A late-Ediacaran crown-group sponge animal.

Sponges are the most basal metazoan phylum1 and may have played important roles in modulating the redox architecture of Neoproterozoic oceans2. Although molecular clocks predict that sponges diverged in the Neoproterozoic era3,4, their fossils have not been unequivocally demonstrated before the Cambrian period5-8, possibly because Precambrian sponges were aspiculate and non-biomineralized9. Here we describe a late-Ediacaran fossil, Helicolocellus cantori gen. et sp. nov., from the Dengying Formation (around 551-539 million years ago) of South China. This fossil is reconstructed as a large, stemmed benthic organism with a goblet-shaped body more than 0.4 m in height, with a body wall consisting of at least three orders of nested grids defined by quadrate fields, resembling a Cantor dust fractal pattern. The resulting lattice is interpreted as an organic skeleton comprising orthogonally arranged cruciform elements, architecturally similar to some hexactinellid sponges, although the latter are built with biomineralized spicules. A Bayesian phylogenetic analysis resolves H. cantori as a crown-group sponge related to the Hexactinellida. H. cantori confirms that sponges diverged and existed in the Precambrian as non-biomineralizing animals with an organic skeleton. Considering that siliceous biomineralization may have evolved independently among sponge classes10-13, we question the validity of biomineralized spicules as a necessary criterion for the identification of Precambrian sponge fossils.

Molecular Expression and Prognostic Implications of Krüppel-Like Factor 3 (KLF3) in Clear Cell Renal Cell Carcinoma.

A major subtype of renal cancer is clear cell renal cell carcinoma (ccRCC). Krüppel-like factor 3 (KLF3) dysfunction is also revealed leading to poor prognosis in multiple cancer types. However, dysregulation and molecular dynamics of KLF3 underlying ccRCC progression still remains elusive. Here KLF3 gene and protein expressions in ccRCC were explored using data cohorts from The Cancer Genome Atlas (TCGA), Human Protein Atlas (HPA), Clinical Proteomic Tumor Analysis Consortium (CPTAC) and verified them in our patient cohort. Correlations of KLF3 expression with clinicopathological features, epigenetic modification, and immune microenvironment characteristics were further investigated. KLF3 was significantly down-regulated expressed in ccRCC tissues compared to adjacent normal controls. Adverse pathological parameters and poor prognosis were associated with lower expression of KLF3. Mechanically, KLF3 regulation was mainly attributed to CpG island methylation. KLF3-high expression subgroup was significantly enriched in cell signaling pathways most associated with EMT markers, angiogenesis, inflammatory response, apoptosis, TGF-ß, degradation of ECM, G2M checkpoint, and PI3K-AKT-mTOR. Based on GDSC database, KLF3 upregulation was identified to be associated with higher sensitivities towards PI3K-Akt-mTOR pathway inhibitors such as PI-103, PIK-93, and OSI-027. In addition, patients with down-regulated KLF3 expressions were found more sensitive towards Trametinib, Cetuximab, and Erlotinib. Collectively, our findings suggest that KLF3 may act as a suitable biomarker for prognosis prediction, tumor microenvironment (TME) phenotype identification, thereby helping ccRCC patients to make better therapeutic decisions.

Diverging asymmetry of intrinsic functional organization in autism.

Autism is a neurodevelopmental condition involving atypical sensory-perceptual functions together with language and socio-cognitive deficits. Previous work has reported subtle alterations in the asymmetry of brain structure and reduced laterality of functional activation in individuals with autism relative to non-autistic individuals (NAI). However, whether functional asymmetries show altered intrinsic systematic organization in autism remains unclear. Here, we examined inter- and intra-hemispheric asymmetry of intrinsic functional gradients capturing connectome organization along three axes, stretching between sensory-default, somatomotor-visual, and default-multiple demand networks, to study system-level hemispheric imbalances in autism. We observed decreased leftward functional asymmetry of language network organization in individuals with autism, relative to NAI. Whereas language network asymmetry varied across age groups in NAI, this was not the case in autism, suggesting atypical functional laterality in autism may result from altered developmental trajectories. Finally, we observed that intra- but not inter-hemispheric features were predictive of the severity of autistic traits. Our findings illustrate how regional and patterned functional lateralization is altered in autism at the system level. Such differences may be rooted in atypical developmental trajectories of functional organization asymmetry in autism.

