An exposome atlas of serum reveals the risk of chronic diseases in the Chinese population.

Although adverse environmental exposures are considered a major cause of chronic diseases, current studies provide limited information on real-world chemical exposures and related risks. For this study, we collected serum samples from 5696 healthy people and patients, including those with 12 chronic diseases, in China and completed serum biomonitoring including 267 chemicals via gas and liquid chromatography-tandem mass spectrometry. Seventy-four highly frequently detected exposures were used for exposure characterization and risk analysis. The results show that region is the most critical factor influencing human exposure levels, followed by age. Organochlorine pesticides and perfluoroalkyl substances are associated with multiple chronic diseases, and some of them exceed safe ranges. Multi-exposure models reveal significant risk effects of exposure on hyperlipidemia, metabolic syndrome and hyperuricemia. Overall, this study provides a comprehensive human serum exposome atlas and disease risk information, which can guide subsequent in-depth cause-and-effect studies between environmental exposures and human health.

[Exposure characteristics and health risk assessment of 97 typical chemical pollutants in human serum].

Rapid industrial and agricultural developments in China have led to the wide use and discharge of chemical products and pesticides, resulting in extensive residues in environmental media. These residues can enter the human body through various pathways, leading to high exposure risks and health hazards. Because the human body is exposed to a variety of chemical pollutants, accurately quantifying the exposure levels of these pollutants in the human body and evaluating their health risks are of great importance. In this study, the serum concentrations of 97 typical chemical pollutants of 60 adults in central China were simultaneously determined using solid-phase extraction coupled with gas chromatography-tandem mass spectrometry (SPE-GC-MS/MS). In this method, 200 µL of a serum sample was mixed with 10 µL of an isotope-labeled internal standard solution. The sample was vortexed and refrigerated overnight at 4 ℃. Each sample was then deproteinized by the addition of 200 µL of 15% formic acid aqueous solution and vortexed. The serum sample was loaded into a preconditioned Oasis® PRiME HLB SPE cartridge and rinsed with 3 mL of methanol-water (6∶1, v/v). The SPE cartridge was subsequently vacuumed. The analytes were eluted with 3 mL of dichloromethane followed by 3 mL of n-hexane. The eluent was concentrated to near dryness under a gentle nitrogen stream and reconstituted with 100 µL of acetone. The samples were determined by GC-MS/MS and separated on a DB-5MS capillary column (30 m×0.25 mm×0.25 µm) with temperature programming. The column temperature was maintained at 70 ℃ for 2 min, increased at a rate of 25 ℃/min to 150 ℃, increased at a rate of 3 ℃/min to 200 ℃, and then held for 2 min. Finally, the column temperature was increased at a rate of 8 ℃/min to 300 ℃ and maintained at this temperature for 8 min. The samples were detected in multiple-reaction monitoring (MRM) mode and quantitatively analyzed using the internal standard method. Multiple linear regression models were used to analyze the effects of demographic characteristics, lifestyle habits, and diet on the concentrations of the chemical pollutants in the serum samples, and known biomonitoring equivalents (BEs) and human biomonitoring (HBM) values were combined to compute hazard quotients (HQs) and hazard indices (HIs) and evaluate the health risks of single and cumulative exposures to the chemical pollutants. The results showed that the main pollutants detected in human serum were organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), and polycyclic aromatic hydrocarbons (PAHs). The detection rates of eight pollutants, including hexachlorobenzene (HCB) (100%), pentachlorophenol (PCP) (100%), p,p'-dichlorodiphenylene (p,p'-DDE) (100%), PCB-138 (100%), PCB-153 (98.3%), ß-hexachlorocyclohexane (ß-HCH) (91.7%), fluorene (Flu) (85.0%), and anthracene (Ant) (75.0%), were greater than 70%. The serum levels of ß-HCH were higher in females than in males, and age was positively correlated with exposure to p,p'-DDE, PCB-138, PCB-153, and ß-HCH. Increased exposure levels to p,p'-DDE and ß-HCH may be associated with a high frequency of meat intake, whereas increased exposure level to PCP may be associated with a high frequency of vegetable intake. The serum HQ of PCP was greater than 1 in 6.7% of the samples, and no risk was observed for HCB and p,p'-DDE exposure in the study population. Approximately 28.3% of the study subjects had HI values greater than 1. Overall, the general adult population in this region is widely exposed to a wide range of chemical pollutants, and gender, age, and diet are likely to be the main factors influencing the concentration of chemical pollutants. The health risk of single and compound exposures to chemical pollutants should not be ignored.

