Search

2-ethylhexyl diphenyl phosphate (EHDPHP) is a widely used organophosphorus flame retardant and plasticizer, which is commonly found in the environment. EHDPHP not only potentially harms the environment but also causes different degrees of damage to the organism. In this study, the duodenum of chicks was selected as the potential toxic target organ to explore the mechanism of duodenal injury induced by EHDPHP exposure. Ninety one-day-old healthy male chicks were selected and randomly divided into C1(control group), C2(solvent control group), L(800 mg/kg), M(1600 mg/kg), H(3200 mg/kg) according to different doses of EHDPHP after one week of environmental adaptation. The chicks were given continuous gavage for 14 d, 28 d, and 42 d. It was found that constant exposure to EHDPHP caused an increase in duodenal MDA content, a decrease in P-gp, SOD, GSH-Px activities, and a decrease in duodenal mucosal immune factor (sIgA, GSH-Px). The expression of sIgM and mucosal link proteins (CLDN, OCLN, ZO-1, JAM) decreased, and the expression of the inflammatory protein (NF-κB, COX2) in duodenal tissues was up-regulated. The results showed that continuous exposure to EHDPHP could cause duodenal oxidative stress, inflammation, and mucosal barrier damage in chicks, which provided a basis for studying the mechanism of toxic damage caused by EHDPHP in poultry.

Per- and polyfluoroalkyl substances (PFASs) constitute a broad group of fluorinated organic chemicals that are widely used in consumer products and industrial applications due to their excellent physicochemical properties. Given that people spend a significant portion of their time in office environments, our understanding of the environmental presence and human exposure to these chemicals is crucial. In this study, we conducted a targeted analysis of 24 PFASs in office indoor environments. The ΣPFAS concentrations ranged from 51.6 to 219 ng/g with mean (±SE) and median concentrations of 114 (±5.75) and 107 ng/g, respectively. Hexafluoropropylene oxide dimer acid (HFPO-DA) was the most abundant emerging PFAS detected in the dust, with mean and median concentrations of 40.5 (±1.62) and 40.4 ng/g, respectively, comprising 34.2 % of the ΣPFAS concentrations. Notably, HFPO-DA exhibited a positive correlation with perfluorooctane sulfonate (PFOS) (r: 0.427, p

The extreme weather and the deteriorating water environment have exacerbated the crisis of freshwater resource insufficiency. Many studies have shown that salty water could replace freshwater to partly meet the water demand of plants. To study the effects of early-stage drought hardening and late-stage salt stress on tomatoes (Solanum lycopersicum L.), we conducted a 2-year pot experiment. Based on the multi-objective demands of high yield, high quality, and water saving, yield indicators, quality indicators, and a water-saving indicator were selected as evaluation indicators. Three irrigation levels (W1: 85% field capacity (FC), W2: 70% FC, W3: 55% FC) and three salinity levels (S2: 2 g/L, S4: 4 g/L, S6: 6 g/L) were set as nine treatments. In addition, a control treatment (CK: W1, 0 g/L) was added. Each treatment was evaluated and scored by principal component analysis. The results for 2022 and 2023 found the highest scores for CK, W2S2, W3S2 and CK, W2S4, W2S2, respectively. Based on response surface methodology, we constructed composite models of multi-objective demands, whose results indicated that 66–72% FC and 2 g/L salinity were considered the appropriate water–salt combinations for practical production. This paper will be beneficial for maintaining high yield and high quality in tomato production using salty water irrigation.