The regulation effect of preventing soil nitrogen loss using microbial quorum sensing inhibitors.

Preventing soil nitrogen (N) losses driven by microbial nitrification and denitrification contributes to improving global environmental concerns caused by NO3--N leaching and N2O emission. Quorum sensing (QS) signals regulate nitrification and denitrification of N-cycling bacteria in pure culture and water treatment systems, and mediate the composition of ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB) in activated sludge. However, whether disrupting QS could prevent soil N losses remains unclear. This study explored the feasibility of applying quorum sensing inhibitors (QSIs) as an innovative strategy to reduce N losses from agricultural soils. The two QSIs, penicillic acid and 4-iodo-N-[(3S)-tetrahydro-2-oxo-3-furanyl]-benzeneacetamide (4-iodo PHL), were more effective in reducing N losses than traditional inhibitors, including N-(n-butyl) thiophosphoric triamide and 3,4-dimethylpyrazole phosphate. After 36 days of aerobic incubation, penicillic acid and 4-iodo PHL inhibited nitrification by 39% and 68%, respectively. The inhibitory effects are attributed to the fact that 4-iodo PHL decreased the abundance of archaeal and bacterial amoA genes, as well as the relative abundance of Candidatus Nitrocosmicus (AOA), Candidatus Nitrososphaera (AOA), and Nitrospira (nitrite-oxidizing bacteria/comammox), while penicillic acid reduced archaeal amoA abundance and the relative abundance of Nitrosospira (AOB) and the microbes listed above. Penicillic acid also strongly inhibited denitrification (33%) and N2O emissions (61%) at the peak of N2O production (day 4 of anaerobic incubation) via decreasing nitrate reductase gene (narG) abundance and increasing N2O reductase gene (nosZ) abundance, respectively. Furthermore, the environmental risks of QSIs to microbial community structure and network stability, CO2 emissions, and soil animals were acceptable. Overall, QSIs have application potential in agriculture to reduce soil N losses and the associated effect on climate change. This study established a new method to mitigate N losses from the perspective of QS, and can serve as important basis of decreasing the environmental risks of agricultural non-point source pollution.

Quantifying stakeholders' preference for implantable medical devices in China: a discrete choice experiment.

OBJECTIVES: This study aims to gain insight into each attribute as presented in the value of implantable medical devices, quantify attributes' strength and their relative importance, and identify the determinants of stakeholders' preferences. METHODS: A mixed-methods design was used to identify attributes and levels reflecting stakeholders' preference toward the value of implantable medical devices. This design combined literature reviewing, expert's consultation, one-on-one interactions with stakeholders, and a pilot testing. Based on the design, six attributes and their levels were settled. Among 144 hypothetical profiles, 30 optimal choice sets were developed, and healthcare professionals (decision-makers, health technology assessment experts, hospital administrators, medical doctors) and patients as stakeholders in China were surveyed. A total of 134 respondents participated in the survey. Results were analyzed by mixed logit model and conditional logit model. RESULTS: The results of the mixed logit model showed that all the six attributes had a significant impact on respondents' choices on implantable medical devices. Respondents were willing to pay the highest for medical devices that provided improvements in clinical safety, followed by increased clinical effectiveness, technology for treating severe diseases, improved implement capacity, and innovative technology (without substitutes). CONCLUSIONS: The findings of DCE will improve the current evaluation on the value of implantable medical devices in China and provide decision-makers with the relative importance of the criteria in pricing and reimbursement decision-making of implantable medical devices.

Lightweight Cross-Modal Information Mutual Reinforcement Network for RGB-T Salient Object Detection.

RGB-T salient object detection (SOD) has made significant progress in recent years. However, most existing works are based on heavy models, which are not applicable to mobile devices. Additionally, there is still room for improvement in the design of cross-modal feature fusion and cross-level feature fusion. To address these issues, we propose a lightweight cross-modal information mutual reinforcement network for RGB-T SOD. Our network consists of a lightweight encoder, the cross-modal information mutual reinforcement (CMIMR) module, and the semantic-information-guided fusion (SIGF) module. To reduce the computational cost and the number of parameters, we employ the lightweight module in both the encoder and decoder. Furthermore, to fuse the complementary information between two-modal features, we design the CMIMR module to enhance the two-modal features. This module effectively refines the two-modal features by absorbing previous-level semantic information and inter-modal complementary information. In addition, to fuse the cross-level feature and detect multiscale salient objects, we design the SIGF module, which effectively suppresses the background noisy information in low-level features and extracts multiscale information. We conduct extensive experiments on three RGB-T datasets, and our method achieves competitive performance compared to the other 15 state-of-the-art methods.

