SNORD3A Regulates STING Transcription to Promote Ferroptosis in Acute Kidney Injury.

Acute kidney injury (AKI) signifies a sudden and prolonged decline in kidney function characterized by tubular cell death and interstitial inflammation. Small nucleolar RNAs (snoRNAs) play pivotal roles in oxidative stress and inflammation, and may play an important role in the AKI process, which remains elusive. an elevated expression of Snord3a is revealed in renal tubules in response to AKI and demonstrates that Snord3a deficiency alleviates renal injury in AKI mouse models. Notably, the deficiency of Snord3a exhibits a mitigating effect on the stimulator of interferon genes (STING)-associated ferroptosis phenotypes and the progression of tubular injury. Mechanistically, Snord3a is shown to regulate the STING signaling axis via promoting STING gene transcription; administration of Snord3a antisense oligonucleotides establishes a significant therapeutic advantage in AKI mouse models. Together, the findings elucidate the transcription regulation mechanism of STING and the crucial roles of the Snord3a-STING axis in ferroptosis during AKI, underscoring Snord3a as a potential prognostic and therapeutic target for AKI.

NIPT-PG: empowering non-invasive prenatal testing to learn from population genomics through an incremental pan-genomic approach.

Non-invasive prenatal testing (NIPT) is a quite popular approach for detecting fetal genomic aneuploidies. However, due to the limitations on sequencing read length and coverage, NIPT suffers a bottleneck on further improving performance and conducting earlier detection. The errors mainly come from reference biases and population polymorphism. To break this bottleneck, we proposed NIPT-PG, which enables the NIPT algorithm to learn from population data. A pan-genome model is introduced to incorporate variant and polymorphic loci information from tested population. Subsequently, we proposed a sequence-to-graph alignment method, which considers the read mis-match rates during the mapping process, and an indexing method using hash indexing and adjacency lists to accelerate the read alignment process. Finally, by integrating multi-source aligned read and polymorphic sites across the pan-genome, NIPT-PG obtains a more accurate z-score, thereby improving the accuracy of chromosomal aneuploidy detection. We tested NIPT-PG on two simulated datasets and 745 real-world cell-free DNA sequencing data sets from pregnant women. Results demonstrate that NIPT-PG outperforms the standard z-score test. Furthermore, combining experimental and theoretical analyses, we demonstrate the probably approximately correct learnability of NIPT-PG. In summary, NIPT-PG provides a new perspective for fetal chromosomal aneuploidies detection. NIPT-PG may have broad applications in clinical testing, and its detection results can serve as a reference for false positive samples approaching the critical threshold.

Efficient Discrimination of Hazardous Organophosphate Flame Retardants via Cataluminescence-Based Multidimensional Ratiometric Sensing.

Emerging contaminants have recently evolved into a severe worldwide environmental issue. Organophosphate flame retardants (OPFRs) with neurotoxicity, genotoxicity, and reproductive and developmental toxicity are a class of notorious emerging contaminants that cause great concern. The development of high-efficiency and portable sensors for rapid online monitoring of OPFRs has become the primary demand for the exploration of the environmental migration and transformation of OPFRs. In this work, interestingly, the cataluminescence (CTL) phenomenon of OPFRs is first observed, and an ingenious multidimensional ratiometric CTL sensing strategy is developed for the recognition of multiple OPFRs. Three characteristic ratios are extracted from the multipeak CTL spectral curves based on energy transfer of single Tb/Eu-modified MgO sensing material, and thus a novel three-dimensional (3D) code recognition could be mapped out. This obtained 3D coordinate is found to be a unique characteristic for a given OPFR, just like an exclusive person's ID number, which can successfully discriminate and detect 10 kinds of OPFR vapors, including homologous series and isomers. More importantly, CTL mechanism investigations for OPFRs demonstrate that OPFRs undergo a series of chemical reaction processes, e.g., oxidative pyrolysis and hydroxylation, and different high-energy excited intermediates are generated, which trigger discrepant energy-transfer efficiency toward rare earth ions, leading to multipeak spectral profiles. Briefly, this proposed CTL analytical platform for OPFRs recognition initiates a new sensing principle for the efficient identification of emerging contaminants and shows significant prospects on rapid on-site detection.