Fiber-reinforced polymer (FRP) laminates are popular in the strengthening of concrete structures, but the durability of the strengthened structures is of great concern. Due to the susceptibility of the epoxy resin used for bonding and the deterioration of materials, the bond performance of the FRP–concrete interface could be degraded due to environmental exposure. This paper aimed to establish a data-driven method for bond strength prediction using existing test results. Therefore, a method composed of a Back Prorogation Net (BPNN) and Meta-learning Net was proposed, which can be used to solve the implicit regression problems in few-shot learning and can obtain the deteriorated bond strength and the impact weight of each parameter. First, the pretraining database Meta1, a database of material strength degradation, was established from the existing results and used in the meta-learning network. Then, the database Meta2 was built and used in the meta-learning network for model fine-tuning. Finally, combining all prior knowledge, not only the degradation of the FRP–concrete bond’s strength was predicted, but the respective weights of the environment parameters were also obtained. This method can accurately predict the degradation of the bond performance of FRP–concrete interfaces in complex environments, thus facilitating the further assessment of the remaining service life of FRP-reinforced structures.

Elephants have a unique auditory system that is larger than any other terrestrial mammal. To quantify the impact of larger middle ear (ME) structures, we measured 3D ossicular motion and ME sound transmission in cadaveric temporal bones from both African and Asian elephants in response to air-conducted (AC) tonal pressure stimuli presented in the ear canal (PEC). Results were compared to similar measurements in humans. Velocities of the umbo (VU) and stapes (VST) were measured using a 3D laser Doppler vibrometer in the 7-13,000 Hz frequency range, stapes velocity serving as a measure of energy entering the cochlea-a proxy for hearing sensitivity. Below the elephant ME resonance frequency of about 300 Hz, the magnitude of VU/PEC was an order of magnitude greater than in human, and the magnitude of VST/PEC was 5x greater. Phase of VST/PEC above ME resonance indicated that the group delay in elephant was approximately double that of human, which may be related to the unexpectedly high magnitudes at high frequencies. A boost in sound transmission across the incus long process and stapes near 9 kHz was also observed. We discuss factors that contribute to differences in sound transmission between these two large mammals.

Abstract Human gliomas are lethal brain cancers. Emerging evidence revealed the regulatory role of long noncoding RNAs (lncRNAs) in tumors. Here, we performed a comprehensive analysis of the expression profiles of RNAs in histologically lower‐grade glioma (LGG). Enrichment analysis revealed that glioma is influenced by immune‐related signatures. Survival analysis further established the close correlation between network features and glioma prognosis. Subsequent experiments showed lncRNA RP11‐770J1.4 regulates CTXN1 expression through hsa‐miR‐124‐3p. Correlation analysis identified lncRNA RP11‐770J1.4 was immune related, specifically involved in the cytosolic DNA sensing pathway. Downregulated lncRNA RP11‐770J1.4 resulted in increased spontaneous gene expression of the cGAS–STING pathway. Single‐cell RNA sequencing analysis, along with investigations in a glioblastoma stem cell model and patient sample analysis, demonstrated the predominant localization of CTXN1 within tumor cores rather than peripheral regions. Immunohistochemistry staining established a negative correlation between CTXN1 expression and infiltration of CD8+ T cells. In vivo, Ctxn1 knockdown in GL261 cells led to decreased tumor burden and improved survival while increasing infiltration of CD8+ T cells. These findings unveil novel insights into the lncRNA RP11‐770J1.4–CTXN1 as a potential immune regulatory axis, highlighting its therapeutic implications for histologically LGGs.

Wetlands act as an important natural source of global methane (CH4). The emission rate of wetland CH4 is jointly affected by climate change, carbon dioxide (CO2) fertilization, and wetland distribution. In this study, we implemented a wetland CH4 emission module into the Yale Interactive Biosphere (YIBs) model to quantify the spatiotemporal variations of global wetland CH4 emissions in 2001–2020. Site-level validations showed that the YIBs model reasonably captures the seasonality and magnitude of CH4 emissions at 28 out of 33 sites with significantly positive correlations and low relative biases. On the global scale, the YIBs predicts an annual mean wetland CH4 emission of 147.5 Tg yr−1 in 2000–2017, very close to the estimate of 147.9 Tg yr−1 from the ensemble of 13 process-based models. Global wetland CH4 emissions showed a positive trend of 0.74 Tg yr−2 in the past 2 decades, leading to an increase of 7.4 Tg yr−1 (5.2%) in 2008–2017 than 2000–2009. Climate change and CO2 fertilization accounted for over 70% of global wetland CH4 emission changes. Among them, the impact of CO2 grew steadily and became the dominant factor after the year 2008. The most significant changes in wetland CH4 emissions were located in the tropical regions following the perturbations in temperature that drives the ecosystem productivity. We found limited changes in CH4 emissions over high latitudes because of the moderate variations in wetland area fraction. The rise of wetland CH4 emissions poses an emerging threat to the global warming and likely escalates the tropospheric air pollutants.

