Time-dependent hormesis transfer from five high-frequency personal care product components to mixtures.

There is potential for personal care products (PCPs) components and mixtures to induce hormesis. How hormesis is related to time and transmitted from components to mixtures are not clear. In this paper, we conducted determination of components in 16 PCP products and then ran frequent itemset mining on the component data. Five high-frequency components (HFCs), betaine (BET), 1,3-butanediol (BUT), ethylenediaminetetraacetic acid disodium salt (EDTA), glycerol (GLO), and phenoxyethanol (POE), and 14 mixtures were identified. For each mixture system, one mixture ray with the actual mixture ratios in the products was selected. Time-dependent microplate toxicity analysis was used to test the luminescence inhibition toxicity of five HFCs and 14 mixture rays to Vibrio qinghaiensis sp.-Q67 at 12 concentration gradients and eight exposure times. It is showed that BET, EDTA, POE, and 13 mixture rays containing at least one J-type component showed time-dependent hormesis. Characteristic parameters used to describe hormesis revealed that the absolute value of the maximum stimulatory effect (|Emin|) generally increased with time. Notably, mixtures composed of POE and S-type components showed greater |Emin| than POE alone at the same time. Importantly, the maximum stimulatory effective concentration, NOEC/the zero effective concentration point, and EC50 remained relatively stable. Nine hormesis transmission phenomena were observed in different mixture rays. While all mixtures primarily exhibited additive action, varying degrees of synergism and antagonism were noted in binary mixtures, with no strong synergism or antagonism observed in ternary and quaternary mixtures. These findings offer valuable insights for the screening of HFCs and their mixtures, as well as the study of hormesis transmission in personal care products.

Screening for frequently detected quaternary ammonium mixture systems in waters based on frequent itemset mining and prediction of their toxicity.

Screening and prioritizing research on frequently detected mixture systems in the environment is of great significance, as conducting toxicity testing on all mixtures is impractical. Therefore, the frequent itemset mining (FIM) was introduced and applied in this paper to identify variables that commonly co-occur in a dataset. Based on the dataset of the quaternary ammonium compounds (QACs) in the water environment, the four frequent QAC mixture systems with detection rate ≥ 35 % were found, including [BDMM]+Cl--[BTMM]+Cl- (M1), [BDMM]+Cl--[BHMM]+Cl- (M2), [BTMM]+Cl- -[BHMM]+Cl- (M3), and [BDMM]+Cl--[BTMM]+Cl--[BHMM]+Cl- (M4). [BDMM]+Cl-, [BTMM]+Cl-, and [BHMM]+Cl- are benzyl dodecyl dimethyl ammonium chloride, benzyl tetradecyl dimethyl ammonium chloride, and benzyl hexadecyl dimethyl ammonium chloride, respectively. Then, the toxicity of the representative mixture rays and components for the four frequently detected mixture systems was tested using Vibrio qinghaiensis sp.-Q67 (Q67) as a luminescent indicator organism at 0.25 and 12 h. The toxicity of the mixtures was predicted using concentration addition (CA) and independent action (IA) models. It was shown that both the components and the representative mixture rays for the four frequently detected mixture systems exhibited obvious acute and chronic toxicity to Q67, and their median effective concentrations (EC50) were below 7 mg/L. Both CA and IA models predicted the toxicity of the four mixture systems well. However, the CA model had a better predictive ability for the toxicity of the M3 and M4 mixtures than IA at 12 h.

Liraglutide alleviates high-fat diet-induced kidney injury in mice by regulating the CaMKKß/AMPK pathway.

