Synthesis and biological evaluation of 4-imidazolidinone-containing compounds as potent inhibitors of the MDM2/p53 interaction.

Inhibition of MDM2/p53 interaction with small-molecule inhibitors stabilizes p53 from MDM2 mediated degradation, which is a promising strategy for the treatment of cancer. In this report, a novel series of 4-imidazolidinone-containing compounds have been synthesized and tested in MDM2/p53 and MDM4/p53 FP binding assays. Upon SAR studies, compounds 2 (TB114) and 22 were identified as the most potent inhibitors of MDM2/p53 but not MDM4/p53 interactions. Both 2 and 22 exhibited strong antiproliferative activities in HCT-116 and MOLM-13 cell lines harboring wild type p53. Mechanistic studies show that 2 and 22 dose-dependently activated p53 and its target genes and induced apoptosis in cells based on the Western blot, qPCR, and flow cytometry assays. In addition, the antiproliferative activities of 2 and 22 were dependent on wild type p53, while they were not toxic to HEK-293 kidney cells. Furthermore, the on-target activities of 2 were general and applicable to other cancer cell lines with wild type p53. These attributes make 2 a good candidate for future optimization to discover a potential treatment of wild-type p53 cancer.

Current Status of Novel Multifunctional Targeted Pt(IV) Compounds and Their Reductive Release Properties.

Platinum-based drugs are widely used in chemotherapy for various types of cancer and are considered crucial. Tetravalent platinum (Pt(IV)) compounds have gained significant attention and have been extensively researched among these drugs. Traditionally, Pt(IV) compounds are reduced to divalent platinum (Pt(II)) after entering cells, causing DNA lesions and exhibiting their anti-tumor effect. However, the available evidence indicates that some Pt(IV) derivatives may differ from the traditional mechanism and exert their anti-tumor effect through their overall structure. This review primarily focuses on the existing literature regarding targeted Pt(II) and Pt(IV) compounds, with a specific emphasis on their in vivo mode of action and the properties of reduction release in multifunctional Pt(IV) compounds. This review provides a comprehensive summary of the design and synthesis strategies employed for Pt(II) derivatives that selectively target various enzymes (glucose receptor, folate, telomerase, etc.) or substances (mitochondria, oleic acid, etc.). Furthermore, it thoroughly examines and summarizes the rational design, anti-tumor mechanism of action, and reductive release capacity of novel multifunctional Pt(IV) compounds, such as those targeting p53-MDM2, COX-2, lipid metabolism, dual drugs, and drug delivery systems. Finally, this review aims to provide theoretical support for the rational design and development of new targeted Pt(IV) compounds.

mRNA-Laden Lipid-Nanoparticle-Enabled in Situ CAR-Macrophage Engineering for the Eradication of Multidrug-Resistant Bacteria in a Sepsis Mouse Model.

Sepsis, which is the most severe clinical manifestation of acute infection and has a mortality rate higher than that of cancer, represents a significant global public health burden. Persistent methicillin-resistant Staphylococcus aureus (MRSA) infection and further host immune paralysis are the leading causes of sepsis-associated death, but limited clinical interventions that target sepsis have failed to effectively restore immune homeostasis to enable complete eradication of MRSA. To restimulate anti-MRSA innate immunity, we developed CRV peptide-modified lipid nanoparticles (CRV/LNP-RNAs) for transient in situ programming of macrophages (MΦs). The CRV/LNP-RNAs enabled the delivery of MRSA-targeted chimeric antigen receptor (CAR) mRNA (SasA-CAR mRNA) and CASP11 (a key MRSA intracellular evasion target) siRNA to MΦs in situ, yielding CAR-MΦs with boosted bactericidal potency. Specifically, our results demonstrated that the engineered MΦs could efficiently phagocytose and digest MRSA intracellularly, preventing immune evasion by the "superbug" MRSA. Our findings highlight the potential of nanoparticle-enabled in vivo generation of CAR-MΦs as a therapeutic platform for multidrug-resistant (MDR) bacterial infections and should be confirmed in clinical trials.

Intracavitary Spraying of Nanoregulator-Encased Hydrogel Modulates Cholesterol Metabolism of Glioma-Supportive Macrophage for Postoperative Glioblastoma Immunotherapy.

