectal cancer. All relative articles were located on online databases, including PubMed, Embase, and the Cochrane Library as of June 11, 2018. Risk ratios (RRs) or odds ratio and their 95% confidence intervals (CIs) were calculated through the STATA 12.0 software package. A total of seven studies were included in the meta-analysis. A significant inverse association was found between total anthocyanin consumption and colorectal cancer risk (RR = 0.78; 95% CI, 0.64-0.95). Likewise, there was significant evidence of a relationship between anthocyanin intake and colorectal cancer in the colon site (RR = 0.81; 95% CI, 0.71-0.92); men (RR = 0.88; 95% CI, 0.81-0.95), and case-control studies (RR = 0.69; 95% CI, 0.60-0.78). A dose-response relationship was not found in this meta-analysis. The Grades of Recommendations Assessment, Development, and Evaluation quality in our study was very low. This meta-analysis indicates that anthocyanin consumption is inversely associated with the risk of colorectal cancer. Anthocyanins may play an active role in the prevention of colorectal cancer. Key teaching points: Some epidemiological studies found an inverse correlation between the high consumption of anthocyanins and low risk of colorectal cancer. Because of this structure, anthocyanins/anthocyanidins have a powerful capability of donating electrons, which can be characterized as antioxidant properties. Anthocyanins can also inhibit colon cancer by interfering in the cell cycle and inducing the effect of anti-proliferation and apoptosis. The formation of cytoplasmic vacuoles in cells also indicates that anthocyanins may induce autophagy. From the findings of nonrandomized controlled trials, anthocyanins may play an active role in the prevention of colorectal cancer.

MK-8325: A silyl proline-containing NS5A inhibitor with pan-genotype activity for treatment of HCV.

HCV NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination regimen. Herein, we describe the discovery and characterization of silyl proline-containing HCV NS5A inhibitor MK-8325 with good pan-genotype activity and acceptable pharmacokinetic properties.

Development of a prodrug of hydantoin based TACE inhibitor.

Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors led to fused bi-heteroaryl hydantoin series that demonstrate sub-nanomolar potency (Ki) as well as excellent activity in human whole blood (hWBA). However, lead compound 2 posed some formulation challenges which prevented it for further development. A prodrug approach was investigated to address this issue. The pivalate prodrug 3 can be formulated as stable neutral form and demonstrated improved DMPK properties when compared with parent compound.

Matched and mixed cap derivatives in the tetracyclic indole class of HCV NS5A inhibitors.

A matched and mixed capping SAR study was conducted on the tetracyclic indole class of HCV NS5A inhibitors to examine the influence of modifications of this region on the overall HCV virologic resistance profiles.

Alkyl substituted aminal derivatives of HCV NS5A inhibitor MK-8742.

HCV NS5A inhibitors have demonstrated impressive in vitro potency profiles in HCV replicon assays and robust HCV RNA titer reduction in the clinic making them attractive components for inclusion in an all oral fixed dose combination regimen for the treatment of HCV infection. Herein we describe our continued research efforts around the alkyl "Z group" modification of the tetracyclic indole-based NS5A inhibitor MK-8742, which led to the discovery of a series of potent NS5A inhibitors. Compounds 10 and 19 are of particular interests since they are as potent as our previous leads and have much improved rat pharmacokinetic profiles.

Structure-activity relationships of proline modifications around the tetracyclic-indole class of NS5A inhibitors.

We describe the impact of proline modifications, in our tetracyclic-indole based series of nonstructural protein 5A (NS5A) inhibitors, to their replicon profiles. This work identified NS5A inhibitors with an improved and flattened resistance profiles.

Discovery of fused tricyclic core containing HCV NS5A inhibitors with pan-genotype activity.

HCV NS5A inhibitors have demonstrated impressive in vitro potency profiles in HCV replicon assays and robust HCV RNA titer reduction in the clinic making them attractive components for inclusion in an all oral fixed dose combination regimen for the treatment of HCV infection. Herein, we describe research efforts that led to the discovery of a series of fused tricyclic core containing HCV NS5A inhibitors such as 24, 39, 40, 43, and 44 which have pan-genotype activity and are orally bioavailable in the rat.

Discovery of silyl proline containing HCV NS5A inhibitors with pan-genotype activity: SAR development.

HCV NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination treatment regimen. Herein we describe the research efforts that led to the discovery of silyl proline containing HCV NS5A inhibitors such as 7e and 8a with pan-genotype activity profile and acceptable pharmacokinetic properties.

IV. Discovery of CXCR3 antagonists substituted with heterocycles as amide surrogates: improved PK, hERG and metabolic profiles.