Glutamate alterations in the premature infant brain during different gestational ages with glutamate chemical exchange saturation transfer imaging: a pilot study.

OBJECTIVES: To elucidate the change in glutamate levels in preterm infants at different gestational ages by glutamate chemical exchange saturated transfer (GluCEST) magnetic resonance imaging and to compare the difference in glutamate levels among different brain regions between very early preterm infants and middle and late preterm infants. METHODS: Fifty-three preterm infants (59% males; median gestational age = 33.6 weeks) underwent MRI, including conventional MRI and GluCEST. The original data were postprocessed in MATLAB. Correlation analysis was used to determine the relationship between the MTRasym and gestational age. The differences in MTRasym signals among different ROIs were statistically analysed by one-way analysis of variance (ANOVA). The MTRasym difference of the bilateral hemispherical ROI was compared by a paired T test. RESULTS: In all ROIs, glutamate concentration was positively correlated with gestational age. The glutamate concentration in the thalamus was higher than that in the frontal lobe in very early, middle and late preterm infants. A difference in glutamate concentration was not found in the bilateral ROIs. CONCLUSIONS: The concentration of glutamate in the brains of preterm infants of different gestational ages increased with gestational age, which may be one of the factors contributing to the higher incidence of neurodevelopmental dysfunction in very early preterm infants compared to that in middle and late preterm infants. Meanwhile, the glutamate concentrations among different brain regions were also diverse. KEY POINTS: • The glutamate concentration was positively correlated with gestational age in preterm infants of the brain. • Glutamate concentrations were dissimilar in different brain regions of preterm infants. • Glutamate concentration during the process of brain development in premature infants was not found to be asymmetric.

Temperature-Dependent Bioaccumulation, Metabolism, and Hepatotoxicity of Flufiprole in Lizards (Eremias argus).

As a phenylpyrazole insecticide, flufiprole is an important substitute for fipronil in the agricultural field of China. However, its bioaccumulation and metabolism in terrestrial organisms especially in the lizards living in the agricultural area have rarely been investigated. As an ectothermic animal, lizards are also sensitive to temperature changes. Considering global warming, this study measured bioaccumulation, metabolism, and hepatotoxicity of flufiprole in the Chinese native lizard (Eremias argus) under different temperature stresses. Lizards exposed to flufiprole-contaminated soil adsorbed flufiprole through the skin and flufiprole was preferred to accumulate in lizard liver and brain. The oxidation product fipronil sulfone was the main metabolite of flufiprole in both lizard liver and human liver microsomes, which were mainly metabolized by lizard CYP3A19 or human CYP3A4. The fipronil sulfone concentration increased with increased temperature in lizard tissues. In addition, more serious oxidative damage was shown under higher temperature as the glutathione (GSH), malondialdehyde (MDA), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in lizards increased with increased temperature after flufiprole exposure. Flufiprole exposure also induced lizard liver lesions, and these lesions became more serious in the higher-temperature groups. This study provided new insights into the risk assessment of flufiprole in lizards under global warming.

Cost-effectiveness of preimplantation genetic testing for aneuploidy for women with subfertility in China: an economic evaluation using evidence from the CESE-PGS trial.

