Drug interaction with Udp-Glucuronosyltransferase (UGT) enzymes is a predictor of drug-induced liver injury.

DILI frequently contributes to the attrition of new drug candidates and is a common cause for the withdrawal of approved drugs from the market. Although some noncytochrome P450 (non-CYP) metabolism enzymes have been implicated in DILI development, their association with DILI outcomes has not been systematically evaluated. In this study, we analyzed a large data set comprising 317 drugs and their interactions in vitro with 42 non-CYP enzymes as substrates, inducers, and/or inhibitors retrieved from historical regulatory documents. We examined how these in vitro drug-enzyme interactions are correlated with the drugs' potential for DILI concern, as classified in the Liver Toxicity Knowledge Base database. Our study revealed that drugs that inhibit non-CYP enzymes are significantly associated with high DILI concern. Particularly, interaction with UDP-glucuronosyltransferases (UGT) enzymes is an important predictor of DILI outcomes. Further analysis indicated that only pure UGT inhibitors and dual substrate inhibitors, but not pure UGT substrates, are significantly associated with high DILI concern. Notably, drug interactions with UGT enzymes may independently predict DILI, and their combined use with the rule-of-two model further improves overall predictive performance. These findings could expand the currently available tools for assessing the potential for DILI in humans.

Medical device report analyses from MAUDE: Device and patient outcomes, adverse events, and sex-based differential effects.

Post-market medical device-associated failures and patient problems are reported in Medical Device Reports (MDRs) to the US Food and Drug Administration. Reports are accessible through Manufacturer and User Facility Device Experience (MAUDE), a database including both required and voluntary submissions. We present an overview of >10 million MDRs received from 2011 to 2021. Approximately 92% of reporting issues represent medical device physical or functional failures, categorized from 1704 codes related to medical device integrity or function. ∼8% were coded adverse events (AEs). Patient outcomes are reported via 998 patient codes in 19 medical specialties (cardiovascular, orthopedic, etc.). ∼40% of patient reports indicated "no health consequences"; however, a small number of devices had consistently high AE reports. While overall reports did not exhibit a sex-based dichotomy, ∼9% of the reported AEs occurred more frequently in females, many of which were related to immune effects. The analyses are subject to uncertainties and potential bias based on data available and data selected for analysis. However, such an overview of post-market MDR data, not previously published, fills a gap in understanding medical device issues and patient-based outcomes related to medical device use. Trends identified may be subjects of additional hypotheses, analysis, and research.

Microfluidic Fabrication of Monodisperse and Recyclable TiO2-Poly(ethylene glycol) Diacrylate Hybrid Microgels for Removal of Methylene Blue from Aqueous Medium.

Nearly monodisperse titanium oxide-polyethylene glycol diacrylate [TiO2-P(EGDA)] hybrid microbeads containing 0.5 wt % TiO2 nanoparticles entrapped within a P(EGDA) cross-linked polymeric network were synthesized using a modular Lego-inspired glass capillary microfluidic device. TiO2-P(EGDA) hybrid microgels were characterized by optical microscopy, scanning electron microscopy, X-ray diffraction, energy dispersive X-ray spectroscopy, and thermogravimetric analysis. The fabricated TiO2-P(EGDA) hybrid microgel system showed 100% removal efficiency of methylene blue (MB) from its 1-3 ppm aqueous solutions after 4 h of UV light irradiation at 0.2 mW/cm2 at the loading of 25 g/L photocatalyst beads in the reaction mixture, corresponding to the loading of naked TiO2 of just 0.025 g/L. No decrease in photocatalytic efficiency was observed in 10 repeated runs with recycled photocatalyst using a fresh 1 ppm MB solution in each cycle. The rate of photocatalytic degradation was controlled by the UV light irradiance, catalyst loading, and the initial dye concentration. Physical adsorption of MB onto the surface of composite microgel was also observed. The adsorption data was best fitted with the Langmuir adsorption isotherm and the Elovich kinetic model. TiO2-P(EGDA) microgel beads are biocompatible, can be prepared with a tunable size in the microfluidic device, and can easily be separated from the reaction mixture by gravity settling. The TiO2-P(EGDA) system can be used for the removal of other toxic dyes and micropollutants from industrial wastewater.