The association between urinary metals/metalloids and chronic kidney disease among general adults in Wuhan, China.

The relation between exposure to single metal/metalloid and the risk of chronic kidney disease (CKD) remains unclear. We aimed to determine the single and mixed associations of 21 heavy metals/metalloids exposure and the risk of CKD. We performed a cross-sectional study that recruited 4055 participants. Multivariate logistic regression, linear regression and weighted quantile sum (WQS) regression were conducted to explore the possible effects of single and mixed metals/metalloids exposure on the risk of CKD, the risk of albuminuria and changes in the estimated glomerular filtration rate (eGFR). In single-metal models, Cu, Fe, and Zn were positively associated with increased risks of CKD (P-trend < 0.05). Compared to the lowest level, the highest quartiles of Cu (OR = 2.94; 95% CI: 1.70, 5.11; P-trend < 0.05), Fe (OR = 2.39; 95% CI: 1.42, 4.02; P-trend < 0.05), and Zn (OR = 2.35; 95% CI: 1.31, 4.24; P-trend < 0.05) were associated with an increased risk of CKD. After multi-metal adjustment, the association with the risk of CKD remained robust for Cu (P < 0.05). Weighted quantile sum regression revealed a positive association between mixed metals/metalloids and the risk of CKD, and the association was largely driven by Cu (43.7%). Specifically, the mixture of urinary metals/metalloids was positively associated with the risk of albuminuria and negatively associated with eGFR.

Individual and mixtures of polychlorinated biphenyls and organochlorine pesticides exposure in relation to metabolic syndrome among Chinese adults.

Polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) are commonly detected in humans due to their persistence and bioaccumulation, and are suspected risk factors for metabolic syndrome (MetS). However, most studies have focused on individual rather than combined exposure. We explored the associations between individual and combined PCBs/OCPs exposure and MetS to better assess the health effects of PCBs and OCPs. This cross-sectional study included 1996 adults from Wuhan, China. A total of 338 participants fulfilled criteria for MetS. Eight PCBs and OCPs were detected in >50 % of the samples. Most of the hexachlorocyclohexanes (HCHs) in the serum were derived from the recent environmental input of lindane, while the high levels of dichlorodiphenyltrichloroethane (DDTs) were mainly due to historical use. Multivariate linear regression analyses revealed that ß-HCH, p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE), PCB-52, PCB-153, and PCB-180 were positively correlated with increased odds of MetS. The profiles of the PCBs and OCPs associated with the different components of MetS were distinct. Furthermore, quantile-based g computation (qgcomp) analyses showed that PCB and OCP mixtures were positively associated with the risk of MetS, and p,p'-DDE was the largest contributor to our model. These findings suggest that PCB and OCP concentrations, both individually and as mixtures, are associated with MetS risk. Prospective studies are needed to confirm these results.

Improved detection of homologous recombination deficiency in Chinese patients with ovarian cancer: a novel non-exonic single-nucleotide polymorphism-based next-generation sequencing panel.