Abstract Background An increased susceptibility to COVID-19 has been suggested for individuals with neurodegenerative diseases, but data are scarce from longitudinal studies. Methods In this community-based cohort study, we included 96,275 participants of the UK Biobank who had available SARS-CoV-2 test results in Public Health England. Of these, 2617 had a clinical diagnosis of neurodegenerative diseases in the UK Biobank inpatient hospital data before the outbreak of COVID-19 (defined as January 31st, 2020), while the remaining participants constituted the reference group. We then followed both groups from January 31st, 2020 to June 14th, 2021 for ascertainment of COVID-19 outcomes, including any COVID-19, inpatient care for COVID-19, and COVID-19 related death. Logistic regression was applied to estimate the association between neurogenerative disease and risks of COVID-19 outcomes, adjusted for multiple confounders and somatic comorbidities. Results We observed an elevated risk of COVID-19 outcomes among individuals with a neurodegenerative disease compared with the reference group, corresponding to a fully adjusted odds ratio of 2.47 (95%CI 2.25–2.71) for any COVID-19, 2.18 (95%CI 1.94–2.45) for inpatient COVID-19, and 3.67 (95%CI 3.11–4.34) for COVID-19 related death. Among individuals with a positive test result for SARS-CoV-2, individuals with neurodegenerative diseases had also a higher risk of COVID-19 related death than others (fully adjusted odds ratio 2.08; 95%CI 1.71–2.53). Conclusion Among UK Biobank participants who received at least one test for SARS-CoV-2, a pre-existing diagnosis of neurodegenerative disease was associated with a subsequently increased risk of COVID-19, especially COVID-19 related death.

Abstract Background With the increasing number of people infected with and recovered from coronavirus disease 2019 (COVID-19), the extent of major health consequences of COVID-19 is unclear, including risks of severe secondary infections. Methods Based on 445,845 UK Biobank participants registered in England, we conducted a matched cohort study where 5151 individuals with a positive test result or hospitalized with a diagnosis of COVID-19 were included in the exposed group. We then randomly selected up to 10 matched individuals without COVID-19 diagnosis for each exposed individual (n = 51,402). The life-threatening secondary infections were defined as diagnoses of severe secondary infections with high mortality rates (i.e., sepsis, endocarditis, and central nervous system infections) from the UK Biobank inpatient hospital data, or deaths from these infections from mortality data. The follow-up period was limited to 3 months after the initial COVID-19 diagnosis. Using a similar study design, we additionally constructed a matched cohort where exposed individuals were diagnosed with seasonal influenza from either inpatient hospital or primary care data between 2010 and 2019 (6169 exposed and 61,555 unexposed individuals). After controlling for multiple confounders, Cox models were used to estimate hazard ratios (HRs) of life-threatening secondary infections after COVID-19 or seasonal influenza. Results In the matched cohort for COVID-19, 50.22% of participants were male, and the median age at the index date was 66 years. During a median follow-up of 12.71 weeks, the incidence rate of life-threatening secondary infections was 2.23 (123/55.15) and 0.25 (151/600.55) per 1000 person-weeks for all patients with COVID-19 and their matched individuals, respectively, which corresponded to a fully adjusted HR of 8.19 (95% confidence interval [CI] 6.33–10.59). The corresponding HR of life-threatening secondary infections among all patients with seasonal influenza diagnosis was 4.50, 95% CI 3.34–6.08 (p for difference < 0.01). Also, elevated HRs were observed among hospitalized individuals for life-threatening secondary infections following hospital discharge, both in the COVID-19 (HR = 6.28 [95% CI 4.05–9.75]) and seasonal influenza (6.01 [95% CI 3.53–10.26], p for difference = 0.902) cohorts. Conclusion COVID-19 patients have increased subsequent risks of life-threatening secondary infections, to an equal extent or beyond risk elevations observed for patients with seasonal influenza.