Facile Microfluidic Fabrication of Biocompatible Hydrogel Microspheres in a Novel Microfluidic Device.

Poly(ethylene glycol) diacrylate (PEGDA) microgels with tuneable size and porosity find applications as extracellular matrix mimics for tissue-engineering scaffolds, biosensors, and drug carriers. Monodispersed PEGDA microgels were produced by modular droplet microfluidics using the dispersed phase with 49-99 wt% PEGDA, 1 wt% Darocur 2959, and 0-50 wt% water, while the continuous phase was 3.5 wt% silicone-based surfactant dissolved in silicone oil. Pure PEGDA droplets were fully cured within 60 s at the UV light intensity of 75 mW/cm2. The droplets with higher water content required more time for curing. Due to oxygen inhibition, the polymerisation started in the droplet centre and advanced towards the edge, leading to a temporary solid core/liquid shell morphology, confirmed by tracking the Brownian motion of fluorescent latex nanoparticles within a droplet. A volumetric shrinkage during polymerisation was 1-4% for pure PEGDA droplets and 20-32% for the droplets containing 10-40 wt% water. The particle volume increased by 36-50% after swelling in deionised water. The surface smoothness and sphericity of the particles decreased with increasing water content in the dispersed phase. The porosity of swollen particles was controlled from 29.7% to 41.6% by changing the water content in the dispersed phase from 10 wt% to 40 wt%.

Elevated bilirubin, alkaline phosphatase at onset, and drug metabolism are associated with prolonged recovery from DILI.

BACKGROUND & AIMS: Although most drug-induced liver injury (DILI) cases resolve after the offending medication is discontinued, time to recovery varies among patients, with 6 -12% developing a chronic disease. Herein, we investigated clinical factors and drug properties as potential risk determinants that influence the time course for DILI recovery and developed a model to predict its trajectory. METHODS: We applied an accelerated failure time model to 294 cases collected by the International Drug-Induced Liver Network Consortium (iDILIC). Factors included in the multivariate recovery score model were selected through univariate analysis. The model was externally validated using 257 cases from the Spanish DILI Registry and 191 cases from the LiverTox database. RESULTS: Higher serum bilirubin and alkaline phosphatase (ALP) at DILI onset, a longer time to onset, and non-significant drug metabolism were associated with a longer recovery and were included in the recovery score model. We defined high- and low-risk groups based on the scores assigned by the model. The estimated probability of recovery by 6 months was 0.46 (95% CI 0.26-0.61) for the high-risk group and 0.93 (95% CI 0.58-0.99) for the low-risk group in the iDILIC. Model performance was validated in both validation sets. The high- and low-risk cases identified by the model showed a significantly different time course for recovery, with a majority of low-risk cases recovering sooner. CONCLUSION: The trajectory of biochemical recovery from DILI is predicted by the extent of drug metabolism, serum bilirubin and ALP at DILI onset. The model can be used to compute an estimated DILI recovery and, when a significant delay is predicted, clinicians may consider additional investigations such as histologic evaluation or extended follow-up. LAY SUMMARY: In this study, we investigated whether drug properties and clinical factors are associated with the time it takes to recover from drug-induced liver injury (DILI). We found that total bilirubin, alkaline phosphatase level at DILI onset, time to onset, and extent of drug metabolism were consistently associated with recovery time. Using these factors, we built a model to predict the trajectory of recovery from DILI and validated this model in 2 independent cohorts. Our findings offer important insights into the factors influencing the trajectory of recovery from DILI. Additional investigations and longer follow-ups can be planned in those for whom a delayed recovery is predicted.

Drug properties and host factors contribute to biochemical presentation of drug-induced liver injury: a prediction model from a machine learning approach.