BACKGROUND: There are a large number of infertile couples in China, but its treatment is notoriously expensive and not currently covered by insurance. The utility of preimplantation genetic testing for aneuploidy as an adjunct to in vitro fertilization has been debated. OBJECTIVE: To investigate the cost-effectiveness of preimplantation genetic testing for aneuploidy (PGT-A) versus conventional technology in in vitro fertilization (IVF) from the perspective of the healthcare system in China. METHODS: Following the exact steps in the IVF protocol, a decision tree model was developed, based on the data from the CESE-PGS trial and using cost scenarios for IVF in China. The scenarios were compared for costs per patient and cost-effectiveness. One-way sensitivity analysis and probabilistic sensitivity analysis were performed to confirm the robustness of the findings. MAIN OUTCOME MEASURES: Costs per live birth, Costs per patient, Incremental cost-effectiveness for miscarriage prevention. RESULTS: The average costs per live birth of PGT-A were estimated as ¥39230.71, which is about 16.8% higher than that of the conventional treatment. Threshold analysis revealed that PGT-A would need to increase the pregnancy rate of 26.24-98.24% or a cost reduction of ¥4649.29 to ¥1350.71 to achieve the same cost-effectiveness. The incremental costs per prevented miscarriage was approximately ¥45600.23. The incremental cost-effectiveness for miscarriage prevention showed that the willingness to pay would be ¥43422.60 for PGT-A to be cost-effective. CONCLUSION: The present cost-effectiveness analysis demonstrates that embryo selection with PGT­A is not suitable for routine applications from the perspective of healthcare providers in China, given the cumulative live birth rate and the high costs of PGT­A.

Early life climate and adulthood mental health: how birth seasonality influences depressive symptoms in adults.

BACKGROUND: Early life in-utero can have long-term influence on the mental health status of individuals in adulthood, such as depression. Age, gender, socio-economic status, education, and geography are demographic factors shown to be particularly vulnerable towards the development of depressive symptoms. In addition, climate risks on depression include sunlight, rain, and temperature. However, whether climate factors in early life have a long-term influence on depression related to demographic vulnerability remains unknown. Here, the present study explored the association between birth seasonality and adulthood depressive symptoms. METHODS: We employed data from the project of Chinese Labour-forces Dynamic Survey (CLDS) 2016, containing the epidemiological data of depressive symptoms with a probability proportional to size cluster and random cluster sampling method in 29 provinces of China. A final sample size of 16,185 participants was included. Birth seasonality included spring (March, April, and May), summer (June, July, and August), autumn (September, October, and November), and winter (December, January, and February). RESULTS: We found that born in Autumn peaked lowest rate of having depressive symptoms (16.8%) and born in Summer (vs. Autumn) had a significant higher ratio (OR = 1.14, 95%CI = 1.02, 1.29) when controlling for demographic variables. In addition, demographic odds ratio of having depressive symptoms differed between people born in different seasons, particular for age and geography. CONCLUSION: Our findings suggest that birth seasonality influences the sensitive link of depressive symptoms with age and geography. It implicates early life climate environment may play a role in the development of adulthood depressive symptoms.

Inhibition of ecdysone receptor (DcEcR) and ultraspiracle (DcUSP) expression in Diaphorina citri increased susceptibility to pesticides.

Diaphorina citri Kuwayama is of great concern because of its ability to transmit devastating citrus greening illness (Huanglongbing). One strategy for controlling HLB may involve limiting the spread of D. citri. Insecticides using dsRNA target genes may be a useful option to control D. citri. The ecdysone receptor (EcR) and ultraspiracle (USP) are crucial for the growth and reproduction of insects. This study identified the genes for D. citri ecdysone receptor (DcEcR) and ultraspiracle (DcUSP). According to the qPCR data, DcUSP peaked at the 5th-instar nymph stage, while DcEcR peaked at the adult stage. Females expressed DcEcR and DcUSP at much higher levels than males. RNAi was used to examine DcEcR and DcUSP function. The findings demonstrated that inhibition of DcEcR and DcUSP delayed nymph development and decreased survival and eclosion rates. dsEcR caused adults to develop deformed wings, and dsUSP caused nymphs to wither and die. Female adult ovaries developed slowly, and the females laid fewer eggs. Additionally, DcEcR and DcUSP were inhibited, increasing D. citri susceptibility to pesticides. These findings suggest that DcEcR and DcUSP are critical for D. citri development, growth, and reproduction and may serve as potential targets for D. citri management.

The loss of Halloween gene function seriously affects the development and reproduction of Diaphorina citri (Hemiptera: Liviidae) and increases its susceptibility to pesticides.