The structure-human CXCR3 binding affinity relationship of a series of pyridyl/pyrazinyl-piperazinyl-piperidine derivatives were explored with a focus to improve PK, hERG and metabolic profiles. Several small heterocycles were identified as amide surrogates, which minimized many potential metabolite issues. During the course of SAR development, we have observed the additive effect of desirable functional groups to improve hERG and PK profiles which lead to the discovery of many clinically developable CXCR3 antagonists with excellent overall profile.

[The inhibitory effect of latent transforming growth factor ß1 activation and silicosis by CD36 targeted RNA interference in silicosis model of rat].

OBJECTIVE: To investigate the inhibitory effects of CD36-targeting RNA interference on the latent transforming growth factor ß1 (L-TGF-ß1) activation and silicotic fibrosis in rat silicosis model. METHODS: Wistar rats were divided into four groups: saline control group (n=24), SiO2 model group (10 mg SiO2 per rat) (n=24), SiO2+Lv-shCD36 group (lentiviral vector expressing specific shRNA against CD36) (n=24), and SiO2+Lv-shCD36-NC group (non-silence control lentivirus) (n=24). At 7, 21, and 28 d after instillation, the rats were sacrificed. The activity of TGF-ß1 in bronchoalveolar lavage fluid (BALF) was measured by evaluating its inhibitory effect on the proliferation of mink lung epithelial cells. The pathological changes of lung tissue were observed by HE staining and van Gieson staining. The hydroxyproline content in the lungs was determined by alkaline lysis method. RESULTS: At 7 d after instillation, the expression of CD36 mRNA in alveolar macrophages was significantly lower in the SiO2+Lv-shCD36 group than in the saline control group, SiO2 model group, and SiO2+Lv-shCD36-NC group (P < 0.05); the quantity and percentage of active TGF-ß1 in BALF were significantly lower in the SiO2+Lv-shCD36 group than in the SiO2 model group and SiO2+Lv-shCD36-NC group (P < 0.05). At 28 d after instillation, there were cellular silicotic nodules in the lungs of rats in SiO2+Lv-shCD36 group and fibrotic cellular silicotic nodules in the lungs of rats in SiO2 model group and SiO2+Lv-shCD36-NC group. At 21 and 28 d after instillation, the hydroxyproline content was significantly lower in the SiO2+Lv-shCD36 group than in the SiO2 model group and SiO2+Lv-sh CD36-NC group (P < 0.05). CONCLUSION: CD36-targeting RNA interference has inhibitory effects on the L-TGF-ß1 activation and silicotic fibrosis in rat silicosis model.

[Effect of subchronic inhalation of ethylbenzene on expression of heme oxygenase-1 in rat renal tissues].

OBJECTIVE: To investigate the effect of ethylbenzene on the expression of heme oxygenase-1 (HO-1) intrarenal tissues. METHODS: Forty male Sprague-Dawley rats were randomly and equally allocated to control group, low-dose exposure group, moderate-dose exposure group, and high-dose exposure group to inhale different doses of ethylbenzene (0, 433.5 mg/m(3) (100 ppm), 4335.0 mg/m(3) (1000 ppm), and 6500.0 mg/m(3) (1500 ppm)) for 6 h per day, 5 days per week, for 13 weeks. After the rat model of subchronic ethylbenzene exposure was established, the activities of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and catalase (CAT) in renal tissues were measured, and the mRNA and protein expression levels of HO-1 in renal tissues were measured by real-time PCR and Western blot. RESULTS: Compared with the control group, all exposure groups showed significantly decreased activities of GSH-Px and CAT in renal tissues and the moderate- and high-dose exposure groups showed significantly decreased activity of SOD in renal tissues (P < 0.05). All exposure groups showed significantly higher expression of HO-1 than the control group (P < 0.05). The high-dose exposure group showed significantly higher expression of HO-1 than the low- and moderate-dose exposure group (P < 0.05), and the moderate- and high-dose exposure group had significantly higher expression of HO-1 than the control group and low-dose exposure group (P < 0.05). CONCLUSION: A certain dose of ethylbenzene can induce elevated expression of HO-1 and decreased antioxidant levels in rat renal tissues, thus leading to oxidative stress damage.

[Effect of toluene diisocyanate on lung function of workers].