Objectives Given the role of intraocular pressure in glaucoma, the patient’s sleeping pattern might contribute to the development and progression of glaucoma. We performed a study to understand the association between sleep behaviours and glaucoma.Design Our study was a prospective cohort study.Setting This was a prospective cohort study in the UK Biobank. Self-reported data on five sleep behaviours were collected using a questionnaire at baseline. We identified four sleep patterns based on a cluster analysis of the sleep behaviours.Participants In the UK Biobank, 409 053 participants were recruited between 2006 and 2010 and followed for a diagnosis of glaucoma. We identified glaucoma as any hospital admission with a diagnosis of glaucoma, based on UK Biobank inpatient hospital data. Individuals who withdrew from the UK Biobank, or were diagnosed with glaucoma before recruitment, or had self-reported surgery or laser treatment for glaucoma, or had no information on sleep behaviors were excluded.Primary and secondary outcome measures We estimated hazard ratios (HRs) with 95% confidence intervals (CI) using Cox proportional hazards models to estimate the associations of different sleep behaviors, as well as identified sleep patterns, with the risk of glaucoma, adjusting for multiple confounders.Results Compared with individuals who had a healthy sleep pattern, an excess risk of any glaucoma was observed among individuals with snoring and daytime sleepiness (HR 1.11, 95% CI 1.03 to 1.19) or insomnia and short/long sleep duration (HR 1.13, 95% CI 1.06 to 1.20), but not late chronotype sleep pattern (HR 0.98, 95% CI 0.93 to 1.03).Conclusion Snoring, daytime sleepiness, insomnia, and short/long duration, individually or jointly, were all associated with the risk of glaucoma. These findings underscore the need for sleep intervention for individuals at high risk of glaucoma as well as potential ophthalmologic screening among individuals with chronic sleep problems for glaucoma prevention.

Surface PM2.5 concentrations and aerosol optical depth (AOD) are two air pollution metrics tightly connected. Many studies have used AOD to derive PM2.5 concentrations without investigating their inconsistencies. Here, we explored the associations between surface PM2.5 and AOD using ground-level data from 19 stations in China during 2017–2019. Unexpectedly, we found low correlation coefficients of 0.03–0.60 between daily PM2.5 and AOD for most sites. Such decoupling between PM2.5 and AOD is further compared to simultaneous meteorological factors such as air temperature, specific humidity, sea level pressure, and wind speed. We found that specific humidity dominates the correlations with normalized PM2.5-AOD differences at 14 out of 19 sites. On average, specific humidity increases from 2.83 g kg−1 for the cases with low AOD but high PM2.5–11.89 g kg−1 for those with high AOD but low PM2.5, indicating that hygroscopic growth of aerosols may play an important role in decoupling the associations between PM2.5 and AOD. Random forest (RF) models using AOD as the only input yield a low R of 0.49 between the predicted and observed PM2.5 concentrations. The inclusion of specific humidity in the RF model increases the R to 0.74, close to the R of 0.81 with three additional meteorological factors. Our study revealed a strong decoupling between PM2.5 and AOD and suggested including specific humidity as a key parameter in the retrieval of long-term PM2.5 using AOD data in China.