As homologous recombination deficiency (HRD) is a biomarker to predict the efficiency of PARP inhibitor treatment, this study developed a non-exonic single-nucleotide polymorphism (SNP)-based targeted next-generation sequencing panel and comprehensively examined it both on standard and clinical ovarian cancer tissues. The HRD scores calculated by the panel and whole-genome sequencing were consistent, with the analysis by sequenza being the most reliable. The results on clinical samples revealed that the panel performed better in HRD analysis compared with the SNP microarray. There are several distinctions between this newly developed kit and reported HRD detection panels. First, the panel covers only 52 592 SNPs, which makes it capable of detecting genomic instability. Secondly, all the SNPs are non-exonic; as a result, the panel can be used cooperatively with any exon panel. Thirdly, all the SNPs selected have a high minor allele frequency in Chinese people, making it a better choice for HRD detection in Chinese patients. In summary, this panel shows promise as a clinical application to guide PARP inhibitors or platinum drugs used in the treatment of ovarian and other cancers.

Accumulative levels, temporal and spatial distribution of common chemical pollutants in the blood of Chinese adults.

China has been in a rapid development period in recent decades, the mass production and use of chemical industrial products and pesticides have resulted in a large amount of pollutants in the environment. These pollutants enter the human body through environmental exposure and dietary intake, causing adverse health effects. Although many of them have been banned and restricted in the production and use in China, these pollutants still remain in the human body due to their high persistence and strong bioaccumulation. In this review, we aim to reveal the accumulation levels and profiles, as well as the temporal and spatial distribution of common chemical pollutants including chlorinated paraffins (CPs), polycyclic aromatic hydrocarbons (PAHs), organochlorine pesticides (OCPs), polybrominated diphenyl ethers, organophosphorus flame retardants (OPFRs), new halogenated flame retardants (NHFRs), polychlorinated biphenyls, phthalic acid esters, perfluorinated compounds, bisphenols, organophosphorus pesticides and pyrethroid insecticides in the blood (including whole blood, serum and plasma) of Chinese adults by extracting 93 related studies published from 1990 to 2021. Results have shown that CPs, OCPs and PAHs were the main pollutants in China, the levels of short-chain chlorinated paraffin, p,p'-DDE and phenanthrene in blood even reached 11,060.58, 740.41 and 498.28 ng/g lipid respectively. Under the strict control of pollutants in China, the levels of most pollutants have been on a downward trend except for perfluoro octanoate and perfluoro nonanoate. Besides, OPFRs, NHFRs and PAHs may have a potential upward trend, requiring further research and observation. As for spatial distribution, East China (Bohai Bay and Yangtze River Delta) and South China (Pearl River Delta) were the major polluted regions due to their fast development of industry and agriculture.

Aboveground Biomass of Wetland Vegetation Under Climate Change in the Western Songnen Plain.

Understanding the spatiotemporal dynamics of aboveground biomass (AGB) is crucial for investigating the wetland ecosystem carbon cycle. In this paper, we explored the spatiotemporal change of aboveground biomass and its response to climate change in a marsh wetland of western Songen Plain by using field measured AGB data and vegetation index derived from MODIS datasets. The results showed that the AGB could be established by the power function between measured AGB density and the annual maximum NDVI (NDVImax) of marsh: Y = 302.06 × NDVImax 1.9817. The averaged AGB of marshes showed a significant increase of 2.04 g⋅C/m2/a, with an average AGB value of about 111.01 g⋅C/m2 over the entire western Songnen Plain. For the influence of precipitation and temperature, we found that the annual mean temperature had a smaller effect on the distribution of marsh AGB than that of the total precipitation in the western Songnen Plain. Increased precipitation in summer and autumn would increase AGB by promoting marshes' vegetation growth. In addition, we found that the minimum temperature (Tmin) and maximum temperatures (Tmax) have an asymmetric effect on marsh AGB on the western Songnen Plain: warming Tmax has a significant impact on AGB of marsh vegetation, while warming at night can non-significantly increase the AGB of marsh wetland. This research is expected to provide theoretical guidance for the restoration, protection, and adaptive management of wetland vegetation in the western Songnen Plain.