Bilateral Renal Ischemia-Reperfusion Model for Acute Kidney Injury in Mice.

Acute kidney injury (AKI) is defined as a rapid decline in renal function, in which persistent kidney dysfunction gradually progresses to chronic kidney disease (CKD) due to the irreversible loss of nephrons and their maladaptive repair. In recent years, the incidence of AKI has been increasing concerning diverse etiologies, including volume depletion, sepsis, nephrotoxicity, muscle injury, and major trauma, in which ischemia-reperfusion injury (IRI) accounts for most episodes. Development of the IRI model in mice is induced by surgical clamping of the renal pedicles, which provides powerful and controllable tools for preclinical models of AKI. Importantly, the IRI model is deployed at different stages of the AKI development, especially in the processes of AKI to CKD. Despite the IRI model being widely practiced in many laboratories, a series of variables still influence the results of this model. Here, we describe the procedure of IRI model development to provide a repeatable and reliable method for researchers to explore the underlying pathogenesis in the development of AKI and the progression of AKI to CKD.

Association of Mitochondrial Pyruvate Carrier with the Clinical and Histological Features in Lupus Nephritis.

Background: Mounting evidence suggests that mitochondrial dysfunction contributes to lupus nephritis (LN) pathogenesis. Mitochondrial pyruvate carrier 1 (MPC1) and mitochondrial pyruvate carrier 2 (MPC2) mediating pyruvate transport from the cytoplasm to the mitochondrial matrix, determines the cell survival and cellular energy supply. Here, we aimed to investigate the association of mitochondrial pyruvate carrier expression with the clinical and histological features in LN. Methods: Patients with biopsy-proven proliferative LN (class III and class IV, n=18) and membranous LN (class V, n=18) were included. Expression of MPC1 and MPC2 were examined by immunohistochemistry. MPC protein levels in the two groups were evaluated by the Student's t-test. Correlation analysis between MPC levels and clinicopathological features was performed by Spearman's rank correlation. Results: Both MPC1 and MPC2 were exclusively expressed in renal tubules of enrolled LN. Significantly lower MPC1 and MPC2 were observed in patients with proliferative LN compared to membranous LN. In addition, the MPC1 and MPC2 were negatively correlated with SLEDAI-2K score, renal function, and renal pathology activity index. Conclusion: Both MPC1 and MPC2 were localized in renal tubules, and decreased MPC content was more pronounced in proliferative LN than membranous LN. MPC levels were significantly correlated with renal functions and renal pathology activity.

Related health burden with the improvement of air quality across China.

BACKGROUND: Substantial progress in air pollution control has brought considerable health benefits in China, but little is known about the spatio-temporal trends of economic burden from air pollution. This study aimed to explore their spatio-temporal features of disease burden from air pollution in China to provide policy recommendations for efficiently reducing the air pollution and related disease burden in an era of a growing economy. METHODS: Using the Global Burden of Disease method and willingness to pay method, we estimated fine particulate matter (PM2.5) and/or ozone (O3) related premature mortality and its economic burden across China, and explored their spatio-temporal trends between 2005 and 2017. RESULTS: In 2017, we estimated that the premature mortality and economic burden related to the two pollutants were RMB 0.94 million (68.49 per 100,000) and 1170.31 billion yuan (1.41% of the national gross domestic product [GDP]), respectively. From 2005 to 2017, the total premature mortality was decreasing with the air quality improvement, but the economic burden was increasing along with the economic growth. And the economic growth has contributed more to the growth of economic costs than the economic burden decrease brought by the air quality improvement. The premature mortality and economic burden from O3 in the total loss from the two pollutants was substantially lower than that of PM2.5, but it was rapidly growing. The O3-contribution was highest in the Yangtze River Delta region, the Fen-Wei Plain region, and some western regions. The proportion of economic burden from PM2.5 and O3 to GDP significantly declined from 2005 to 2017 and showed a decreasing trend pattern from northeast to southwest. CONCLUSION: The disease burden from O3 is lower than that of PM2.5, the O3-contribution has a significantly increasing trend with the growth of economy and O3 concentration.

Heat inactivation does not alter host plasma cell-free DNA characteristics in infectious disease research.

