Adipogenic Effects of Cresyl Diphenyl Phosphate (Triphenyl Phosphate Alternative) through Peroxisome Proliferator-Activated Receptor Gamma Pathway: A Comprehensive Study Integrating In Vitro, In Vivo, and In Silico from Molecule to Health Risk.

Cresyl diphenyl phosphate (CDP), a novel organophosphate ester (OPE), has been detected in various environmental and human samples. However, there is very limited knowledge regarding its toxicity, mechanisms of action, and potential health risks. Using new alternative methods (NAMs), across the molecular interactions, signaling pathways, cell functions, animal effects, and population risks, we investigated the potential adipogenic effects and associated risks of CDP and legacy OPE triphenyl phosphate (TPHP) by acting on peroxisome proliferator-activated receptor gamma (PPARγ). Among the 19 screened OPEs, CDP bound to PPARγ with the highest binding potency, followed by TPHP. CDP activated PPARγ through fitting into the binding pocket with strong hydrophobicity and hydrogen bond interactions; CDP exhibited higher potency compared to TPHP. In 3T3-L1 cells, CDP enhanced the PPARγ-mediated adipogenesis activity, exhibiting greater potency than TPHP. The intracellular concentration and receptor-bound concentrations (RBC) of CDP were also higher than those of TPHP in both HEK293 cells and 3T3-L1 cells. In mice, exposure to CDP activated the PPARγ-mediated adipogenic pathway, leading to an increased white adipose tissue weight gain. Overall, CDP could bind to and activate PPARγ, thereby promoting preadipocyte differentiation and the development of white adipose tissue. Its potential obesogenic risks should be of high concern.

Fine particulate matter disrupts bile acid homeostasis in hepatocytes via binding to and activating farnesoid X receptor.

Fine particulate matter (PM2.5)-induced metabolic disorders have attracted increasing attention, however, the underlying molecular mechanism of PM2.5-induced hepatic bile acid disorder remains unclear. In this study, we investigated the effects of PM2.5 components on the disruption of bile acid in hepatocytes through farnesoid X receptor (FXR) pathway. The receptor binding assays showed that PM2.5 extracts bound to FXR directly, with half inhibitory concentration (IC50) value of 21.7 µg/mL. PM2.5 extracts significantly promoted FXR-mediated transcriptional activity at 12.5 µg/mL. In mouse primary hepatocytes, we found PM2.5 extracts (100 µg/mL) significantly decreased the total bile acid levels, inhibited the expression of bile acid synthesis gene (Cholesterol 7 alpha-hydroxylase, Cyp7a1), and increased the expression of bile acid transport genes (Multidrug resistance associated protein 2, Abcc2; and Bile salt export pump, Abcb11). Moreover, these alterations were significantly attenuated by knocking down FXR in hepatocytes. We further divided the organic components and water-soluble components from PM2.5, and found that two components bound to and activated FXR, and decreased the bile acid levels in hepatocytes. In addition, benzo[a]pyrene (B[a]P) and cadmium (Cd) were identified as two bioactive components in PM2.5-induced bile acid disorders through FXR signaling pathway. Overall, we found PM2.5 components could bind to and activate FXR, thereby disrupting bile acid synthesis and transport in hepatocytes. These new findings also provide new insights into PM2.5-induced toxicity through nuclear receptor pathways.

Uncovering Susceptibility Risk to Online Deception in Aging.