Meta-analysis on the association between the frequency of tooth brushing and hypertension risk.

It is unclear whether the frequency of tooth brushing affects the risk of hypertension; thus, we conducted the first meta-analysis to focus on this topic. In this meta-analysis, we systematically searched the PubMed, Scopus, and Web of Science databases from their inception to October 2021 to identify eligible studies, while reference lists from retrieved review paper were also reviewed. We then conducted a meta-analysis of the highest compared with the lowest tooth brushing frequency, along with a dose-response meta-analysis, to explore this association. Subgroup and sensitivity analyses were conducted to identify the sources of heterogeneity. Publication bias was evaluated using Begg's and Egger's tests. We found eight relevant studies, three cohort and five cross-sectional, involving a total of 274 124 patients. Compared to the highest tooth brushing frequency, the lowest increased the risk of hypertension by 84.0% (OR 1.84; 95% CI, 1.44-2.35). Furthermore, a nonlinear dose-response relationship was observed (P < .05). The exclusion of any studies did not significantly alter the combined risk estimate, and no publication bias was detected. In conclusions, we report that epidemiological evidence supports the hypothesis that a lower frequency of tooth brushing is significantly associated with a higher risk of hypertension. Preventive interventions, such as adopting a good oral health routine, should be encouraged to maintain good general health.

Occupational stress and associated factors among general practitioners in China: a national cross-sectional study.

BACKGROUND: Occupational stress among general practitioners (GPs) is a public health concern. This study aimed to investigate the prevalence and factors associated with occupational stress among GPs in China. METHODS: A cross-sectional design was used. Data were collected from 3,236 GPs in eastern, central, and western China (response rate, 99.75%) between October 2017 and February 2018 using a structured self-administered questionnaire. An ordinal logistic regression model was used to identify the factors associated with occupational stress among GPs. RESULTS: Among these respondents, 313 (9.67%), 1,028 (31.77%), and 1,895 (58.56%) of GPs had a low, medium, and high level of occupational stress, respectively. GPs from central China, with temporary work contracts, without management responsibility, receiving a moderate level of income, and with moderate occupational development opportunities had a lower level of occupational stress. GPs with greater than 40 working hours per week and those who worked overtime occasionally or frequently had a higher level of occupational stress. CONCLUSIONS: The prevalence of occupational stress among GPs is high in China. Substantial regional variation in determinants of occupational stress among GPs was observed. These findings should inform the design of policies to reduce the occupational stress of GPs.

Bidirectional Mendelian randomization to explore the causal relationships between Sleep traits, Parkinson's disease and Amyotrophic lateral sclerosis.

OBJECTIVE: Sleep disturbances have been linked with Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) in observational studies, and the comorbidity of PD and ALS has been reported in clinical case reports, but the causalities remain unclear. This study aims to examine bidirectional causal relationships between sleep traits, PD and ALS. METHODS: Bidirectional two sample Mendelian randomisation (MR) analyses were conducted, with data from individuals of mainly European ancestry. Genetic instruments were obtained from the largest published genome-wide association studies (GWAS) concerning various sleep traits, PD and ALS. MR estimates from each genetic instrument were combined by inverse variance weighted method, with alternate methods (eg, weighted median, MR Egger, MR-PRESSO) and statistical graphs to assess horizontal pleiotropy and remove outliers. RESULTS: MR analysis failed to observe any causal association between sleep disorders and PD, but found a possible causal effect of PD risk on ALS risk (odds ratio [OR] = 1.07; 95% CI: 1.01-1.14, P < 0.01), albeit with a horizontal pleiotropy. Furthermore, MR analyses indicated that excessive daytime sleepiness (EDS) (OR = 2.29; 95% CI: 1.04-5.03, P = 0.04) contributed to a modest increase in risk of ALS, but the reverse causalities were not significant. Higher risk of ALS may be associated with being a "morning person" (OR = 1.03, P = 0.02), a longer sleep duration (OR = 1.01, P < 0.01), and a mean of 9 h or more total sleep duration (ß = 0.02, P = 0.04). CONCLUSIONS: Aided by large-scale GWAS, a shortage of evidence supporting causal relationships of sleep traits and PD risk, while significant evidence supports that EDS, higher PD risk may causally influence ALS risk. Future researches are required to explore the underlying pathological mechanism as well as the clinically significance, and replicate our findings using independent samples when data become available.