OBJECTIVE: Liraglutide, a glucagon-like peptide-1 receptor agonist, has been shown to regulate blood sugar and control body weight, but its ability to treat obesity-related nephropathy has been poorly studied. Therefore, this study was designed to observe the characteristics and potential mechanism of liraglutide against obesity-related kidney disease. METHODS: Thirty-six C57BL/6J male mice were randomly divided into six groups (n = 6 per group). Obesity-related nephropathy was induced in mice by continuous feeding of high-fat diet (HFD) for 12 weeks. After 12 weeks, liraglutide (0.6 mg/kg) and AMP-activated protein kinase (AMPK) agonists bortezomib (200 µg/kg) were injected for 12 weeks, respectively. Enzyme-linked immunosorbent assay was employed to detect the levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, blood urea nitrogen, creatinine in serum, as well as urinary protein in urine. Besides, hematoxylin-eosin staining and periodic acid-Schiff staining were used to observe the pathological changes of kidney tissue; immunohistochemistry, western blot, and real-time quantitative PCR to assess the calmodulin-dependent protein kinase kinase beta (CaMKKß)/AMPK signaling pathway activation. RESULTS: Liraglutide significantly reduced serum lipid loading, improved kidney function, and relieved kidney histopathological damage and glycogen deposition in the mouse model of obesity-related kidney disease induced by HFD. In addition, liraglutide also significantly inhibited the CaMKKß/AMPK signaling pathway in kidney tissue of HFD-induced mice. However, bortezomib partially reversed the therapeutic effect of liraglutide on HDF-induced nephropathy in mice. CONCLUSIONS: Liraglutide has a therapeutic effect on obesity-related kidney disease, and such an effect may be achieved by inhibiting the CaMKKß/AMPK signaling pathway in kidney tissue.

Design, synthesis, biological evaluation and molecular dynamics simulation studies of imidazolidine-2,4-dione derivatives as novel PTP1B inhibitors.

Protein tyrosine phosphatase 1B (PTP1B) is a member of the phosphotyrosine phosphatase family and plays an important role in the signal transduction of diabetes. Inhibition of PTP1B activity can increase insulin sensitivity and reduce blood sugar levels. Therefore, it is urgent to find compounds with novel structures that can inhibit PTP1B. This study designed imidazolidine-2,4-dione derivatives through the computer-aided drug design (CADD) strategy, and the Comp#10 showed outstanding inhibitory ability. (IC50 = 2.07 µM) and selectivity. The inhibitory mechanism at molecular level of Comp#10 on PTP1B was studied by molecular dynamics simulation. The results show that the catalytic region of PTP1B protein is more stable, which makes the catalytic sites unsuitable for exposure. Interestingly, the most obvious changes in the interaction between residues in the P-loop region (such as: His214, Cys215, and Ser216). In short, this study reported for the first time that imidazolidine-2,4-dione derivatives as novel PTP1B inhibitors had good inhibitory activity and selectivity, providing new ideas for the development of small molecule PTP1B inhibitors.

The amino acid variants in HLA II molecules explain the major association with adult-onset Still's disease in the Han Chinese population.

Adult-onset Still's disease (AOSD) is a rare autoinflammatory disease with systemic involvement, and its pathophysiology remains unclear. Genome-wide association studies (GWAS) in the Chinese population have revealed an association between AOSD and the major histocompatibility complex (MHC) locus; however, causal variants in the MHC remain undetermined. In the present study, we identified independent amino-acid polymorphisms in human leukocyte antigen (HLA) molecules that are associated with Han Chinese patients with AOSD by fine-mapping the MHC locus. Through conditional analyses, we identified position 34 in HLA-DQα1 (p = 1.44 × 10-14) and Asn in HLA-DRß1 position 37 (p = 5.12 × 10-11) as the major determinants for AOSD. Moreover, we identified the associations for three main HLA class II alleles: HLA-DQB1*06:02 (OR = 2.70, p = 3.02 × 10-14), HLA-DRB1*15:01 (OR = 2.44, p = 3.66 × 10-13), and HLA-DQA1*01:02 (OR = 1.97, p = 1.09 × 10-9). This study reveals the relationship between functional variations in the class II HLA region and AOSD, implicating the MHC locus in the pathogenesis of AOSD.

Water quality criteria and ecological risk assessment for ammonia in the Shaying River Basin, China.

Current Chinese surface water environmental quality standard GB3838-2002 for ammonia fails to take water quality factors and native organism distributions in different basins into consideration. In this study, ammonia toxicity tests were performed using three aquatic organisms native to the Shaying River Basin (China). Published ammonia toxicity data with pH and temperature, and toxicity data acquired in this study were used to establish water quality criteria. The final criterion maximum concentration (CMC) and criterion continuous concentration (CCC) for the Shaying River Basin were 5.09 and 1.36 (mg total ammonia nitrogen (TAN))/L (pH 7 and 20 °C), respectively. In addition, based on the corresponding relationship between ammonia toxicity and temperature and pH, the ecological risk assessment of ammonia was conducted in different seasons for the Shaying River using a tiered approach of both hazard quotient (HQ) and the joint probability (JPC) methods. Two methods gave consistent results: the ecological risks of ammonia to aquatic species in the Shaying River Basin were severe and the risk could be ranked as wet season > flat season > dry season. It is therefore indicating that monitoring, evaluation, and early warning of ammonia pollution need to be taken to prevent and control the risks posed by ammonia pollution, especially for wet season (because of high temperatures and pH) or flat season (because of high pH values). We hope the present work could provide valuable information to manage and control ammonia pollution in the Shaying River Basin.