BACKGROUND: Cell-free DNA (cfDNA) is a promising analyte for non-invasive liquid biopsy, carrying abundant signatures for disease diagnosis and monitoring. In infectious disease researches, blood plasma samples are routinely heat-inactivated before proceeding with downstream analyses. However, the effects of heat inactivation on cfDNA fragmentomic analysis remain largely unclear, potentially introducing biases or altering the characteristics of cfDNA. METHODS: We performed a comprehensive investigation of cfDNA concentrations and fragmentomics in 21 plasma samples from 7 healthy individuals, by comparing the sample group without the heat inactivation to those exposed to once or twice heat-inactivation at 56 °C for 30 min and following freeze-thaw. RESULTS: Plasma samples with once and twice heat inactivation displayed no significant deviations in primary characteristics, including cfDNA concentrations, size profiles, end motif features, and genome-wide distributions, compared to samples without heat treatment. CONCLUSIONS: Heat-inactivated cfDNA can be utilized for liquid biopsy in infectious disease researches, without substantial impact on cfDNA concentrations and fragmentomic properties. This study provides essential insights into the effects of heat inactivation on cfDNA properties and will contribute to the development of reliable non-invasive biomarkers for infectious disease.

Assessment of human exposure to cadmium and its nephrotoxicity in the Chinese population.

BACKGROUND: Cadmium (Cd) is a toxic heavy metal that widely detected in environment and accumulated in kidney, posing a great threat to human health. However, there is a lack of systematic investigation of exposure profile and association of Cd exposure with renal function in the Chinese population. METHODS: Related articles were searched from PubMed, Web of Science, China National Knowledge Internet, and Wanfang to construct an aggregate exposure pathway (AEP) framework for Cd and to explore the correlation between Cd and renal function using random effects models. RESULTS: A total of 220 articles were included in this study, among which 215 investigated human exposure and 12 investigated the association of Cd with renal outcomes. The AEP framework showed that 96.5 % and 62.5 % of total Cd intake were attributed to dietary intake in nonsmokers and smokers, respectively. And 35.2 % originated from cigarette smoke inhalation in smokers. In human body, Cd was detected in blood, urine, placenta, etc. Although the concentrations of Cd in blood and urine from subjects living in polluted areas showed a sharp downward trend since the early 21st century, higher concentration of Cd in the environment and human body in polluted areas was found. Kidney was the target organ. The level of blood Cd was positively associated with urinary ß2-microglobulin [ß2-MG, r (95 % CI) = 0.12 (0.05, 0.19)], albumin [0.13 (0.06, 0.20)], and retinol-binding protein [RBP, 0.14 (0.03, 0.24)]. Elevated urinary Cd was correlated with increases in ß2-MG [0.22 (0.15, 0.29)], albumin [0.23 (0.16, 0.29)], N-acetyl-ß-d-glucosaminidase [NAG, 0.33 (0.22, 0.44)], and RBP [0.22 (0.14, 0.30)]. CONCLUSIONS: Foods and cigarette smoke were two major ways for Cd intake, and Cd induced renal injury in the Chinese population. This study enhanced the understanding of human exposure and nephrotoxicity of Cd, and emphasized the need for controlling Cd level in polluted areas.

Cinchonine and cinchonidine alleviate cisplatin-induced ototoxicity by regulating PI3K-AKT signaling.

AIM: Cinchonine (CN) and its isomer cinchonidine (CD), two of the common cinchona alkaloids, are wildly used as antimalarial drugs. However, the effects of CN and CD on the auditory system are unknown. METHODS: Molecular docking and molecular dynamics (MD) simulation were used for predicting effective drugs. The CCK-8 assay was conducted for assessing cell viability in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells. MitoSox Red staining revealed reactive oxygen species (ROS) amounts. TMRM staining was used to assess the mitochondrial membrane potential (ΔΨm). Immunofluorescence staining of myosin 7a was used to examine hair cells (HCs) in cisplatin-treated neonatal mouse cochlear explants, while TUJ-1 immunostaining was used for the detection of spiral ganglion neurons (SGNs). Cleaved caspase-3 and TUNEL immunostaining were utilized for apoptosis assessment. Immunoblot was carried out to detect PI3K-AKT signaling effectors. RESULTS: Pretreatment with CN or CD significantly increased cell viability and reduced mitochondrial dysfunction and ROS accumulation in cisplatin-treated HEI-OC1 cells. Immunofluorescent staining of cochlear explants showed that CN and CD attenuated cisplatin-induced damage to SGNs and HCs. Immunoblot revealed that CN and CD downregulated the expression of cleaved caspase-3 and activated PI3K-AKT signaling in cisplatin-injured HEI-OC1 cells. CONCLUSION: CD and CN can reduce ototoxicity caused by cisplatin and might help treat cisplatin-associated hearing loss.