Drug-induced liver injury (DILI) presentation varies biochemically and histologically. Certain drugs present quite consistent injury patterns, i.e., DILI signatures. In contrast, others are manifested as broader types of liver injury. The variety of DILI presentations by a single drug suggests that both drugs and host factors may contribute to the phenotype. However, factors determining the DILI types have not been yet elucidated. Identifying such factors may help to accurately predict the injury types based on drugs and host information and assist the clinical diagnosis of DILI. Using prospective DILI registry datasets, we sought to explore and validate the associations of biochemical injury types at the time of DILI recognition with comprehensive information on drug properties and host factors. Random forest models identified a set of drug properties and host factors that differentiate hepatocellular from cholestatic damage with reasonable accuracy (69-84%). A simplified logistic regression model developed for practical use, consisting of patient's age, drug's lipoaffinity, and hybridization ratio, achieved a fair prediction (68-74%), but suggested potential clinical usability, computing the likelihood of liver injury type based on two properties of drugs taken by a patient and patient's age. In summary, considering both drug and host factors in evaluating DILI risk and phenotypes open an avenue for future DILI research and aid in the refinement of causality assessment.

Crosslinking Strategies for the Microfluidic Production of Microgels.

This article provides a systematic review of the crosslinking strategies used to produce microgel particles in microfluidic chips. Various ionic crosslinking methods for the gelation of charged polymers are discussed, including external gelation via crosslinkers dissolved or dispersed in the oil phase; internal gelation methods using crosslinkers added to the dispersed phase in their non-active forms, such as chelating agents, photo-acid generators, sparingly soluble or slowly hydrolyzing compounds, and methods involving competitive ligand exchange; rapid mixing of polymer and crosslinking streams; and merging polymer and crosslinker droplets. Covalent crosslinking methods using enzymatic oxidation of modified biopolymers, photo-polymerization of crosslinkable monomers or polymers, and thiol-ene "click" reactions are also discussed, as well as methods based on the sol-gel transitions of stimuli responsive polymers triggered by pH or temperature change. In addition to homogeneous microgel particles, the production of structurally heterogeneous particles such as composite hydrogel particles entrapping droplet interface bilayers, core-shell particles, organoids, and Janus particles are also discussed. Microfluidics offers the ability to precisely tune the chemical composition, size, shape, surface morphology, and internal structure of microgels by bringing multiple fluid streams in contact in a highly controlled fashion using versatile channel geometries and flow configurations, and allowing for controlled crosslinking.

The landscape of hepatobiliary adverse reactions across 53 herbal and dietary supplements reveals immune-mediated injury as a common cause of hepatitis.

Recent evidence suggests herbal-induced liver injury (HILI) to account for 20% of cases among the U.S. Drug-Induced-Liver-Injury-Network. To define injury patterns of HILI, we reviewed the clinical data of 413 patients exposed to 53 HDS products by considering the evidence for HILI and its grades of severity. Outstandingly, females developed HILI more rapidly (p = 0.018) and the time to recovery was significantly increased (p = 0.0153). > 90% of reported cases were severe and half of HDS products caused acute liver failure (ALF) requiring liver transplantation or resulted in fatal outcomes. Liver biopsies of 243 patients defined 13 histological features; two-thirds of products elicited immune-mediated hepatitis and included 154 Hy's law positive cases. The histological injury patterns were confirmed among unrelated patients, while accidental re-challenges evidenced culprits as causative. Furthermore, one-fifth of patients presented elevated autoantibody titres indicative of autoimmune-like HILI, and one-third of the products were linked to chronic hepatitis and cholestatic injuries not resolving within 6 months. Lastly, INR and TBL are critical laboratory parameters to predict progression of severe HILI to ALF. Our study highlights the need for a regulatory framework to minimize the risk for HILI. Better education of the public and a physician-supervised self-medication plan will be important measures to abate risk of HILI.

Natural variation of ZmHKT1 affects root morphology in maize at the seedling stage.