[Simultaneous determination of 35 organochlorine pesticides and polychlorinated biphenyls in the serum of the general population in Wuhan by solid phase extraction-gas chromatography-tandem mass spectrometry].

Owing to their persistence, ease of accumulation in organisms, and high toxicity, the use of persistent organic pollutants (POPs) has been limited ever since the Stockholm Convention on Persistent Organic Pollutants was signed in 2001 by the United Nations Environment Programme (UNEP). As typical POPs, organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) can persist in the environment for long periods. They can enter human bodies through many pathways and pose a high exposure risk to humans. OCPs and PCBs can lead to endocrine disruption, neurotoxicity, immunotoxicity, reproductive toxicity, and cancer in human beings. Accurate quantification of pollutant load levels in vivo is crucial for the evaluation of health effects. In this study, a rapid and sensitive method based on solid phase extraction-gas chromatography-tandem mass spectrometry (SPE-GC-MS/MS) was developed for the simultaneous determination of 35 OCPs and PCBs in serum. Accordingly, 100 µL of the serum sample was gently mixed with the isotope-labeled internal standard solution (10 µL) to obtain a final mass concentration of 10 ng/mL for each internal standard. After incubation overnight, the samples were mixed with 100 µL purified water for dilution. After protein precipitation with 100 mg urea, the serum samples were passed through preconditioned Oasis® HLB cartridges, washed with 6 mL purified water, and eluted with 5 mL hexane-dichloromethane (1∶1, v/v). The SPE eluant was collected, evaporated to near dryness under a gentle nitrogen stream, and dissolved in 100 µL n-hexane. The reconstitution in the vial insert was injected into the GC-MS/MS instrument for analysis. The analytes were separated on an Agilent J&W DB-5MS capillary column (30 m×0.25 mm×0.25 µm) with temperature programming. The mass spectrometer was operated in the electron ionization (EI) mode. The optimal mass spectrometry conditions were realized by optimizing the instrument parameters such as ion pairs and collision energies. The analytes were detected in the multiple reaction monitoring (MRM) mode, and the internal standard method was used for quantitative analysis. The OCPs and PCBs had good linearities in the range of 0.05-50.0 ng/mL. The limits of detection (LODs, S/N=3) ranged from 1.2 to 71.4 ng/L. The recoveries of the 35 compounds were 72.6%-142% with relative standard deviations (RSDs) of less than 25% at the three spiked levels. The developed SPE-GC-MS/MS method was successfully applied to the simultaneous analysis of OCPs and PCBs in serum samples obtained from the general population in Wuhan. The results showed that the general population in Wuhan was widely exposed to OCPs and PCBs, especially the former. The detection frequencies of eight OCPs and seven PCBs were greater than 50%, and p,p'-DDE, p,p'-DDD, and methoxychlor were detected in all serum sample pools. Non-dioxin-like PCBs (NDL-PCBs) were the dominant PCB congeners, while PCB-28, PCB-153, and PCB-52 were the dominant PCBs in the general population of Wuhan. The concentration of OCPs increased with age. Moreover, the concentration of OCPs in individuals who were more than 66 years old was significantly higher as compared to that in younger individuals. The positive association differing by gender was significant in individuals over 60 years of age. There were no significant differences in PCB concentrations according to gender or age. There were no seasonal differences in the residue levels of OCPs and PCBs in the general population of Wuhan. The developed method is rapid and sensitive; it has the advantages of low limits of detection, satisfactory recoveries, accurate precision, and microsample volume, thus allowing for the simultaneous analysis of trace OCPs and PCBs in microserum samples in epidemiological studies. This robust analytical method also provides a powerful tool for the health risk assessment of OCP and PCB exposure.