A high-resolution haplotype-resolved Reference panel constructed from the China Kadoorie Biobank Study.

Precision medicine depends on high-accuracy individual-level genotype data. However, the whole-genome sequencing (WGS) is still not suitable for gigantic studies due to budget constraints. It is particularly important to construct highly accurate haplotype reference panel for genotype imputation. In this study, we used 10 000 samples with medium-depth WGS to construct a reference panel that we named the CKB reference panel. By imputing microarray datasets, it showed that the CKB panel outperformed compared panels in terms of both the number of well-imputed variants and imputation accuracy. In addition, we have completed the imputation of 100 706 microarrays with the CKB panel, and the after-imputed data is the hitherto largest whole genome data of the Chinese population. Furthermore, in the GWAS analysis of real phenotype height, the number of tested SNPs tripled and the number of significant SNPs doubled after imputation. Finally, we developed an online server for offering free genotype imputation service based on the CKB reference panel (https://db.cngb.org/imputation/). We believe that the CKB panel is of great value for imputing microarray or low-coverage genotype data of Chinese population, and potentially mixed populations. The imputation-completed 100 706 microarray data are enormous and precious resources of population genetic studies for complex traits and diseases.

Reactive Oxygen Species-Triggered Curcumin Release from Hollow Mesoporous Silica Nanoparticles for PM2.5-Induced Acute Lung Injury Treatment.

Exposure to fine particulate matter with a diameter ≤2.5 µm (PM2.5) can result in serious inflammation and oxidative stress in lung tissue. However, there is presently very few effective treatments for PM2.5-induced many pulmonary diseases, such as acute lung injury (ALI). Herein, curcumin-loaded reactive oxygen species (ROS)-responsive hollow mesoporous silica nanoparticles (Cur@HMSN-BSA) are proposed for scavenging the intracellular ROS and suppressing inflammatory responses against PM2.5-induced ALI. The prepared nanoparticles were coated with bovine serum albumin (BSA) via an ROS-sensitive thioketal (TK)-containing linker, in which the TK-containing linker would be cleaved by the excessive amounts of ROS in inflammatory sites to induce the detachment of BSA from the nanoparticles surface and thus triggering release of loaded curcumin. The Cur@HMSN-BSA nanoparticles could be used as ROS scavengers because of their excellent ROS-responsiveness, which were able to efficiently consume high concentrations of intracellular ROS. Furthermore, it was also found that Cur@HMSN-BSA downregulated the secretion of several important pro-inflammatory cytokines and promoted the polarization from M1 phenotypic macrophages to M2 phenotypic macrophages for eliminating PM2.5-induced inflammatory activation. Therefore, this work provided a promising strategy to synergistically scavenge intracellular ROS and suppress the inflammation responses, which may serve as an ideal therapeutic platform for pneumonia treatment.

Nanodrugs with intrinsic radioprotective exertion: Turning the double-edged sword into a single-edged knife.

Ionizing radiation (IR) poses a growing threat to human health, and thus ideal radioprotectors with high efficacy and low toxicity still receive widespread attention in radiation medicine. Despite significant progress made in conventional radioprotectants, high toxicity, and low bioavailability still discourage their application. Fortunately, the rapidly evolving nanomaterial technology furnishes reliable tools to address these bottlenecks, opening up the cutting-edge nano-radioprotective medicine, among which the intrinsic nano-radioprotectants characterized by high efficacy, low toxicity, and prolonged blood retention duration, represent the most extensively studied class in this area. Herein, we made the systematic review on this topic, and discussed more specific types of radioprotective nanomaterials and more general clusters of the extensive nano-radioprotectants. In this review, we mainly focused on the development, design innovations, applications, challenges, and prospects of the intrinsic antiradiation nanomedicines, and presented a comprehensive overview, in-depth analysis as well as an updated understanding of the latest advances in this topic. We hope that this review will promote the interdisciplinarity across radiation medicine and nanotechnology and stimulate further valuable studies in this promising field.

linc01515 regulates PM2.5-induced oxidative stress via targeting NRF2 in airway epithelial cells.