Clinical features and current treatments of adult-onset Still's disease: a multicentre survey of 517 patients in China.

OBJECTIVES: As a rare systemic autoinflammatory disease, adult-onset Still's disease (AOSD) has heterogeneous clinical manifestations, response to treatment and outcome. This study tried to assess the clinical characteristics, laboratory tests, and treatments of Chinese AOSD patients, and make a retrospective analysis. METHODS: We collected from 7 hospitals in China a total of 517 Chinese patients with AOSD who satisfied the Yamaguchi criteria. We retrospectively evaluated their clinical features, laboratory tests, treatments and compared them with published data from different studies. All the data in this study were from medical records and further statistic analyses. RESULTS: We evaluated a total of 517 AOSD patients, 72% female, average age of onset was 37.7; spiking fever, rash and arthralgia occurred in 472 (91.3%), 413 (79.9%), 378 (73.1%) cases, respectively. There were 439/513 (85.6%) cases with leukocytosis and 456/476 (95.8%) cases with raised serum ferritin. The highest frequently used medications and regimens for remission were glucocorticoids (498/517, 96.3%), methotrexate (273/517, 52.8%) and hydroxychloroquine (174/517, 33.7%). 84.4%. 357/423 of AOSD cases were able to achieve initial remission with different regimens, mostly including glucocorticoids, methotrexate or hydroxychloroquine. 47.2% of them (244/517) received 30

[Effect of Individualized Intervention on Postpartum Breast-feeding Behavior after Cesarean Section].

OBJECTIVE: To investigate the effects of individualized intervention on postpartum breast-feeding behavior and satisfaction after cesarean section (CS). METHODS: 341 pregnant women who had cesarean section in West China Second Hospital of Sichuan University from 1st July to 30th August in 2018 were randomly divided into intervention group (171 cases) and control group (170 cases). The participants in experimental group received individualized intervention through the combination of prenatal and postnatal. The participants in control group received routine nursing care. The basic clinical data and breastfeeding information at discharge and day 42 postpartum were compared between the two groups. RESULTS: There were no significant differences in age, ethnicity, anesthesia type, preoperative feeding time between the two groups (P>0.05). At the time of discharge and day 42 postpartum, the rate of exclusive breastfeeding, breastfeeding satisfaction and planned breastfeeding duration in the intervention group were higher than those in the control group (P < 0.05). The incidence and degree of breast distending pain, the incidence of cracked nipples, the times of adding formula milk in 24 h, the rate of using feeding bottle and the incidence of feeding problems were all higher in the control group than those in the intervention group (P < 0.05). The knowledge scores of breastfeeding in both groups were higher at discharge than at admission, and the score was higher in the intervention group than that in the control group at the time of discharge. CONCLUSION: The combination of prenatal and postnatal individualized intervention can significantly improve the knowledge, behavior and satisfaction of breastfeeding.

Fibroblast activation proteins-α suppress tumor immunity by regulating T cells and tumor-associated macrophages.

Fibroblast activation protein-α (FAPα) is a type-II cell-surface-bound integral transmembrane serine protease and selectively overexpressed by tumor-associated stromal fibroblasts (TAFs), which are the main components in the tumor microenvironment, in >90% of malignant epithelial carcinomas. FAPα regulates the immunosuppression of tumor cells in the tumor microenvironment. Regulatory T cells (Tregs) and tumor-associated macrophages (TAMs) are the major immunosuppressive cells in the tumor microenvironment. However, the effect of FAPα on Tregs and TAMs is unknown. The non-enzymatic function of FAPα on Treg and TAM was investigated. In this study, we confirm that FAPα can promote the generation of Tregs and TAMs, which suggests that FAPα plays a immunosuppressive role in the tumor microenvironment and provides evidence for FAP α as a potent immunotherapeutic target for cancer.

Time-dependent nonmonotonic concentration-response and synergism of alkyl glycosides with different alkyl side chain to Vibrio qinghaiensis sp. -Q67.