Dose-response association of early-life antibiotic exposure and subsequent overweight or obesity in children: A meta-analysis of prospective studies.

The objective of this study is to investigate the dose-response relationship between antibiotic exposure in early life and the risk of subsequent overweight or obesity. Electronic databases were searched from inception to December 2020. Prospective studies that reported the odds ratios (ORs) of childhood overweight or obesity for three or more quantitative categories of antibiotic exposure were identified. A random-effect model was used to pool the ORs and 95% confidence intervals (CIs). Generalized least squares and restricted cubic splines were used to explore the dose-response association. A total of 12 sets of results from 10 articles involving 427,453 participants were included in this meta-analysis. The pooled OR for increased risk of overweight or obesity was 1.30 in high-level antibiotic exposure (95% CI: 1.20 to 1.41) and 1.06 in low-level antibiotic exposure (95% CI: 1.02 to 1.10), as compared with children who never exposed to antibiotics. There was a logarithmic-curve relationship between early-life antibiotic exposure and the risk of subsequent overweight or obesity. The OR was 1.08 (95% CI: 1.06 to 1.11) for one prescription, 1.16 (95% CI 1.11 to 1.21) for two prescriptions, 1.24 (95% CI: 1.16 to 1.32) for three prescriptions, 1.30 (95% CI: 1.20 to 1.41) for four prescriptions, and less than a 5% increase for more prescriptions. Early-life antibiotic exposure is associated with the risk of childhood overweight or obesity in a dose-response manner. Further studies are needed to confirm our results.

Hydrological and microtopographic effects on community ecological characteristics of Carex schmidtii tussock wetland.

Hydrology and microtopography are important factors affecting the structure and function of wetland ecosystems and controlling plant community distribution and succession. This study aims to identify the effects of hydrology and microtopography on the structure and function of a wetland plant community. A field survey was conducted in Carex schmidtii tussock wetland. Vegetation was sampled in different microtopographic regions (hummock and interspaces) in three types of tussock wetlands with different hydrological conditions (i.e., droughty, seasonally flooded and long-term flooded). Relative importance value (RIV), species richness, diversity, dominance, as well as community similarity and productivity were calculated. We recorded a total of 52 species of plants, belonging to 21 families and 39 genera, in sample plots. Community ecological characteristics significantly differed under varying hydrological conditions and microtopographic regions. Drought decreased the dominance of the C. schmidtii community but increased the frequency of mesophytes. Species richness and diversity in seasonally and long-term flooded sites were significantly lower than droughty sites, while community dominance and productivity in these areas were significantly higher than in droughty sites. Biodiversity in hummocks was significantly lower than in interspaces, but with higher community dominance and productivity. In droughty sites, C. schmidtii on hummocks lost its dominance, resulting in higher community similarity between hummocks and interspaces. Conversely, in seasonally and long-term flooded sites, C. schmidtii on hummocks was absolutely dominant with RIV of 77.0 ± 2.78% and low community similarity between hummocks and interspaces. Moreover, hummock community structure was more similar to that of the overall community, and C. schmidtii biomass in hummocks was the main source of community productivity, indicating the supporting effects of hummocks on community structure. In conclusion, hydrology and microtopography jointly affect the plant community. Attention should be paid to the protection and maintenance of hummock structure and the dominance of C. schmidtii communities in tussock wetland conservation and management.

[Comparison of ecological characteristics of Carex tussock under natural and artificial reco-very.] / 人工恢复与自然恢复模式下苔草草丘生态特征比较.