The citrus industry has suffered severe losses as a result of Huanglongbing spread by Diaphorina citri. Controlling the population of D. citri is the key to preventing and controlling the spread of Huanglongbing. Ecdysteroids are key hormones that regulate insect development and reproduction. Therefore, the Halloween gene family involved in the ecdysone synthesis of D. citri is an ideal target for controlling the population growth of this insect. In this study, we successfully cloned four Halloween genes expressed during D. citri development. Silencing of one of the four genes resulted in a significant decrease in 20E titers in nymphs and significant decreases in the developmental, survival and emergence rates. Inhibiting Halloween gene expression in adults impeded the growth of the female ovary, diminished yolk formation, lowered vitellogenin transcription levels, and hence impaired female fecundity. This showed that Halloween genes were required for D. citri development and reproduction. DcCYP315A1 and DcCYP314A1 were highly expressed when D. citri was exposed to thiamethoxam and cypermethrin, and silencing these two genes made D. citri more sensitive to these two pesticides. Inhibition of DcCYP315A1 and DcCYP314A1 expression not only significantly delayed the development and reproduction of D. citri but also increased its susceptibility to pesticides. Therefore, these two genes are more suitable as potential target genes for controlling D. citri.

Bioengineered Platelets Combining Chemotherapy and Immunotherapy for Postsurgical Melanoma Treatment: Internal Core-Loaded Doxorubicin and External Surface-Anchored Anti-PD-L1 Antibody Backpacks.

The pivotal factors affecting the survival rate of patients include metastasis and tumor recurrence after the resection of the primary tumor. Anti-PD-L1 antibody (aPD-L1) has promising efficacy but with some side effects for the off-target binding between aPD-L1 and normal tissues. Here, inspired by the excellent targeting capability of platelets with respect to tumor cells, we propose bioengineered platelets (PDNGs) with inner-loaded doxorubicin (DOX) and outer-anchored aPD-L1-cross-linked nanogels to reduce tumor relapse and metastatic spread postoperation. The cargo does not impair the normal physiological functions of platelets. Free aPD-L1 is cross-linked to form nanogels with a higher drug-loading efficiency and is sustainably released to trigger the T-cell-mediated destruction of tumor cells, reversing the tumor immunosuppressive microenvironment. PDNGs can reduce the postoperative tumor recurrence and metastasis rate, prolonging the survival time of mice. Our findings indicate that bioengineered platelets are promising in postsurgical cancer treatment by the tumor-capturing and in situ microvesicle-secreting capabilities of platelets.

Determination of virtual source position using back projecting zero and convergent arcTAN method for scanning-passive scatter beam in carbon ion therapy.

OBJECTIVE: This study aims to develop and test a new technique by using the convergent arcTAN (cATAN) method capable of dealing with the virtual source position delivered by different carbon ion energies from the pattern of scanning-passive scatter beam. MATERIALS AND METHODS: A homemade large-format CMOS sensor and Gaf Chromic EBT3 films are used for the virtual source position measurement. The Gaf films are embedded in a self-designed rectangular plastic frame to tighten films and set up on a treatment couch for irradiation in air with the film perpendicular to the carbon ion beam at the nominal source-axis-distance (SAD) as well as upstream and downstream from the SAD. The horizontal carbon ion beam with 5 energies at a machine opening field size is carried out in this study. The virtual source position is determined by using the convergent arcTAN (cATAN) method and compared with a linear regression by back projecting FWHM to zero at a distance upstream from the various source-film-distance. RESULTS: The film FWHM measurement error of 0.5 mm leads to 0.001% deviation of α (cATAN) at every assumed textend. The overall uncertainty for the reproducibility of calculated virtual source position by the assumed textend in the vertical and horizontal directions amounts to 0.1%. The errors of calculated virtual source position by assumed textend with back projecting FWHM to zero methods are within 1.1±0.001, p = 0.033. CONCLUSION: We develop a new technique capable of dealing with the virtual source position with a convergent arcTAN method to avoid any manual measurement mistakes in scanning-passive scatter carbon ion beam. The readers are encouraged to conduct the proposed cATAN method in this study to investigate the virtual source position in the Linac-based external electron beams and the proton beams.

Developmental toxicity of TCBPA on the nervous and cardiovascular systems of zebrafish (Danio rerio): A combination of transcriptomic and metabolomics.