MAIN CONCLUSION: Eight variants in ZmHKT1 promoter were significantly associated with root diameter, four haplotypes based on these significant variants were found, and Hap2 has the largest root diameter. Roots play an important role in uptake of water, nutrients and plant anchorage. Identification of gene and corresponding SNPs associated with root traits would enable develop maize lines with better root traits that might help to improve capacity for absorbing nutrients and water acquisition. The genomic sequences of a salt tolerance gene ZmHKT1 was resequenced in 349 maize inbred lines, and the association between nucleotide polymorphisms and seedling root traits was detected. A total of 269 variants in ZmHKT1 were identified, including 226 single nucleotide polymorphisms and 43 insertions and deletions. The gene displayed high level of nucleotide diversity, especially in non-genic regions. A total of 19 variations in untranslated region of ZmHKT1 were found to be associated with six seedling traits. Eight variants in promoter region were significantly associated with average root diameter (ARD), four haplotypes were found based on these significant variants, and Hap2 has the largest ARD. Two SNPs in high-linkage disequilibrium (SNP-415 and SNP 2169) with pleiotropic effects were significantly associated with plant height, root surface area, root volume, and shoot dry weight. This result revealed that ZmHKT1 was an important contributor to the phenotypic variations of seedling root traits in maize, these significant variants could use to develop functional markers to improve root traits.

The influence of drug properties and host factors on delayed onset of symptoms in drug-induced liver injury.

BACKGROUND & AIMS: Most patients with drug-induced liver injury (DILI) manifest clinical symptoms while on therapy, while some patients manifest days or weeks after drug cessation (delayed onset). This challenges DILI causality assessment and diagnosis. Factors contributing to the delayed onset phenotype are currently unknown. We explored factors contributing to delayed onset of DILI by analysing culprit drug properties, host factors and their interactions in a large patient population from the Spanish DILI Registry. METHODS: Clinical information from 388 patients (69 presented delayed onset) and drug properties of 43 causative drugs (45 active ingredients) were analysed. A two-tier regression-based model was used to assess host/drug interactions affecting the probability of delayed onset. RESULTS: Antibacterial and anti-inflammatory drugs accounted for the delayed onset cases. Drug property of <50% hepatic metabolism (odds ratio [OR] 11.06, 95% confidence interval [95% CI]: 4.4-32.2, P = 0.0003), daily dose ≥1000 mg (OR: 2.77, 95% CI: 1.3-6.1, P = 0.0063) and the absence of pre-existing conditions in a patient (OR: 2.55, 95% CI: 1.3-4.9, P = 0.0043) were independently associated with delayed onset. The findings were consistent when externally validated using Latin American DILI Network cases (N = 131). Likewise, drug properties of mitochondrial liability and Pauling electronegativity were associated with delayed onset, but dependent on specific host factors such as age, sex and pre-existing cardiac diseases. CONCLUSIONS: This study demonstrated that delayed onset, a specific DILI phenotype, is explained by complex interactions among drug properties and host factors and provided mechanistic hypotheses for future studies. These findings can help improve the diagnostic capability and causality assessment.

Atmospheric PM2.5 aspiration causes tauopathy by disturbing the insulin signaling pathway.

Epidemiological and toxicological studies have shown that ambient fine particulate matter (PM2.5) is a healthy risk factor for neurodegenerative diseases. Hyperphosphorylated tau is the common feature of numerous neurodegenerative diseases known as tauopathy, which could be inhibited by insulin stimulation. However, the effects of PM2.5 on tau protein injury by disturbing the insulin signaling pathway still need to be illuminated. In present study, male C57BL/6 J mice were administered with PM2.5 to determine whether PM2.5 inhalation can induce tauopathy via the insulin resistance (IR) related pathway (IRS-1/AKT/GSK-3ß signaling pathway). The results showed that PM2.5 treatment induced the generation of phosphorylated tau (P-tau) and contributed to the development of tauopathy because of the insulin signaling disorders in insulin targeting organs. As expected, the occurrence of central and peripheral IR and accompanying hyperinsulinemia aggravated the disturbance of the IRS-1/AKT/GSK-3ß signaling pathway. These observations indicated that PM2.5 exposure led to neurodegenerative tau lesion, and insulin signaling pathway might be a potential therapeutic target for tauopathy.