Summary: Background: Prior research provides suggestive evidence on an association between stress-related disorders and mortality. No previous study has however addressed the role of familial confounding on such association. Methods: We conducted a nationwide cohort study of 189,757 individuals with a first-onset stress-related disorder between January 1, 1981 and December 31, 2016 in Sweden (i.e., exposed patients), 1,896,352 matched unexposed individuals, and 207,479 unaffected full siblings of the exposed patients. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of all-cause and cause-specific mortality. Findings: During a mean follow-up of 9.42 years, an elevated risk of all-cause mortality was observed during the entire follow-up among patients with stress-related disorders, compared with either unexposed individuals or their unaffected full siblings. Such excess risk was most pronounced within the first year after diagnosis of stress-related disorders (HR, 3.19 [95% CI, 2.87-3.54] in population-based comparison; HR, 3.21 [95% CI, 2.56-4.02] in sibling-based comparison). The excess risk decreased but remained statistically significant thereafter (HR, 1.64 [95% CI, 1.60-1.67] in population-based comparison; HR, 1.61 [95% CI, 1.54-1.68] in sibling-based comparison). An increased risk was observed for almost all cause-specific mortality, with greater risk increase for deaths from unnatural causes, especially suicide, and potentially avoidable causes. Interpretation: Stress-related disorders were associated with an increased risk of all-cause mortality and multiple cause-specific mortality, and the risk elevation was independent of familial confounding. The excess mortality attributable to unnatural causes and potentially avoidable causes highlights the importance of clinical surveillance of major health hazards among patients with stress-related disorders. Funding: EU Horizon 2020 Research and Innovation Action Grant, 1.3.5 Project for Disciplines of Excellence at West China Hospital of Sichuan University, National Natural Science Foundation of China, Icelandic Research Fund (Grant of Excellence), ERC Consolidator Grant, and Swedish Research Council.

Background/Aims: Nephropathy related with renin can be alleviated with ACE-inhibitors or AT1R blockers, whereas they might be ineffective after long-term administration because of a feedback production of enhanced renin. Therefore, it is urgent to develop a new category of anti-nephropathy medicine directly targeting renin. Riligustilide (C20), originally isolated from the Chinese herb Ligusticumporteri, a rhizome, was confirmed effective against many diseases. Methods: The therapeutic effect of C20 on renal injury and its underlying mechanism were investigated in three different nephrotic models, which were spontaneously hypertension rats (SHR) model, diabetic nephropathy in BTBR ob/ob mice model and 5/6-nephrectomized (5/6NX) rats model. Results: The intensity of kidney fibrosis was extensively decreased in the C20-treated rats compared to the vehicle animals. C20 significantly alleviated renal injury much more in 5/6 NX rats than in vehicle group. The rats in 5/6 NX without administrated C20 developed albuminuria earlier with more severe symptoms. Additionally, our findings showed that C20 down-regulated the renin expression and relocation of CREB-CBP complex in vivo and in vitro. Conclusion: C20 plays importantly reno-protective roles most likely through the relocation of CREB-CBP complex.

A series of butylphthalide derivatives (BPDs) 1–8 were isolated from the extract of the dried rhizome of Ligusticum chuanxiong Hort. (Umbelliferae). The cytotoxic activities of BPDs 1–8 were evaluated using a panel of human cancer cell lines. In addition, the SAR analysis and potential anti-invasion activities were investigated. The sp2 carbons at C-7 and C-7a appeared to be essential for the cytotoxic activities of BPDs. BPDs 5 and 6 remarkably inhibited the migration and invasion of cancer cells. The anti-invasion activity of dimer 6 was demonstrated to be significantly higher than monomer 5.

In the course of synthesizing 3-demethyltylophorine (1) by Lewis acid catalyzed intramolecular Friedel-Crafts reaction starting from N-(3-hydroxy-2,6,7-trimethoxy-phenanthr-9-ylmethyl)-2-chloromethylpyrrolidine, two chlorinated phenanthrene derivatives N-(4,10-dichloro-3-hydroxy-2,6,7-trimethoxyphenanthr-9-ylmethyl)-2-chloromethylpyrrolidine (4) and N-(4-chloro-3-hydroxy-2,6,7-trimethoxyphenanthr-9-ylmethyl)-2-chloromethylpyrrolidine (5) were obtained. The structures of these compounds were determined by spectroscopic analysis.