Tetrachlorobisphenol A (TCBPA), a widely used halogenated flame retardant, is frequently detected in environmental compartments and human samples. However, unknown developmental toxicity and mechanisms limit the entire understanding of its effects. In this study, zebrafish (Danio rerio) embryos were exposed to various concentrations of TCBPA while a combination of transcriptomics, behavioral and biochemical analyzes as well as metabolomics were applied to decipher its toxic effects and the potential mechanisms. We found that TCBPA could interfere with nervous and cardiovascular development through focal adhesion and extracellular matrix-receptor (ECM-receptor) interaction pathways through transcriptomic analysis. Behavioral and biochemical analysis results indicated abnormal swimming behavior of zebrafish larvae. Morphological observations revealed that TCBPA could cause the loss of head blood vessels. Metabolomic analysis showed that arginine-related metabolic pathways were one of the main pathways leading to TCBPA developmental toxicity. Our study demonstrated that by using omics, TCBPA was shown to have neurological and cardiovascular developmental toxicity and the underlying mechanisms were uncovered and major pathways identified.

Mechanistic insights into the amelioration effects of lipopolysaccharide-induced acute lung injury by baicalein: An integrated systems pharmacology study and experimental validation.

BACKGROUND: Acute lung injury is an acute progressive respiratory failure caused by several of non-cardiogenic factors which involves in excessive amplification or uncontrolled inflammatory response. OBJECTIVES: In this study, we investigated the protective effect of baicalein against acute lung injury induced by LPS and explored the underlying mechanisms. METHODS: Forty-eight SPF male C57BL/6 mice were randomly divided into normal group, model group, dexamethasone group and baicalein low-dose, medium-dose and high-dose groups. After 5 days of adaptive feeding, the mice were intraperitoneally injected with LPS and dissected after 12 h. Hematoxylin-eosin staining, ELISA assay, immunofluorescence assay and Western-Blot were applied to appraise microstructural changes and protein expressions of lung tissues. Systems pharmacology study was used to evaluate the protection of baicalein on acute lung injury. FINDINGS: The results showed that baicalein administration could significantly inhibit LPS-induced lung morphological changes, inhibit inflammatory response and pyroptosis. A total of forty-three potential targets of baicalein and acute lung injury were obtained. And PI3K-Akt, TNF and NF-κB were mainly signaling pathways. It is worth mentioning that this experiment also confirmed that NLRP3, caspase-1 and other inflammasome are involved in pyroptosis. CONCLUSION: Baicalein has protected against LPS-induced lung tissues injury via inhibiting inflammatory response and pyroptosis.

Pd-Catalyzed ipso,meta-Dimethylation of ortho-Substituted Iodoarenes via a Base-Controlled C-H Activation Cascade with Dimethyl Carbonate as the Methyl Source.

A methyl group can have a profound impact on the pharmacological properties of organic molecules. Hence, developing methylation methods and methylating reagents is essential in medicinal chemistry. We report a palladium-catalyzed dimethylation reaction of ortho-substituted iodoarenes using dimethyl carbonate as a methyl source. In the presence of K2CO3 as a base, iodoarenes are dimethylated at the ipso- and meta-positions of the iodo group, which represents a novel strategy for meta-C-H methylation. With KOAc as the base, subsequent oxidative C(sp3)-H/C(sp3)-H coupling occurs; in this case, the overall transformation achieves triple C-H activation to form three new C-C bonds. These reactions allow expedient access to 2,6-dimethylated phenols, 2,3-dihydrobenzofurans, and indanes, which are ubiquitous structural motifs and essential synthetic intermediates of biologically and pharmacologically active compounds.

Ethyl ferulate protects against lipopolysaccharide-induced acute lung injury by activating AMPK/Nrf2 signaling pathway.

Ethyl ferulate (EF) is abundant in Rhizoma Chuanxiong and grains (e.g., rice and maize) and possesses antioxidative, antiapoptotic, antirheumatic, and anti-inflammatory properties. However, its effect on lipopolysaccharide (LPS)-induced acute lung injury (ALI) is still unknown. In the present study, we found that EF significantly alleviated LPS-induced pathological damage and neutrophil infiltration and inhibited the gene expression of proinflammatory cytokines (TNF-α, IL-1ß, and IL-6) in murine lung tissues. Moreover, EF reduced the gene expression of TNF-α, IL-1ß, IL-6, and iNOS and decreased the production of NO in LPS-stimulated RAW264.7 cells and BMDMs. Mechanistic experiments revealed that EF prominently activated the AMPK/Nrf2 pathway and promoted Nrf2 nuclear translocation. AMPK inhibition (Compound C) and Nrf2 inhibition (ML385) abolished the beneficial effect of EF on the inflammatory response. Furthermore, the protective effect of EF on LPS-induced ALI was not observed in Nrf2 knockout mice. Taken together, the results of our study suggest that EF ameliorates LPS-induced ALI in an AMPK/Nrf2-dependent manner. These findings provide a foundation for developing EF as a new anti-inflammatory agent for LPS-induced ALI/ARDS therapy.