Alkyl glycosides (AGs), commonly used nonionic surfactants, may have toxic effects on the environmental organisms. However, the complex concentration-response patterns of AGs with varying alkyl side chains and their mixtures have not been thoroughly studied. Therefore, the luminescence inhibition toxicities of six AGs with different alkyl side chains, namely, ethyl (AG02), butyl (AG04), hexyl (AG06), octyl (AG08), decyl (AG10), and dodecyl (AG12) glucosides, were determined in Vibrio qinghaiensis sp. -Q67 (Q67) at 0.25, 3, 6, 9, and 12 h. The six AGs exhibited time- and side-chain-dependent nonmonotonic concentration- responses toward Q67. AG02, with a short side chain, presented a concentration-response curve (CRC) with two peaks after 6 h and stimulated the luminescence of Q67 at both 6 and 9 h. AG04, AG06, and AG08 showed S-shaped CRCs at five exposure time points, and their toxicities increased with the side-chain length. AG10 and AG12, with long side chains, exhibited hormesis at 9 and 12 h. Molecular docking was performed to explore the mechanism governing the possible influence of AGs on the luminescence response. The effects of AGs on Q67 could be attributed to multiple luminescence-regulatory proteins, including LuxA, LuxC, LuxD, LuxG, LuxI, and LuxR. Notably, LuxR was identified as the primary binding protein among the six AGs. Given that they may co-exist, binary mixtures of AG10 and AG12 were designed to explore their concentration-response patterns and interactions. The results revealed that all AG10-AG12 binary mixture rays showed time-dependent hormesis on Q67, similar to that shown by their individual components. The interactions of these binary mixtures were mainly characterized by low-concentration additive action and high-concentration synergism at different times.

The Application of PiCCO-guided Fluid Resuscitation in Patients With Traumatic Shock.

BACKGROUND: The aim of this study was to evaluate the application of pulse contour cardiac output (PiCCO) in patients with traumatic shock. METHODS: Seventy-eight patients with traumatic shock were included and grouped. The control group (CG, n = 39) underwent fluid resuscitation through transthoracic echocardiography (TTE) monitoring, and the research group (RG, n = 39) received PiCCO-guided fluid resuscitation. RESULTS: The mechanical ventilation time, duration of vasoactive drug use, and duration of stay in the intensive care unit were lower in the RG compared to the CG (P < .05). At 72 h after fluid resuscitation, the mean arterial pressure and central venous pressure in the RG were higher than those in the CG (P < .05). The stroke volume variation and distensibility index of the inferior vena cava were lower at 72 h after fluid resuscitation, but the levels of extravascular lung water, global end-diastolic volume index, and intrathoracic blood volume index were higher in the RG (P < .05). The levels of endothelial 1, nitrogen monoxide, tumor necrosis factor-α, procalcitonin, C-reactive protein, and partial pressure of carbon dioxide at 72 h after fluid resuscitation in the RG were lower than those in the CG (P < .05). CONCLUSION: PiCCO-guided liquid resuscitation may help to accurately evaluate the volumetric parameters, alleviate symptoms of ischemia and hypoxia, regulate hemodynamics and blood gas analysis, reduce inflammatory reactions, improve endothelial functions, and effectively guide the usage of vascular active drugs.

Time-dependent hormetic dose responses of skin care product mixtures to Vibrio qinghaiensis sp.-Q67: Appearance and quantification.