OBJECTIVES: Fraud in the aged is an emerging public health problem. An increasingly common form of deception is conducted online. However, identification of cognitive and socioemotional risk factors has not been undertaken yet. In this endeavor, this study extended previous work suggesting age effects on susceptibility to online deception. METHODS: Susceptibility was operationalized as clicking on the link in simulated spear-phishing emails that young (18-37 years), young-old (62-74 years), and middle-old (75-89 years) Internet users received, without knowing that the emails were part of the study. Participants also indicated for a set of spear-phishing emails how likely they would click on the embedded link (susceptibility awareness) and completed cognitive and socioemotional measures to determine susceptibility risk profiles. RESULTS: Higher susceptibility was associated with lower short-term episodic memory in middle-old users and with lower positive affect in young-old and middle-old users. Greater susceptibility awareness was associated with better verbal fluency in middle-old users and with greater positive affect in young and middle-old users. DISCUSSION: Short-term memory, verbal fluency, and positive affect in middle-old age may contribute to resilience against online spear-phishing attacks. These results inform mechanisms of online fraud susceptibility and real-life decision-supportive interventions toward fraud risk reduction in aging.

Empirical Analysis of Weapons of Influence, Life Domains, and Demographic-Targeting in Modern Spam - An Age-Comparative Perspective.

Spam has been increasingly used for malware distribution. This paper analyzed modern spam from an age-comparative perspective to (i) discover the extent to which psychological weapons of influence and life domains were represented in today's spam emails and (ii) clarify variations in the use of these weapons and life domains by user demographics. Thirty five young and 32 older participants forwarded 18,605 emails from their spam folder to our study email account. A random set of 961 emails were submitted to qualitative content coding and quantitative statistical analysis. Reciprocation was the most prevalent weapon; financial, leisure, and independence the most prevalent life domains. Older adults received health and independence-related spam emails more frequently, while young adults received leisure and occupation-related spam emails more often. These age differences show a level of targeting by user demographics in current spam campaigns. This targeting shows the need for age-tailored demographic warnings highlighting the presence of influence and pretexting (life domains) for suspicious emails for improved response to cyber-attacks that could result from spam distribution. The insights from this study and the produced labeled dataset of spam messages can inform the development of the next generation of such solutions, especially those based on machine learning.

C10orf99 contributes to the development of psoriasis by promoting the proliferation of keratinocytes.

Psoriasis is a chronic, relapsing inflammatory skin disease. The pathogenesis of psoriasis is complex and has not been fully understood. C10orf99 was a recently identified human antimicrobial peptide whose mRNA expression is elevated in psoriatic human skin samples. In this study, we investigated the functional roles of C10orf99 in epidermal proliferation under inflammatory condition. We showed that C10orf99 protein was significantly up-regulated in psoriatic skin samples from patients and the ortholog gene expression levels were up-regulated in imiquimod (IMQ)-induced psoriasis-like skin lesions in mice. Using M5-stimulated HaCaT cell line model of inflammation and a combinational approach of knockdown and overexpression of C10orf99, we demonstrated that C10orf99 could promote keratinocyte proliferation by facilitating the G1/S transition, and the pro-proliferation effect of C10orf99 was associated with the activation of the ERK1/2 and NF-κB but not the AKT pathways. Local depletion of C10orf99 by lentiviral vectors expressing C10orf99 shRNA effectively ameliorated IMQ-induced dermatitis. Taken together, these results indicate that C10orf99 plays a contributive role in psoriasis pathogenesis and may serve as a new target for psoriasis treatment.

ERK-mediated phosphorylation regulates SOX10 sumoylation and targets expression in mutant BRAF melanoma.

In human mutant BRAF melanoma cells, the stemness transcription factor FOXD3 is rapidly induced by inhibition of ERK1/2 signaling and mediates adaptive resistance to RAF inhibitors. However, the mechanism underlying ERK signaling control of FOXD3 expression remains unknown. Here we show that SOX10 is both necessary and sufficient for RAF inhibitor-induced expression of FOXD3 in mutant BRAF melanoma cells. SOX10 activates the transcription of FOXD3 by binding to a regulatory element in FOXD3 promoter. Phosphorylation of SOX10 by ERK inhibits its transcription activity toward multiple target genes by interfering with the sumoylation of SOX10 at K55, which is essential for its transcription activity. Finally, depletion of SOX10 sensitizes mutant BRAF melanoma cells to RAF inhibitors in vitro and in vivo. Thus, our work discovers a novel phosphorylation-dependent regulatory mechanism of SOX10 transcription activity and completes an ERK1/2/SOX10/FOXD3/ERBB3 axis that mediates adaptive resistance to RAF inhibitors in mutant BRAF melanoma cells.