Dysregulation of long non-coding RNAs (lncRNAs) is involved in the adverse effects caused by fine particulate matter (PM2.5). However, the molecular mechanism is not fully clarified. In this study, we performed lncRNA sequencing on PM2.5-treated human bronchial epithelial (HBE) cells to identify vital lncRNAs, and verified the differential expression of the lncRNAs by RT-qPCR in HBE and human normal lung epithelial (BEAS-2B) cells. A total of 657 and 652 lncRNAs were dysregulated after exposure to 125 and 250 µg/mL of PM2.5, respectively. Of these, lncRNA linc01515 was upregulated in HBE and BEAS-2B cells with PM2.5 treatment. Subcellular localization experiments showed that linc01515 was mostly localized in the nucleus. Functionally, we downregulated the expression of linc01515 in HBE and BEAS-2B cells before PM2.5 treatment, which can decrease malonydialdehyde (MDA) and reactive oxygen species (ROS) levels, and improve superoxide dismutase (SOD) activity. Correspondingly, linc01515 overexpression enhanced PM2.5-induced oxidative injury in airway epithelial cells. Mechanistically, N6-methyladenosine RNA binding protein immunoprecipitation (MeRIP) assay showed that the enrichment level of m6A on linc01515 was increased after PM2.5 treatment, and the m6A modification level and expression of linc01515 was decreased in the HBE cells with 3-deazaadenosine (DAA) treatment or knockdown of METTL3 to inhibit the RNA methylation level. Western blot found that NRF2, a vital transcription factor, was enhanced remarkably in linc01515-silenced cells and decreased in linc01515-overexpressed cells. Furthermore, inhibition of NRF2 activity significantly rescued effect of downregulated linc01515 expression on PM2.5-induced cytotoxicity. In addition, we observed the similar effect when downregulating linc01515 and NRF2 expression in HBE and BEAS-2B cells before PM2.5 treatment. Taken together, our findings demonstrated that PM2.5 treatment may upregulate the expression of linc01515 by enhancing its m6A modification, and then regulate NRF2 to induce oxidative damage of airway epithelial cells.

ROS Scavenging and inflammation-directed polydopamine nanoparticles regulate gut immunity and flora therapy in inflammatory bowel disease.

Dysfunction of the intestinal mucosal immune system and dysbiosis of the intestinal microflora can induce inflammatory bowel disease. However, drug-mediated clinical treatment remains a challenge due to its poor therapeutic efficacy and severe side effects. Herein, a ROS scavenging and inflammation-directed nanomedicine is designed and fabricated by coupling polydopamine nanoparticles with mCRAMP, an antimicrobial peptide, while wrapping macrophage membrane in the outer layer. The designed nanomedicine reduced the secretion of pro-inflammatory cytokines and elevate the expression of anti-inflammatory cytokine in vivo and in vitro inflammation models, demonstrating its significant ability of improving inflammatory responses. Importantly, the macrophage membrane encapsulated nanoparticles exhibit the obviously enhanced targeting performance in local inflamed tissues. Furthermore, the 16S rRNA sequencing of fecal microorganisms showed that probiotics increased and pathogenic bacteria were inhibited after oral delivery the nanomedicine, indicating that the designed nano platform played a significant role in optimizing intestinal microbiome. Taken together, the designed nanomedicine are not only easy to prepare and exhibit high biocompatibility, but also show the inflammatory targeting property, anti-inflammatory function and positive regulation of intestinal flora, thus providing a new idea for the intervention and treatment of colitis. STATEMENT OF SIGNIFICANCE: Inflammatory bowel disease (IBD), a chronic and intractable disease, may lead to colon cancer in severe cases without effective treatment. However, clinical drugs are largely ineffective owing to insufficient therapeutic efficacies and side effects. Herein, we constructed a biomimetic polydopamine nanoparticle for oral administration to treat the IBD by modulating mucosal immune homeostasis and optimizing intestinal microorganisms. In vitro and in vivo experiments showed that the designed nanomedicine not only exhibits the anti-inflammatory function and inflammatory targeting property but also positively regulate the gut microflora. Taken together, the designed nanomedicine combined immunoregulation and intestinal microecology modulation to significantly enhance the therapeutic effect on colitis in mice, thus providing a new approach for the clinical treatment of colitis.