Hormesis is a widely recognized and extensively studied phenomenon. However, few studies have described the quantitative characteristics of hormesis required for appropriate risk assessment. Although skin care product (SCP) mixtures and their active ingredients can induce the hormesis of Vibrio qinghaiensis sp.-Q67 (Q67), the quantitative characteristics of time-dependent hormetic dose responses in SCPs have not yet been investigated. In this study, 28 SCP mixtures were tested for luminescence toxicity against Q67 after five exposure durations (0.25, 3, 6, 9, and 12 h). With increasing exposure duration, the concentration response curves (CRCs) were classified as constant monotonic nonlinear (S-shaped) for four SCPs, S- to hormetic (J-shaped) for 13 SCPs, and constant J-shaped for 11 SCPs. Of 140 CRCs, 98 were J-shaped. An increased frequency of SCPs inducing hormesis was observed. The toxicity (pEC50) of the SCPs was independent of the exposure duration and product type. The maximum stimulatory effect (Emin) of the 12 SCPs increased with exposure duration. We proposed a modified parameter, the width of inhibition dose zone (WIDZ; EC50/EC10), to depict the width of inhibition dose zone. The WIDZ of S-shaped CRCs were significantly larger than that of J-shaped CRCs. In addition, the characteristic parameters reported in the general literature were analyzed. The good linear relationship between EC50 and the maximum stimulatory effective concentration (ECmin) indicated that toxicity may be transformed into stimulatory effects over exposure durations. The width of stimulation dose zone (WSDZ) and Emin of the seven SCPs had the same increasing trends with increasing exposure duration. The combination of WIDZ with other characteristic parameters (e.g., zero effective concentration point, ECmin, etc.) could better depict hormesis with low-dose stimulation and high-dose inhibition. The quantitative characteristics of the dose-responses of hormesis-inducing SCPs could provide reference basis for the risk assessment of SCP mixtures.

Optimized Derivation of Predicted No-Effect Concentrations (PNECs) for Eight Polycyclic Aromatic Hydrocarbons (PAHs) Using HC10 Based on Acute Toxicity Data.

For persistent organic pollutants, a concern of environmental supervision, predicted no-effect concentrations (PNECs) are often used in ecological risk assessment, which is commonly derived from the hazardous concentration of 5% (HC5) of the species sensitivity distribution (SSD). To address the problem of a lack of toxicity data, the objectives of this study are to propose and apply two improvement ideas for SSD application, taking polycyclic aromatic hydrocarbons (PAHs) as an example: whether the chronic PNEC can be derived from the acute SSD curve; whether the PNEC may be calculated by HC10 to avoid solely statistical extrapolation. In this study, the acute SSD curves for eight PAHs and the chronic SSD curves for three PAHs were constructed. The quantity relationship of HC5s between the acute and chronic SSD curves was explored, and the value of the assessment factor when using HC10 to calculate PNEC was derived. The results showed that, for PAHs, the chronic PNEC can be estimated by multiplying the acute PNEC by 0.1, and the value of the assessment factor corresponding to HC10 is 10. For acenaphthene, anthracene, benzo[a]pyrene, fluoranthene, fluorene, naphthalene, phenanthrene, and pyrene, the chronic PNECs based on the acute HC10s were 0.8120, 0.008925, 0.005202, 0.07602, 2.328, 12.75, 0.5731, and 0.05360 µg/L, respectively.

Beneficial or harmful: Time-dependent hormesis induced by typical disinfectants and their mixtures with toxicological interaction.

Disinfectants and their mixtures can induce hormesis. However, how the mixture hormesis is related to those of components and the interactions in disinfectant mixtures remain unclear. In this paper, the luminescence inhibition toxicities of chlorinated sodium phosphate (CSP), dodecyl dimethyl benzyl ammonium bromide (DOB), dodecyl dimethyl benzyl ammonium chloride (DOC), ethanol (EtOH), glutaraldehyde (GLA), hydrogen peroxide (H2O2), isopropyl alcohol (IPA), n-propanol (NPA), and 20 mixture rays in four mixture systems (EtOH-H2O2, DOB-H2O2, DOC-EtOH, and EtOH-IPA-NPA) containing at least one component showing hormesis to Vibrio qinghaiensis sp.-Q67 (Q67) were determined at 0.25, 3, 6, 9, and 12 h. The synergism-antagonism heatmap based on independent action model (noted as SAHmapIA) was developed to systematically evaluate the interactions in various mixtures. It was shown that five disinfectants (CSP, EtOH, H2O2, NPA, and IPA) and 17 mixture rays exhibited time-dependent hormesis. The hormetic component was responsible for the hormesis of the mixture rays. Most mixture rays showed low- concentration/dose additive action and high-concentration/dose synergism at different time. This study further exemplified the interrelationship between the hormesis in the mixtures and their components and implied the need to pay attention to the time-dependent hormesis and interactions induced by the disinfectants.

Environmental exposure and ecological risk of perfluorinated substances (PFASs) in the Shaying River Basin, China.