Spectrum maps can model the received signal strength over a geographical region and will play a pivotal role in the intended spectrum management scheme. Traditional spectrum map construction methods cannot fully utilize the spatial-temporal correlation characteristics of observed spectrum data in a time-varying spectrum situation. The computational complexity for real-time scenes is unaffordable, and the current spectrum situation cannot be estimated promptly. To address this problem, we first model the spatial-temporal spectrum data by tensors. Then, based on the low-rank statistical characteristic of the spectrum map, we apply the tensor ring low-rank factors (TRLRF) algorithm to recover the missing spectrum data. Finally, a dynamic window mechanism is introduced to reduce the computational complexity further. The simulation results show that the proposed dynamic window size tensor ring low-rank factors (DW-TRLRF) algorithm yields higher accuracy than other state-of-the-art algorithms with significantly lower complexity [ABSTRACT FROM AUTHOR]

Land ecosystems are important sources and sinks of atmospheric components. In turn, air pollutants affect the exchange rates of carbon and water fluxes between ecosystems and atmosphere. However, these biogeochemical processes are usually not well presented in the Earth system models, limiting the explorations of interactions between land ecosystems and air pollutants from the regional to global scales. Here, we develop and validate the interactive Model for Air Pollution and Land Ecosystems (iMAPLE) by upgrading the Yale Interactive terrestrial Biosphere model with process-based water cycles, fire emissions, wetland methane (CH4) emissions, and the trait-based ozone (O3) damages. Within the iMAPLE, soil moisture and temperature are dynamically calculated based on the water and energy balance in soil layers. Fire emissions are dependent on dryness, lightning, population, and fuel load. Wetland CH4 is produced but consumed through oxidation, ebullition, diffusion, and plant-mediated transport. The trait-based scheme unifies O3 sensitivity of different plant functional types (PFTs) with the leaf mass per area. Validations show correlation coefficients (R) of 0.59-0.86 for gross primary productivity (GPP) and 0.57-0.84 for evapotranspiration (ET) across the six PFTs at 201 flux tower sites, and yield an average R of 0.68 for CH4 emissions at 44 sites. Simulated soil moisture and temperature match reanalysis data with the high R above 0.86 and low normalized mean biases (NMB) within 7%, leading to reasonable simulations of global GPP (R=0.92, NMB=1.3%) and ET (R=0.93, NMB=-10.4%) against satellite-based observations for 2001-2013. The model predicts an annual global area burned of 507.1 Mha, close to the observations of 475.4 Mha with a spatial R of 0.66 for 1997-2016. The wetland CH4 emissions are estimated to be 153.45 Tg [CH4] yr-1 during 2000-2014, close to the multi-model mean of 148 Tg [CH4] yr-1. The model also shows reasonable responses of GPP and ET to the changes in diffuse radiation, and yields a mean O3 damage of 2.9% to global GPP. The iMAPLE provides an advanced tool for studying the interactions between land ecosystem and air pollutants. [ABSTRACT FROM AUTHOR]

Plants regulate various biological activities in cells by producing reactive oxygen species (ROS) as signal molecules. Plant NADPH oxidases, respiratory burst oxidase homologues (Rbohs), are the main source of ROS and participate in a variety of plant physiological processes. However, there are few studies regarding the function of Rbohs in rhizobium-legume symbiotic nodulation. A Rbohs subfamily gene GmRbohK was cloned and the gene expression and its subcellular localization were studied. The GmRbohK gene was highly expressed in soybean roots and nodules and greatly induced by rhizobia. GmRbohK was located at the cell membrane of Arabidopsis protoplasts. Moreover, RNA interference (RNAi) of GmRbohK resulted in a decrease in the number of nodules and nitrogenase activity. Meanwhile, the expression levels of nodulation marker genes decreased in association with the decrease in GmRbohK expression level. RNAi of GmRbohK inhibited the production of ROS and blocked infection events at the initial stage of nodule formation. Further analysis of nodule tissue sections revealed that RNAi of GmRbohK significantly reduced the number of bacteroids in the nodule infection area. In conclusion, GmRbohK is heavily involved in the regulation of soybean nodule formation. [ABSTRACT FROM AUTHOR]