OBJECTIVE: To investigate the effect of long-term exposure to toluene diisocyanate (TDI) on the lung function of TDI-exposed workers. METHODS: A factory was selected for this occupational epidemiological investigation. The workers who were exposed to TDI and had complete physical examination records in recent 3 years were the exposed group (n = 45), while the company's administrative staff, logistics staff, and other non-TDI-exposed workers who had complete physical examination records in recent 3 years were the control group (n = 47). The two groups were compared in terms of lung function indices. RESULTS: Compared with the control group, the 2009 exposure group had significantly lower forced expiratory volume in one second (FEV1.0), FEV1.0/forced vital capacity (FVC), and maximal expiratory flow at 25% of FVC (MEF25) (P < 0.05), the 2010 exposure group had significantly lower FEV1.0, FEV1.0/FVC,maximum voluntary ventilation (MVV), and maximal expiratory flow at 50% of FVC (MEF50) (P < 0.05), and the 2011 exposure group had significantly lower FEV1.0, FEV1.0/FVC, peak expiratory flow (PEF), MEF25, and MEF50 (P < 0.05). CONCLUSION: Long-term exposure to TDI can lead to certain impairment of lung function in workers, which may be reflected by decreased lung function indices such as vital capacity, FVC, FEV1.0, FEV1.0/FVC, PEF, and MVV.

[Influence of ethylbenzene on oxidative damage and apoptosis in rat renal epithelial cells NRK-52e].

OBJECTIVE: To study the oxidative damage and apoptosis of renal tubular epithelial cells (NRK-52e cell line) induced by ethylbenzene. METHODS: NRK-52e cells were exposed to 30, 60, 90, 120 µmol/L ethylbenzene for 24 hours. Cell viability were measured using MTT, the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT), the contents of malondialdehyde (MDA) and glutathione (GSH) were detected respectively. PI fluorescent staining assay was applied to detect percentage of apoptosis in ethylbenzene-treated groups. RESULTS: Compared with control group, cell outline became clear, cell diopter increased, cell became smaller and shrinkage, some cells broke in 60 µmol/L ethylbenzene-treated group. Plenty of cells died, suspension cells increased significantly in 90 µmol/L ethylbenzene-treated group. Compared with control group, cell viability the activities of SOD and CAT and the content of GSH were significantly decreased in 60 and 90 µmol/L ethylbenzene-treated groups (P<0.05). The MDA content were remarkably elevated in 90 µmol/L ethylbenzene-treated groups (P<0.05). CONCLUSION: Ethylbenzene can induce oxidative stress and apoptosis in NRK-52e cells (P<0.05).

[Time-series analysis on effect of air pollution on stroke mortality in Tianjin, China].

OBJECTIVE: To investigate the effect of air pollution on stroke mortality in Tianjin, China, and to provide basis for stroke control and prevention. METHODS: Total data of mortality surveillance were collected by Tianjin Centers for Disease Control and Prevention. Meteorological data and atmospheric pollution data were from Tianjin Meteorological Bureau and Tianjin Environmental Monitoring Center, respectively. Generalized additive Poisson regression model was used in time-series analysis on the relationship between air pollution and stroke mortality in Tianjin. Single-pollutant analysis and multi-pollutant analysis were performed after adjustment for confounding factors such as meteorological factors, long-term trend of death, "days of the week" effect and population. RESULTS: The crude death rates of stroke in Tianjin were from 136.67 in 2001 to 160.01/100000 in 2009, with an escalating trend (P = 0.000), while the standardized mortality ratios of stroke in Tianjin were from 138.36 to 99.14/100000, with a declining trend (P = 0.000). An increase of 10 µg/m³ in daily average concentrations of atmospheric SO2, NO2 and PM10 led to 1.0105 (95%CI: 1.0060 ∼ 1.0153), 1.0197 (95%CI: 1.0149 ∼ 1.0246) and 1.0064 (95%CI: 1.0052 ∼ 1.0077), respectively, in relative risks of stroke mortality. SO2 effect peaked after 1-day exposure, while NO2 and PM10 effects did within 1 day. CONCLUSION: Air pollution in Tianjin may increase the risk of stroke mortality in the population and induce acute onset of stroke. It is necessary to carry out air pollution control and allocate health resources rationally to reduce the hazard of stroke mortality.

III. Identification of novel CXCR3 chemokine receptor antagonists with a pyrazinyl-piperazinyl-piperidine scaffold.

The SAR of a novel pyrazinyl-piperazinyl-piperidine scaffold with CXCR3 receptor antagonist activity was explored. Optimization of the DMPK profile and reduction of hERG inhibition is described. Compound 16e with single-digit CXCR3 affinity, good rat PK and hERG profiles has been identified as a lead for further study.

[The changes of blood neurotransmitter levels in workers occupationally exposed to ethylbenzene].