Exosomal circCLIP1 regulates PM2.5-induced airway obstruction via targeting SEPT10 in vitro.

Fine particulate matter (PM2.5) exposure correlates with airway obstruction, but the mechanism remains to be fully elucidated. We aim to investigate the role of exosomal circular RNAs (circRNAs)-mediated communication between airway epithelial cells and airway smooth muscle cells in PM2.5-induced airway obstruction. RNA sequencing revealed that acute PM2.5 exposure altered the expression profiles of 2904 exosomal circRNAs. Among them, exosomal hsa_circ_0029069 (spliced from CLIP1, thus termed circCLIP1 hereafter) with a loop structure was upregulated by PM2.5 exposure and mainly encapsulated in exosomes. Then, the biological functions and the underlying mechanisms were explored by Western blot, RNA immunoprecipitation and RNA pull-down, etc. Phenotypically, exosomal circCLIP1 entered recipient cells, inducing mucus secretion in recipient HBE cells and contractility of sensitive HBSMCs. Mechanistically, circCLIP1 was upregulated by METTL3-mediated N6-methyladenine (m6A) modification in PM2.5-treated producer HBE cells and exosomes, then enhancing the expression of SEPT10 in recipient HBE cells and sensitive HBSMCs. Our study revealed that exosomal circCLIP1 played a critical role in PM2.5-induced airway obstruction and provided a new potential biomarker for the assessment of PM2.5-related adverse effects.

The impacts of public hospital comprehensive reform policies on hospital medicine cost, revenues and healthcare expenditures 2014-2019: An analysis of 103 tertiary public hospitals in China.

Objective: To explore the impact of implementation of the comprehensive public hospital reform policy (CPHRP) on medicine costs, revenues and medical expenditures in tertiary public hospitals in China. Methods: The data of this study was collected from local administrations to obtain operational data of healthcare institutions and medicine procurement data for 103 tertiary public hospitals from 2014 to 2019. The propensity matching score method and the difference-in-difference method were used jointly to assess the impact of reform policies on tertiary public hospitals. Results: After the implementation of the policy, drug revenue in the intervention group decreased by ¥ 86.3 million (p = 0.076) compared to the control group; medical service revenue increased by ¥ 108.5 million (p < 0.001); government financial subsidies increased by ¥ 20.3 million (p = 0.085); the average medicine cost per outpatient and emergency visit decreased by ¥ 15.2 (p = 0.062); the average medicine cost per hospitalization decreased by ¥ 504 (p = 0.040); however, the medicine cost decreased by ¥ 38.2 million (p = 0.351), the average cost per visit for outpatient and emergency decreased by ¥ 0.562 (p = 0.966), the average cost per hospitalization decreased by ¥ 152 (p = 0.844), which are not significant. Conclusions: The implementation of reform policies has changed the revenue structure of public hospitals; the proportion of drug revenue decreased, while the proportion of service income increased, especially in service income and government subsidies. Meanwhile, the average medicine cost of outpatient, emergency, and inpatient visits per time were all reduced, which played a certain role in reducing the disease burden of patients.

5,7-Dihydroxy-4-methylcoumarin modulates the JNK/FoxO1 signaling pathway to attenuate cisplatin-induced ototoxicity by suppressing oxidative stress and apoptosis in vitro.