There have been concerns raised about the environmental effects of perfluoroalkyl substances (PFASs) because of their toxicity, widespread distribution, and persistence. Understanding the occurrences and ecological risk posed by PFASs is essential, especially for the short-chain replacements perfluorobutanoic acid (PFBA) and perfluorobutane sulfonic acid (PFBS), which are now becoming predominant PFASs. The lack of aquatic life criteria (ALC), however, prevents an accurate assessment of the ecological risks of PFBA and PFBS. This study thus investigated the occurrence of 15 PFASs at 29 sampling sites in Shaying River Basin (in China) systematically, conducted the toxicity tests of PFBA and PFBS on eight resident aquatic organisms in China, and derived the predicted non-effect concentration (PNEC) values for PFBA and PFBS for two environmental media in China. The results showed that the total PFASs concentrations (ΣPFASs) ranged from 5.07 to 20.32 ng/L (average of 10.95 ng/L) in surface water, whereas in sediment, ΣPFASs ranged from 6.46 to 20.05 ng/g (dw) (average of 11.51 ng/g). The presence of PFBS was the most prominent PFASs in both water (0.372-8.194 ng/L) and sediment (4.54-15.72 ng/g), demonstrating that short-chain substitution effects can be observed in watersheds. The PNEC values for freshwater and sediment were 6.60 mg/L and 8.30 mg/kg (ww), respectively, for PFBA, and 14.04 mg/L, 37.08 mg/kg (ww), respectively, for PFBS. Ecological risk assessment of two long-chain PFASs, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), and two short-chain PFASs, PFBA and PFBS, using the hazard quotient method revealed that Shaying River and other major River Basins in China were at risk of PFOS contamination. This study contributes to a better understanding of the presence and risk of PFASs in the Shaying River and first proposes the ALCs for PFBA and PFBS in China, which could provide important reference information for water quality standards.

A novel equal frequency sampling of factor levels (EFSFL) method is applied to identify the dominant factor inducing the combined toxicities of 13 factors.

The research framework combining global sensitivity analysis (GSA) with quantitative high-throughput screening (qHTS), called GSA-qHTS, provides a potentially feasible way to screen for important factors that induce toxicities of complex mixtures. Despite its value, the mixture samples designed using the GSA-qHTS technique still have a shortage of unequal factor levels, which leads to an asymmetry in the importance of elementary effects (EEs). In this study, we developed a novel method for mixture design that enables equal frequency sampling of factor levels (called EFSFL) by optimizing both the trajectory number and the design and expansion of the starting points for the trajectory. The EFSFL has been successfully employed to design 168 mixtures of 13 factors (12 chemicals and time) that each have three levels. By means of high-throughput microplate toxicity analysis, the toxicity change rules of the mixtures are revealed. Based on EE analysis, the important factors affecting the toxicities of the mixtures are screened. It was found that erythromycin is the dominant factor and time is an important non-chemical factor in mixture toxicities. The mixtures can be classified into types A, B, and C mixtures according to their toxicities at 12 h, and all the types B and C mixtures contain erythromycin at the maximum concentration. The toxicities of the type B mixtures increase firstly over time (0.25 âˆ¼ 9 h) and then decrease (12 h), while those of the type C mixtures consistently increase over time. Some type A mixtures produce stimulation that increases with time. With the present new approach to mixture design, the frequency of factor levels in mixture samples is equal. Consequently, the accuracy of screening important factors is improved based on the EE method, providing a new method for the study of mixture toxicity.

Study on the characterization of pesticide modes of action similarity and the multi-endpoint combined toxicity of pesticide mixtures to Caenorhabditis elegans.

With the widespread use of pesticides, the coexistence of multiple low-residue pesticides in environmental media has increased significantly, and the "cocktail" effect caused by this phenomenon has garnered increasing attention. However, owing to the scarcity of information regarding the modes of action (MOAs) of chemicals, the application of concentration addition (CA) models for evaluating and predicting the toxicity of mixture with similar MOAs is limited. Additionally, the joint toxicity laws of complex mixture systems to different toxicity endpoints in organisms remain unclear, and effective methods to test the mixture toxicity on lifespan and reproductive inhibition are lacking. Therefore, in this study, the similarity of pesticide MOAs was characterized using molecular electronegativity-distance vector (MEDV-13) descriptors based on eight pesticides (aldicarb, methomyl, imidacloprid, thiamethoxam, dichlorvos, dimethoate, methamidophos and triazophos). Additionally, the methods of lifespan and reproduction inhibition microplate toxicity analysis of elegans (EL-MTA and ER-MTA) were established to test the lifespan and reproduction inhibition toxicity of Caenorhabditis elegans. Finally, a unified scale synergistic-antagonistic heatmap (SAHscale) method was proposed to explore the combined toxicity of the mixtures on the lifespan, reproduction, and mortality of nematodes. The results showed that the MEDV-13 descriptors could effectively characterize the similarity in MOAs. The lifespan and reproductive ability of Caenorhabditis elegans were significantly inhibited when the pesticide exposure concentration was one order of magnitude lower than the lethal dose. The sensitivity of lifespan and reproductive endpoints to mixtures was dependent on the concentration ratio. The same rays in the mixture had consistent toxicity interactions on the lifespan and reproductive endpoints of Caenorhabditis elegans. In conclusion, we demonstrated the feasibility of MEDV-13 in characterizing the similarity of MOAs, and provided a theoretical basis for exploring the mechanism of chemical mixtures by studying their apparent toxicity of mixtures on nematode lifespan and reproduction endpoints.