Publisher Correction: ERK-mediated phosphorylation regulates SOX10 sumoylation and targets expression in mutant BRAF melanoma.

In the original version of this Article, financial support was not fully acknowledged. The PDF and HTML versions of the Article have now been corrected to include the following: The National Basic Research Program (2015CB553602 to J.L.), the National Natural Science Foundation of China (31570777, 91649106, 31770917 to J.L.) and Tianjin Applied Basic and Frontier Tech Major Project (12JCZDJC34400 to J.L.) and Tianjin Higher Education Sci-Tech Development Project (20112D05 to J.L.).

[Mechanism of Soil Eco-Functional Stability Under Pyrene/Cadmium Simplex and Combined Pollution Stress].

In current scenario,the soil pollution has become very severe and its effects on agricultural and ecological security issues cannot be ignored as various contaminants are discharged into soil.Thus,the soil pollution is exigent and has to be solved.This research took soil resistance (Rt),resilience (Rl) and stability (Sb) as evaluation indexes for judging soil quality by exerting different concentration (concentration ratio) gradient of pyrene (PYR),cadmium (Cd) and pyrene/cadmium (PYR/Cd) combined pollutants.A sympathetic description was showed from the aspects of microbial activity,diversity and abundance of soil ecosystem,and the models were constructed to describe the dose-response relationship between PYR-Sb and Cd-Rt.The research showed that different types of pollutants had certain inhibition on soil DOC content.In Cd and PYR simplex pollution,soil microbial mean biomass and colony number decreased with increasing concentration of pollutants.In PYR/Cd combined pollution,the ratio of PYR and Cd had a negative correlation with the decreasing rate of DOC and resistance,meanwhile Cd had a prominent influence on the above-mentioned correlations,in other words,the soil with higher concentration of Cd had lower DOC decrease rate and resistance,and Cd would have dominant inhibition effect on microorganisms under PYR/Cd combined pollution.In addition,this study found the significant correlation of cPYR-Sb and cCd-Rt,and built the binomial forecasting model to describe the dose-response relationship of cPYR-Sb and cCd-Rt.

Kinetics and mechanism of 2,3,5,4'-tetrahydroxystilbene-2-O-ß-d-glycoside (THSG) degradation in aqueous solutions.

The hydrolytic kinetics and degradation mechanism of 2,3,5,4'-tetrahydroxystilbene-2-O-ß-d-glycoside (THSG) extracted from Radix Polygoni Multiflori (a commonly used official Chinese herbal Heshouwu), were investigated using reversed-phase high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS). The influences of pH (1.5-9.9), temperature (25-60°C) and irradiation on the hydrolysis of THSG were studied in aqueous solutions. The results showed that the degradation of THSG was pH-, temperature- and irradiation-dependent and all followed first-order kinetics. The effect of temperature on the rate of THSG degradation was characterized using the Arrhenius equation. Maximum stability of THSG was found at pH 1.5 (t(0.5)=47.57 d). THSG was unstable in alkaline and irradiation conditions. The active energy (E(a)) of THSG degradation in aqueous solution at pH 6.8 (most frequently adopted extract solvent) under lucifugal and irradiation conditions was 47.7kJmol(-1) and 25.3kJmol(-1), respectively. Three hydrolytic products of THSG were identified by LC-MS. Cis-trans isomerism took place under irradiation, and hydrolysis took place in acid-base conditions. Moreover, further oxidation on aglycon occurred after hydrolytic cleavage of phenolic glycoside in acidic conditions. The possible hydrolytic pathways of THSG are proposed.