Target-specific toxicity knowledgebase (TsTKb): a novel toolkit for in silico predictive toxicology.

As the number of man-made chemicals increases at an unprecedented pace, efforts of quickly screening and accurately evaluating their potential adverse biological effects have been hampered by prohibitively high costs of in vivo/vitro toxicity testing. While it is unrealistic and unnecessary to test every uncharacterized chemical, it remains a major challenge to develop alternative in silico tools with high reliability and precision in toxicity prediction. To address this urgent need, we have developed a novel mode-of-action-guided, molecular modeling-based, and machine learning-enabled modeling approach for in silico chemical toxicity prediction. Here we introduce the core element of this approach, Target-specific Toxicity Knowledgebase (TsTKb), which consists of two main components: Chemical Mode of Action (ChemMoA) database and a suite of prediction model libraries.

A review on machine learning methods for in silico toxicity prediction.

In silico toxicity prediction plays an important role in the regulatory decision making and selection of leads in drug design as in vitro/vivo methods are often limited by ethics, time, budget, and other resources. Many computational methods have been employed in predicting the toxicity profile of chemicals. This review provides a detailed end-to-end overview of the application of machine learning algorithms to Structure-Activity Relationship (SAR)-based predictive toxicology. From raw data to model validation, the importance of data quality is stressed as it greatly affects the predictive power of derived models. Commonly overlooked challenges such as data imbalance, activity cliff, model evaluation, and definition of applicability domain are highlighted, and plausible solutions for alleviating these challenges are discussed.

Interplay of gender, age and drug properties on reporting frequency of drug-induced liver injury.

We examined the effect of gender, age, and drug properties on liver events reporting frequency (RF) to assess patient- and drug-related risks for drug-induced liver injury (DILI). We performed a data-mining analysis of the WHO VigiBase™ to 1) identify drugs with gender- and age-biased RF and 2) characterize drug properties using the Liver Toxicity Knowledge Base. Age-, gender-specific Empirical Bayes Geometric Mean of relative reporting ratio of liver events with 90% confidence interval (CI) was calculated for 375 drugs with DILI potential. Forty-one drugs showed an increased RF in women, which had a higher prevalence of reactive metabolite formation and mitochondrial dysfunction and transporter inhibition. Fifty-nine drugs showed an increased RF in younger women (<50 yrs), many of which had a signature pattern of hepatocellular injury. In contrast, half of 17 drugs that showed an increased RF in men had a cholestatic pattern. In the older group (≥50 yrs), 17 drugs showed an increased RF and had higher transporter inhibition, Cmax, and plasma protein binding, yet shorter plasma elimination. Specific drug properties were associated with gender- and age-biased liver events RF, suggesting possible interactions of drug properties, gender, and age in DILI development.

The Development of a Database for Herbal and Dietary Supplement Induced Liver Toxicity.

The growing use of herbal dietary supplements (HDS) in the United States provides compelling evidence for risk of herbal-induced liver injury (HILI). Information on HDS products was retrieved from MedlinePlus of the U.S. National Library of Medicine and the herbal monograph of the European Medicines Agency. The hepatotoxic potential of HDS was ascertained by considering published case reports. Other relevant data were collected from governmental documents, public databases, web sources, and the literature. We collected information for 296 unique HDS products. Evidence of hepatotoxicity was reported for 67, that is 1 in 5, of these HDS products. The database revealed an apparent gender preponderance with women representing 61% of HILI cases. Culprit hepatotoxic HDS were mostly used for weight control, followed by pain and inflammation, mental stress, and mood disorders. Commonly discussed mechanistic events associated with HILI are reactive metabolites and oxidative stress, mitochondrial injury, as well as inhibition of transporters. HDS⁻drug interactions, causing both synergistic and antagonizing effects of drugs, were also reported for certain HDS. The database contains information for nearly 300 commonly used HDS products to provide a single-entry point for better comprehension of their impact on public health.