OBJECTIVE: To explore the effects of occupational ethylbenzene exposure on blood neurotransmitter levels in population. METHODS: The exposure group consisted of 246 workers occupationally exposed to ethylbenzene and the control group was composed of 122 staffs from the offices. The basic information on ethylbenzene exposure was collected by the questionnaire. The mandelic acid (MA) and phenylglyoxylic acid (PGA) in the post-working urine were measured using the high performance liquid chromatography. The levels of gamma-aminobutyric acid (GABA), dopamine (DA) and acetylcholinesterase (AchE) activity were detected by reversed phase high performance liquid chromatography, spectrofluorometry and DTNB method, respectively. The blood biochemical indexes: alanine transaminase (ALT), aspartate aminotransferase (AST), total protein (TP), albumin (ALB), alkaline phosphatase (ALP), total bilirubin (TBIL) were examined. Also the hematologic indexes: red blood cell (RBC), white blood cell (WBC), hemoglobin (HGB) and platelet (PLT) were determined. RESULTS: The levels of MA, PGA and MA+PGA of urine in the exposed group were significantly higher than those in the control group (P < 0.05). There were no significant differences of the biochemical indexes (AST, ALT, TP, ALB, BUN, Cr, ALP and TBIL), hematologic indexes (WBC, RBC, Hb and PLT) and serum GABA between the exposure group and the control group (P > 0.05). But the serum DA [(0.21 ± 0.011) mg/L] and AChE levels [(0.321 ± 0.066) U/L] in the exposure group were significantly lower than those in the control group [(0.25 ± 0.015) mg/L, (0.583 ± 0.125) U/L], respectively (P < 0.05). CONCLUSION: MA and PGA in urine can serve as the biomarkers of internal exposure dose. Before the obvious changes of biochemical indexes and hematologic indexes appear, the exposure to ethylbenzene can influence the blood neurotransmitter levels in workers exposed to ethylbenzene.

[The neurobehavioral effects of population occupationally exposed to ethylbenzene].

OBJECTIVE: To evaluate the influence of ethylbenzene on the neurobehavior of occupationally exposed workers. METHODS: The exposure group consisted of 246 workers occupationally exposed to ethylbenzene and 172 staffs from the offices served as controls. The basic information on ethylbenzene exposure was collected by the questionnaire. The nervous behavior and function of workers were evaluated by Neurobehavioral Core Test Battery (NCTB). RESULTS: There were no differences of the scores for four emotional states (tension, depression, angry and bewilderment) between exposure group and control group (P > 0.05). The score of emotion (vigor) in exposure group was significantly lower than that in control group (P < 0.05), but the fatigue score in exposure group was significantly higher than that in control group (P < 0.05). The score of mean reaction time in exposure group was significantly higher than that in control group (P < 0.05), the scores of digital span, manual dexterity, visual retention and target tracking in exposure group were significantly lower than those in control group (P < 0.05). The exposure group was divided into 5 sub-groups, according to working duration. There were no differences for the scores of visual retention and target tracking among 5 sub-groups (P > 0.05). The scores of five emotional states (tension, depression, angry, fatigue and bewilderment) in 3 sub-groups exposed to ethylbenzene for 3 ∼, 4 ∼ and 5 ∼ years were significantly higher than those in 2 sub-groups exposed to ethylbenzene for 0 ∼ and 2 ∼ years (P < 0.05). The scores of digital span in 2 sub-groups exposed to ethylbenzene for 3 ∼ or 4 ∼ years and the scores of manual dexterity and digital symbol in 3 sub-groups exposed to ethylbenzene for 3 ∼, 4 ∼ and 5 ∼ years were significantly lower than those in 2 sub-groups exposed to ethylbenzene for 0 ∼ and 2 ∼ years (P < 0.05). CONCLUSION: Ethylbenzene can depress the neurobehavioral functions of exposed workers. The neurobehavioral functions of workers exposed to ethylbenzene for 3 years changed significantly. The workers exposed to ethylbenzene for 3 years may be the susceptible population of neurobehavioral function impairment.

Expansion of SAR studies on triaryl bis sulfone cannabinoid CB2 receptor ligands.

We report further expansion of the structure activity relationship (SAR) on the triaryl bis sulfone class of compounds (I), which are potent CB(2) receptor ligands with excellent selectivity over the CB(1) receptor. This study was extended to B ring changes, followed by simultaneous optimization of the A-, B-, and C-rings. Compound 42 has excellent CB(2) potency, selectivity and rat exposure.

Biaryl substituted hydantoin compounds as TACE inhibitors.

We disclose further optimization of hydantoin TNF-alpha convertase enzyme (TACE) inhibitors. SAR with respect to the non-prime region of TACE active site was explored. A series of biaryl substituted hydantoin compounds was shown to have sub-nanomolar K(i), good rat PK, and good selectivity versus MMP-1, -2, -3, -7, -9, and -13.

Novel TNF-α converting enzyme (TACE) inhibitors as potential treatment for inflammatory diseases.

Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors has led to an acetylene containing series that demonstrates sub-nanomolar potency (K(i)) as well as excellent activity in human whole blood. These studies led to the discovery of highly potent TACE inhibitors with good DMPK profiles.