We compared the ecological characteristics of tussock individuals and populations undergoing natural and artificial restoration in Carex tussock wetlands in the Sun Island in Harbin and identified the relationships between the growth of Carex tussock and environmental factors. Results showed that there were obvious seasonal dynamics in morphological characteristics of C. appendiculata. Tussocks grew rapidly from May to June, peaked in June, and then decreased steadily from July to August. There were significant differences in ecological characteristics of Carex tussocks between natural and artificial restorations. The morphological characteristics of individual tussock, including leaf area, leaf width, fresh weight per ramet, dry weight per ramet, and the hummock shape indicators (hummock height, diameter, volume and surface area) in natural restored area were significantly higher than those in artificial transplanting area. For the Carex tussock community, tussock density, coverage and biomass in natural restoration area were significantly lower than those in artificial transplanting area. Soil water content, water depth and hummock spacing in natural restoration area were significantly higher than those in artificial restoration area, which facilitated the formation and development of individual tussock. Higher transplanting density was the main factor leading to higher density, coverage, and biomass in artificial restoration area. Our results suggested that the distribution characteristics of tussocks in natural restoration area should be taken into account in future restoration and protection works. Appropriate adjustment of the distance between hummock (54.22-117.89 cm) and population density (1.9-3.1 ind·m-2), as well as proper water recharge measures in spring in arid areas to regulate soil water content and water depth, would be conducive to promoting the growth and rapid recovery of Carex tussock, which would maintain the long-term health and stability of tussock wetland.

CPUY201112, a novel synthetic small-molecule compound and inhibitor of heat shock protein Hsp90, induces p53-mediated apoptosis in MCF-7 cells.

Heat-shock protein 90 (Hsp90) is highly expressed in many tumor cells and is associated with the maintenance of malignant phenotypes. Targeting Hsp90 has had therapeutic success in both solid and hematological malignancies, which has inspired more studies to identify new Hsp90 inhibitors with improved clinical efficacy. Using a fragment-based approach and subsequent structural optimization guided by medicinal chemistry principles, we identified the novel compound CPUY201112 as a potent Hsp90 inhibitor. It binds to the ATP-binding pocket of Hsp90 with a kinetic dissociation (Kd) constant of 27 ± 2.3 nM. It also exhibits potent in vitro antiproliferative effects in a range of solid tumor cells. In MCF-7 cells with high Hsp90 expression, CPUY201112 induces the degradation of Hsp90 client proteins including HER-2, Akt, and c-RAF. We prove that treating MCF-7 cells with CPUY201112 results in cell cycle arrest and apoptosis through the wild-type (wt) p53 pathway. CPUY201112 also synergizes with Nutlin-3a to induce cancer cell apoptosis. CPUY201112 significantly inhibited the growth of MCF-7 xenografts in nude mice without apparent body weight loss. These results demonstrate that CPUY201112 is a novel Hsp90 inhibitor with potential use in treating wild-type p53 related cancers.

Discovery and Modification of in Vivo Active Nrf2 Activators with 1,2,4-Oxadiazole Core: Hits Identification and Structure-Activity Relationship Study.

Induction of phase II antioxidant enzymes by activation of Nrf2/ARE pathway has been recognized as a promising strategy for the regulation of oxidative stress-related diseases. Herein we report our effort on the discovery and optimization of Nrf2 activators with 1,2,4-oxadiazole core. Screening of an in-house collection containing 7500 compounds by ARE-luciferase reporter assay revealed a moderate Nrf2 activator, 1. Aimed at obtaining more derivatives efficiently, molecular similarity search by the combination of 2D fingerprint-based and 3D shape-based search was applied to virtually screening the Chemdiv collection. Three derivatives with the same core were identified to have better inductivity of Nrf2 than 1. The best hit 4 was selected as starting point for structurally optimization, leading to a much more potent derivative 32. It in vitro upregulated gene and protein level of Nrf2 as well as its downstream markers such as NQO1, GCLM, and HO-1. It remarkably suppressed inflammation in the in vivo LPS-challenged mouse model. Our results provide a new chemotype as Nrf2-ARE activators which deserve further optimization with the aim to obtain active anti-inflammatory agents through Nrf2-ARE pathway.