Regulation and mechanism of miR-146 on renal ischemia reperfusion injury.

AIM: MicroRNAs (miRs) are endogenous substances that act as important diagnostic and treatment targets in renal diseases. miR-146 plays an important role in the development of endotoxin tolerance through NF-κB pathway, but the underlying mechanism is not clearly understood. The aim of this study was to determine the molecular regulation and function of miR-146 and also the expression of miR-146 in an experimental model of renal ischemia reperfusion injury (IRI). METHODS: IRI was induced in mouse by bilateral IRI for 45 min followed by reperfusion. The male mice were randomized as: sham, I/R, I/R+miR-146, and I/R+antago-miR-146 groups. Renal function, histological damage, and cell apoptosis were evaluated at 24 h after reperfusion. RESULTS: Overexpression of miR-146 protected renal function. Renal cells with upregulated miR-146 had lower plasma levels of blood urea nitrogen (BUN) and creatinine, decreased apoptosis and active caspase-3 protein expressions. miR-146 was shown to have a role in renal IR injury. miR-146 has a protective effect on renal function and plays a significant role in apoptosis. IGSF1 acts as a target of miR-146. IGSF1 rescued the effects of miR-146 on renal IRI. miR-146 protected renal function by activation of PI3K/AKT. CONCLUSION: These findings suggest that miR-146 might regulate apoptosis and can cause injury in I/R via targeting IGSF1 and also exert renal protection property.

A Model to predict severity of drug-induced liver injury in humans.

UNLABELLED: Drug-induced liver injury (DILI) is a major public health concern, and improving its prediction remains an unmet challenge. Recently, we reported the Rule-of-2 (RO2) and found lipophilicity (logP ≥3) and daily dose ≥100 mg of oral medications to be associated with significant risk for DILI; however, the RO2 failed to estimate grades of DILI severity. In an effort to develop a quantitative metrics, we analyzed the association of daily dose, logP, and formation of reactive metabolites (RM) in a large set of Food and Drug Administration-approved oral medications and found factoring RM into the RO2 to highly improve DILI prediction. Based on these parameters and by considering n = 354 drugs, an algorithm to assign a DILI score was developed. In univariate and multivariate logistic regression analyses the algorithm (i.e., DILI score model) defined the relative contribution of daily dose, logP, and RM and permitted a quantitative assessment of risk of clinical DILI. Furthermore, a clear relationship between calculated DILI scores and DILI risk was obtained when applied to three independent studies. The DILI score model was also functional with drug pairs defined by similar chemical structure and mode of action but divergent toxicities. Specifically, for drug pairs where the RO2 failed, the DILI score correctly identified toxic drugs. Finally, the model was applied to n = 159 clinical cases collected from the National Institutes of Health's LiverTox database to demonstrate that the DILI score correlated with the severity of clinical outcome. CONCLUSIONS: Based on daily dose, lipophilicity, and RM, a DILI score algorithm was developed that provides a scale of assessing the severity of DILI risk in humans associated with oral medications. (Hepatology 2016;64:931-940).

Integrating Drug's Mode of Action into Quantitative Structure-Activity Relationships for Improved Prediction of Drug-Induced Liver Injury.