As a natural aerosol with the largest emissions on land, dust has important impacts on atmospheric environment and climate systems. Both the emissions and transport of dust aerosols are tightly connected to meteorological conditions and as a result are confronted with strong modulations by the changing climate. Here, we project the changes of global dust emissions and loading by the end of the 21st century using an ensemble of model outputs from the Coupled Model Intercomparison Project version 6 (CMIP6) under four Shared Socioeconomic Pathways (SSPs). Based on the validations against site-level observations, we select 5 out of 10 models and estimate an ensemble global dust emission of 3311 Tg a−1 (1 Tg = 1012 g) at present day, in which 75 % is dry deposited and 25 % is wet deposited. Compared to 2005–2014, global dust emissions show varied responses with a reduction of 15.8 Tg a−1 under the SSP3-7.0 scenario but increased emissions up to 53.4 Tg a−1 under the SSP5-8.5 scenario at 2090–2099. For all scenarios, the most significant increase of dust emissions appears in North Africa (0.4 %–4.7 %) due to the combined effects of reduced relative humidity and precipitation but strengthened surface wind. In contrast, all scenarios show decreased emissions in central Asia (−0.6 % to −20 %) and Middle East (0 to −2.8 %) because of the increased precipitation but decreased wind speed regionally. The dust loading shows uniform increases over North Africa (1 %−12.5 %) and the downwind Atlantic following the increased emissions, but decreases over East Asia (−3.4 % to −15.2 %) and the downwind Pacific due to enhanced local precipitation that promotes wet deposition. As a result, global dust loading will increase by 2.1 %–9.3 % at the end of the 21st century under different climate scenarios, suggesting a likely strengthened radiative and climatic perturbations by dust aerosols in a warmer climate. [ABSTRACT FROM AUTHOR]

Sinomenine hydrochloride (SH) is commonly used in the treatment of rheumatoid arthritis. It activates mast cells and induces anaphylaxis in the clinical setting. Adverse drug reactions can be caused by activation of MAS-associated G protein-coupled receptor X2 (MRGPRX2) on mast cells. Because the ligand binding site of MRGPRX2 is easily contacted in dilute solvents, it can be activated by many opioid drug structures. N-Demethylsinomenine (M-3) has a similar chemical structure to that of the opioid scaffold and is a major metabolite of SH. We sought to clarify whether M-3 induces anaphylaxis synergistically with its prototype in a mouse model. Molecular docking computer simulations suggested a similar binding effect between M-3 and SH. M-3 was chemically synthesized and analyzed by surface plasmon resonance to reveal its affinity for MRGPRX2. Temperature monitoring, in vivo hindlimb swelling and exudation test, and in vitro mast cell degranulation test were used to explore the mechanism of MRGPrx2 mediated allergic reaction triggered by M-3. Reduced M-3-induced inflammation was evident in MrgprB2 (the ortholog of MRGPRX2) conditional (Cpa3-Cre/MrgprB2flox) knockout (MrgprB2-CKO) mice. Additionally, LAD2 human mast cells with MRGPRX2 knockdown showed reduced degranulation. M-3 activated LAD2 cells synergistically with SH as regulated by GRK2 signaling and IP3R/PLC/PKC/P38 molecular signaling pathways. The results indicate that the M-3 metabolite can activate mast cells synergistically with its prototype SH via MRGPRX2 and aggravate anaphylaxis. These findings provide important insights into drug safety.