A three dimensional study of upper airway in adult skeletal Class II patients with different vertical growth patterns.

OBJECTIVE: The study was performed to compare the 3D pharyngeal airway dimensions in adult skeletal Class II patients with different vertical growth patterns (low, normal, and high angle) and to investigate whether the upper airway dimensions of untreated skeletal Class II adults were affected by vertical skeletal variables. METHODS: Cone-beam computed tomography (CBCT) records of 64 untreated adult skeletal Class II patients (34 male and 30 female) were collected to evaluate the pharyngeal airway dimensions. Subjects were divided into three subgroups according to the GoGn-SN angle (low angle, normal angle or high angle). All subgroups were matched for sex. ANOVA and SNK-q tests were used to identify differences within and among groups (p<0.05). Coefficient of product-moment correlation (Pearson correlation coefficient) was used to analyze the association between pharyngeal airway dimensions and vertical growth patterns. RESULTS: The results showed that pharyngeal airway measurements were statistically significantly less (p<0.05) in high angle group as compared to normal angle or low angle group. CONCLUSIONS: Adult skeletal Class II subjects with vertical growth patterns have significantly narrower pharyngeal airways than those with normal or horizontal growth patterns, confirming an association between pharyngeal airway measurements and a vertical skeletal pattern.

Effective screening strategy using ensembled pharmacophore models combined with cascade docking: application to p53-MDM2 interaction inhibitors.

Protein-protein interactions (PPIs) play a crucial role in cellular function and form the backbone of almost all biochemical processes. In recent years, protein-protein interaction inhibitors (PPIIs) have represented a treasure trove of potential new drug targets. Unfortunately, there are few successful drugs of PPIIs on the market. Structure-based pharmacophore (SBP) combined with docking has been demonstrated as a useful Virtual Screening (VS) strategy in drug development projects. However, the combination of target complexity and poor binding affinity prediction has thwarted the application of this strategy in the discovery of PPIIs. Here we report an effective VS strategy on p53-MDM2 PPI. First, we built a SBP model based on p53-MDM2 complex cocrystal structures. The model was then simplified by using a Receptor-Ligand complex-based pharmacophore model considering the critical binding features between MDM2 and its small molecular inhibitors. Cascade docking was subsequently applied to improve the hit rate. Based on this strategy, we performed VS on NCI and SPECS databases and successfully discovered 6 novel compounds from 15 hits with the best, compound 1 (NSC 5359), K(i) = 180 ± 50 nM. These compounds can serve as lead compounds for further optimization.

Identification, design and bio-evaluation of novel Hsp90 inhibitors by ligand-based virtual screening.

Heat shock protein 90 (Hsp90), whose inhibitors have shown promising activity in clinical trials, is an attractive anticancer target. In this work, we first explored the significant pharmacophore features needed for Hsp90 inhibitors by generating a 3D-QSAR pharmacophore model. It was then used to virtually screen the SPECS databases, identifying 17 hits. Compound S1 and S13 exhibited the most potent inhibitory activity against Hsp90, with IC50 value 1.61±0.28 µM and 2.83±0.67 µM, respectively. Binding patterns analysis of the two compounds with Hsp90 revealed reasonable interaction modes. Further evaluation showed that the compounds exhibited good anti-proliferative effects against a series of cancer cell lines with high expression level of Hsp90. Meanwhile, S13 induced cell apoptosis in a dose-dependent manner in different cell lines. Based on the consideration of binding affinities, physicochemical properties and toxicities, 24 derivatives of S13 were designed, leading to the more promising compound S40, which deserves further optimization.