Drug-induced liver injury (DILI) is complex in mechanism. Different drugs could undergo different mechanisms but result in the same DILI type, while the same drug could lead to different DILI types via different mechanisms. Therefore, predicting a drug's potential for DILI should take its underlying mechanisms into consideration. To achieve that, we constructed a novel approach by incorporating the drug's Mode of Action (MOA) into Quantitative Structure-Activity Relationship (QSAR) modeling. This MOA-DILI approach was examined using a data set of 333 drugs. The drugs were first grouped according to their MOA profiles (positive or negative in each MOA) based on the Tox21 qHTS assays. QSAR models for individual MOA assays were developed and subsequently combined to obtain the MOA-DILI model. A hold-out testing strategy (222 drugs for training and 111 drugs as a test set) was employed, which yielded a predictive accuracy of 0.711. The MOA-DILI model was directly compared with the standard QSAR approach using the same hold-out strategy, and the QSAR model yielded an accuracy of 0.662. To minimize the random chance in splitting training/test sets, the hold-out testing process was repeated 1000 times, and the observed difference in prediction accuracy between MOA-DILI and QSARs was statistically significant (P value <0.0001). Out of 17 MOAs used, four assays (i.e., antioxidant response elements, PPAR-gamma, estrogen receptor, and thyroid receptor assays) contributed most to the improved prediction of the MOA-DILI model over QSARs. In conclusion, the MOA-DILI approach has the potential to significantly improve predictive outcomes and to reveal complex relationships between MOAs and DILI, all of which would be helpful in developing DILI predictive models in drug screening and for risk assessment of industrial chemicals.

Associations of Drug Lipophilicity and Extent of Metabolism with Drug-Induced Liver Injury.

Drug-induced liver injury (DILI), although rare, is a frequent cause of adverse drug reactions resulting in warnings and withdrawals of numerous medications. Despite the research community's best efforts, current testing strategies aimed at identifying hepatotoxic drugs prior to human trials are not sufficiently powered to predict the complex mechanisms leading to DILI. In our previous studies, we demonstrated lipophilicity and dose to be associated with increased DILI risk and, and in our latest work, we factored reactive metabolites into the algorithm to predict DILI. Given the inconsistency in determining the potential for drugs to cause DILI, the present study comprehensively assesses the relationship between DILI risk and lipophilicity and the extent of metabolism using a large published dataset of 1036 Food and Drug Administration (FDA)-approved drugs by considering five independent DILI annotations. We found that lipophilicity and the extent of metabolism alone were associated with increased risk for DILI. Moreover, when analyzed in combination with high daily dose (≥100 mg), lipophilicity was statistically significantly associated with the risk of DILI across all datasets (p < 0.05). Similarly, the combination of extensive hepatic metabolism (≥50%) and high daily dose (≥100 mg) was also strongly associated with an increased risk of DILI among all datasets analyzed (p < 0.05). Our results suggest that both lipophilicity and the extent of hepatic metabolism can be considered important risk factors for DILI in humans, and that this relationship to DILI risk is much stronger when considered in combination with dose. The proposed paradigm allows the convergence of different published annotations to a more uniform assessment.

Particulate matter (PM2.5) exposure season-dependently induces neuronal apoptosis and synaptic injuries.

Epidemiological studies have shown that particulate matter 2.5 (PM2.5) not only increases the incidence of cardiopulmonary illnesses but also relates to the development of neurodegenerative diseases. Considering that PM2.5 is highly heterogeneous with regional disparity and seasonal variation, we investigated whether PM2.5 exposure induced neuronal apoptosis and synaptic injuries in a season-dependent manner. The results indicated that PM2.5 altered the expression of apoptosis-related proteins (mainly bax and bcl-2), activated caspase-3 and caused neuronal apoptosis. Additionally, PM2.5 decreased the levels of synaptic structural protein postsynaptic density (PSD-95) and synaptic functional protein N-methyl-D-aspartate (NMDA) receptor subunit (NR2B) expression. These effects occurred in a season-dependent manner, and PM2.5 collected from the winter showed the strongest changes. Furthermore, the effect was coupled with the inhibition of phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) and phosphorylated cAMP-response element binding protein (p-CREB). Based on the findings, we analyzed the correlations between the chemical composition of PM2.5 samples and the biological effects, and confirmed that winter PM2.5 played a major role in causing neuronal apoptosis and synaptic injuries among different season samples.