Deriving the predicted no effect concentrations of 35 pesticides by the QSAR-SSD method.

The widespread use of pesticides results in their frequent detection in water bodies and other environmental media. Pesticide residues may cause certain risks to the environment and human health, and reliable predicted no effect concentrations (PNEC) must be obtained when assessing environmental risks. Species sensitivity distribution (SSD) is an important method for the derivation of chemical PNECs. Construction of the SSD model requires sufficient toxicity data to various species including at least eight families in three phyla, suitable nonlinear fitting functions and assessment factors (AFs) with certain uncertainty. However, most chemicals could not collect sufficient species toxicity data, while some chemicals had sufficient species toxicity data but could not find suitable fitting functions, thus hindering the construction of effective SSD models. To this end, the established QSAR models were applied to predict toxicity of chemicals to specific species to fill in the toxicity data gaps required for SSD and selecting multiple nonlinear functions to optimize the SSD model. Combined with QSAR and SSD methods, a new method of PNEC derivation was developed and successfully applied to the derivation of PNEC for 35 pesticides. Three QSAR models were used to predict the toxicities of six pesticides with few toxicity data. Nine two-parameter nonlinear functions were used to fit the toxicity-cumulative probability data one by one to determine the optimal SSD models. The hazardous concentrations at the cumulative probability of 5% and 10%, i. e, HC5 and HC10, respectively, were calculated by the optimal SSD model. The assessment factor used to determine the PNEC of the chemical based on the HC10 was derived from the quantitative correlation between HC10 and HC5 of pesticides found in this study. When the toxicity data are insufficient, it may be more appropriate to calculate the PNECs of chemicals using HC10 than using HC5.

Exploring Dual Agonists for PPARα/γ Receptors using Pharmacophore Modeling, Docking Analysis and Molecule Dynamics Simulation.

BACKGROUND: The Peroxisome Proliferator-Activated Receptors (PPARs) are ligandactivated transcription factors belonging to the nuclear receptor family. The roles of PPARα in fatty acid oxidation and PPARγ in adipocyte differentiation and lipid storage have been widely characterized. Compounds with dual PPARα/γ activity have been proposed, combining the benefits of insulin sensitization and lipid lowering into one drug, allowing a single drug to reduce hyperglycemia and hyperlipidemia while preventing the development of cardiovascular complications. METHODS: The new PPARα/γ agonists were screened through virtual screening of pharmacophores and molecular dynamics simulations. First, in the article, the constructed pharmacophore was used to screen the Ligand Expo Components-pub database to obtain the common structural characteristics of representative PPARα/γ agonist ligands. Then, the accepted ligand structure was modified and replaced to obtain 12 new compounds. Using molecular docking, ADMET and molecular dynamics simulation methods to screen the designed 12 ligands, analyze their docking scores when they bind to the PPARα/γ dual targets, their stability and pharmacological properties when they bind to the PPARα/γ dual targets. RESULTS: We performed pharmacophore-based virtual screening for 22949 molecules in Ligand Expo Components-pub database. The compounds that were superior to the original ligand were performed structural analysis and modification, and a series of compounds with novel structures were designed. Using precise docking, ADMET prediction and molecular dynamics methods to screen and verify newly designed compounds, and the above compounds show higher docking scores and lower side effects. CONCLUSION: 9 new PPARα/γ agonists were obtained by pharmacophore modeling, docking analysis and molecular dynamics simulation.