Incidence and Etiology of Drug-Induced Liver Injury in Mainland China.

BACKGROUND & AIMS: We performed a nationwide, retrospective study to determine the incidence and causes of drug-induced liver injury (DILI) in mainland China. METHODS: We collected data on a total of 25,927 confirmed DILI cases, hospitalized from 2012 through 2014 at 308 medical centers in mainland China. We collected demographic, medical history, treatment, laboratory, disease severity, and mortality data from all patients. Investigators at each site were asked to complete causality assessments for each case whose diagnosis at discharge was DILI (n = 29,478) according to the Roussel Uclaf Causality Assessment Method. RESULTS: Most cases of DILI presented with hepatocellular injury (51.39%; 95% confidence interval [CI] 50.76-52.03), followed by mixed injury (28.30%; 95% CI 27.73-28.87) and cholestatic injury (20.31%; 95% CI 19.80-20.82). The leading single classes of implicated drugs were traditional Chinese medicines or herbal and dietary supplements (26.81%) and antituberculosis medications (21.99%). Chronic DILI occurred in 13.00% of the cases and, although 44.40% of the hepatocellular DILI cases fulfilled Hy's Law criteria, only 280 cases (1.08%) progressed to hepatic failure, 2 cases underwent liver transplantation (0.01%), and 102 patients died (0.39%). Among deaths, DILI was judged to have a primary role in 72 (70.59%), a contributory role in 21 (20.59%), and no role in 9 (8.82%). Assuming the proportion of DILI in the entire hospitalized population of China was represented by that observed in the 66 centers where DILI capture was complete, we estimated the annual incidence in the general population to be 23.80 per 100,000 persons (95% CI 20.86-26.74). Only hospitalized patients were included in this analysis, so the true incidence is likely to be higher. CONCLUSIONS: In a retrospective study to determine the incidence and causes of DILI in mainland China, the annual incidence in the general population was estimated to be 23.80 per 100,000 persons; higher than that reported from Western countries. Traditional Chinese medicines, herbal and dietary supplements, and antituberculosis drugs were the leading causes of DILI in mainland China.

Nrf2 protects against seawater drowning-induced acute lung injury via inhibiting ferroptosis.

BACKGROUND: Ferroptosis is a new type of nonapoptotic cell death model that was closely related to reactive oxygen species (ROS) accumulation. Seawater drowning-induced acute lung injury (ALI) which is caused by severe oxidative stress injury, has been a major cause of accidental death worldwide. The latest evidences indicate nuclear factor (erythroid-derived 2)-like 2 (Nrf2) suppress ferroptosis and maintain cellular redox balance. Here, we test the hypothesis that activation of Nrf2 pathway attenuates seawater drowning-induced ALI via inhibiting ferroptosis. METHODS: we performed studies using Nrf2-specific agonist (dimethyl fumarate), Nrf2 inhibitor (ML385), Nrf2-knockout mice and ferroptosis inhibitor (Ferrostatin-1) to investigate the potential roles of Nrf2 on seawater drowning-induced ALI and the underlying mechanisms. RESULTS: Our data shows that Nrf2 activator dimethyl fumarate could increase cell viability, reduced the levels of intracellular ROS and lipid ROS, prevented glutathione depletion and lipid peroxide accumulation, increased FTH1 and GPX4 mRNA expression, and maintained mitochondrial membrane potential in MLE-12 cells. However, ML385 promoted cell death and lipid ROS production in MLE-12 cells. Furthermore, the lung injury became more aggravated in the Nrf2-knockout mice than that in WT mice after seawater drowning. CONCLUSIONS: These results suggested that Nrf2 can inhibit ferroptosis and therefore alleviate ALI induced by seawater drowning. The effectiveness of ferroptosis inhibition by Nrf2 provides a novel therapeutic target for seawater drowning-induced ALI.