5,7-Dihydroxy-4-methylcoumarin (D4M) is attributed to free radical scavenging effects, with wide application for anti-oxidation. This work aimed to assess D4M's impact on cisplatin-induced ototoxicity. The cell viability was estimated with CCK-8 assay. Apoptosis was detected by the Annexin V-FITC and PI assay. The reactive oxygen species (ROS) level was determined by MitoSOX-Red and CellROX-Green probes. Mitochondrial membrane potential was analyzed with TMRM staining. Immunofluorescence was utilized for hair cells and spiral ganglion neuron detection. Apoptosis-associated proteins were assessed by cleaved caspase-3 and TUNEL staining. These results showed that D4M pretreatment protected hair cells from cisplatin-induced damage, increased cell viability, and decreased apoptosis in House Ear Institute-Organ of Corti1 (HEI-OC1) cells and neonatal mouse cochlear explants. D4M significantly inhibited cisplatin-induced mitochondrial apoptosis and reduced ROS accumulation. In addition, the protective effect of D4M on cisplatin-induced ototoxicity was also confirmed in cochlear hair cells and spiral ganglion neurons in neonatal mice. Mechanistic studies showed that D4M markedly downregulated p-JNK and elevated the expression ratio of p-FoxO1/FoxO1, thereby reducing cisplatin-induced caspase-dependent apoptosis. Meanwhile, D4M-related protection of HEI-OC1 cells was significantly blunted by JNK signaling induction with anisomycin. This study supports the possibility that D4M may be used as a new compound to prevent cisplatin-related hearing loss.

Cardiovascular mortality risks during the 2017 exceptional heatwaves in China.

Climate change has made disastrous heatwaves more frequent. Heatwave-related health impacts are much more devastating for more intense heatwaves. In the summer of 2017, exceptional heatwaves occurred in many regions, including China. This study aims to evaluate the cardiovascular mortality risk associated with the 2017 exceptional heatwaves and compare the mortality risk of the severe heatwaves with those in other years. Using daily data for a spectrum of cardiovascular mortality and temperature for 102 Chinese counties (2014-2017), we estimated the association between heatwave and mortality by generalized linear mixed-effects models. Compared with matched non-heatwave days, mortality risks on heatwaves days in 2017 increased 27.8% (95% CI, 14.8-42.3%), 26.7% (8.0-48.5%), 30.1% (10.2-53.7%), 27.3% (1.4-59.9%), 32.2% (3.4-68.4%), and 25.2% (1.0-57.7%) for total circulatory diseases, cerebrovascular disease, ischemic heart disease (IHD), acute IHD, chronic IHD, and myocardial infarction. The 2017 exceptional heatwaves impacted ischemic heart disease mortality and myocardial infarction mortality more than heatwaves in 2014-2016. Here we show that the severe heatwaves in 2017 posed catastrophic death threats for those under-studied cardiovascular diseases.

Chlorinated Organophosphate Flame Retardants Impair the Lung Function via the IL-6/JAK/STAT Signaling Pathway.

Toxicological studies have revealed the adverse impacts of organophosphate flame retardants (OPFRs) on the respiratory system, while there is a lack of epidemiological evidence, and information for risk assessment remains insufficient. Herein, we investigated the associations of urinary metabolites of OPFRs with the lung function in 987 adults participating in the U.S. National Health and Nutrition Examination Survey 2011-2012. The elevation of three primary metabolites of chlorinated OPFRs [bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), bis(2-chloroethyl) phosphate (BCEP), and bis(1-chloro-2-propyl) phosphate (BCIPP)] was related to pulmonary dysfunction in a sample-weighted regression model. Each one-unit increase in the log-transformed levels of BDCIPP and BCEP was related to 91.52 and 79.34 mL reductions in the forced vital capacity (FVC). Each one-unit elevation in BCIPP was correlated with 130.86, 153.56, 302.26, and 148.24 mL reductions in forced expiratory volume 1st second (FEV1), FVC, peak expiratory flow rate (PEF), and forced expiratory flow at 25-75% of FVC (FEF25-75%), respectively. Then, an adverse outcome pathway (AOP) framework was constructed using the Comparative Toxicogenomics Database, the Toxicity Forecaster, and the GeneCards database. Based on the weight of the evidence, BDCIPP, BCEP, BCIPP, and their parent compounds (TDCIPP, TCEP, and TCIPP) may affect the IL-6/Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, induce airway remodeling, and impair the lung function. Additionally, tobacco smoke exposure may modify the effects of BDCIPP on the lung function (Pint < 0.05) and affect the IL-6-mediated AOP. These results suggested that chlorinated OPFRs were associated with pulmonary dysfunction via the IL-6/JAK/STAT pathway.