Glioblastoma multiforme (GBM) is notoriously resistant to immunotherapy due to its intricate immunosuppressive tumor microenvironment (TME). Dysregulated cholesterol metabolism is implicated in the TME and promotes tumor progression. Here, it is found that cholesterol levels in GBM tissues are abnormally high, and glioma-supportive macrophages (GSMs), an essential "cholesterol factory", demonstrate aberrantly hyperactive cholesterol metabolism and efflux, providing cholesterol to fuel GBM growth and induce CD8+ T cells exhaustion. Bioinformatics analysis confirms that high 7-dehydrocholesterol reductase (DHCR7) level in GBM tissues associates with increased cholesterol biosynthesis, suppressed tumoricidal immune response, and poor patient survival, and DHCR7 expression level is significantly elevated in GSMs. Therefore, an intracavitary sprayable nanoregulator (NR)-encased hydrogel system to modulate cholesterol metabolism of GSMs is reported. The degradable NR-mediated ablation of DHCR7 in GSMs effectively suppresses cholesterol supply and activates T-cell immunity. Moreover, the combination of Toll-like receptor 7/8 (TLR7/8) agonists significantly promotes GSM polarization to antitumor phenotypes and ameliorates the TME. Treatment with the hybrid system exhibits superior antitumor effects in the orthotopic GBM model and postsurgical recurrence model. Altogether, the findings unravel the role of GSMs DHCR7/cholesterol signaling in the regulation of TME, presenting a potential treatment strategy that warrants further clinical trials.

Synthesis and Biological Evaluation of Sclareolide-Indole Conjugates and Their Derivatives.

Sclareolide is a sesquiterpene lactone isolated from various plant sources in tons every year and is commercially used as a flavor ingredient in the cosmetic and food industries. Antitumor and antiviral activities of sclareolide have been previously reported. However, biological studies of sclareolide synthetic analogous are few. In view of these, we developed a robust synthetic method that allows the assembly of 36 novel sclareolide-indole conjugates and their derivatives. The synthetic method was based on TiCl4-promoted nucleophilic substitution of sclareolide-derived hemiacetal 4, while electron-rich aryles including indoles, polyphenol ethers, and pyrazolo [1,5-a]pyridine were good substrates. The stereochemistry of the final products was confirmed by single-crystal X-ray diffraction analysis, while the antiproliferative activities of selected final products were tested in K562 and MV4-11 cancer cell lines. Cytometric flow analysis shows that lead compounds 8k- and 10-induced robust apoptosis in MV4-11 cancer cells, while they exhibited weak impact on cell cycle progression. Taken together, our study suggests that sclareolide could be a good template and substrate for the synthesis of novel antiproliferative compounds.

Clinical cancer immunotherapy: Current progress and prospects.

Immune checkpoint therapy via PD-1 antibodies has shown exciting clinical value and robust therapeutic potential in clinical practice. It can significantly improve progression-free survival and overall survival. Following surgery, radiotherapy, chemotherapy, and targeted therapy, cancer treatment has now entered the age of immunotherapy. Although cancer immunotherapy has shown remarkable efficacy, it also suffers from limitations such as irAEs, cytokine storm, low response rate, etc. In this review, we discuss the basic classification, research progress, and limitations of cancer immunotherapy. Besides, by combining cancer immunotherapy resistance mechanism with analysis of combination therapy, we give our insights into the development of new anticancer immunotherapy strategies.

Aerosol Iron Solubility Specification in the Global Marine Atmosphere with Machine Learning.

Aerosol iron (Fe) solubility is a key factor for the assessment of atmospheric nutrients input to the ocean but poorly specified in models because the mechanism of determining the solubility is unclear. We develop a deep learning model to project the solubility based on the data that we observed in a coastal city of China. The model has five variables: the size range of particles, relative humidity, and the ratios of sulfate, nitrate and oxalate to total Fe (TFe) contents in aerosol particles. Results show excellent statistical agreements with the solubility in the literature over most worldwide seas and margin areas with the Pearson correlation coefficients (r) as large as 0.73-0.97. The exception is the Atlantic Ocean, where good agreement is obtained with the model trained using local data (r: 0.34-0.66). The model further uncovers that the ratio of oxalate/TFe is the most important variable influencing the solubility. These results indicate the feasibility of treating the solubility as a function of the six factors in deep learning models with careful training and validation. Our model and projected solubility provide innovative options for better quantification of air-to-sea input of aerosol soluble Fe in observational and model studies in the global marine atmosphere.

A chemical perspective on the modulation of TEAD transcriptional activities: Recent progress, challenges, and opportunities.

TEADs are transcription factors and core downstream components of the Hippo pathway. Mutations of the Hippo pathway and/or dysregulation of YAP/TAZ culminate in aberrant transcriptional activities of TEADs, which were considered as key contributing factors of mesotheliomas, fibrotic diseases, Alzheimer's diseases, Huntington's diseases, suppressive immune response, and drug resistance, among others. To modulate transcriptional activities of TEADs, several pharmacological approaches have been pursued, including TEAD/YAP protein-protein interaction inhibitors, TEAD PBP inhibitors, and TEAD activators. As summarized in this review, a large number of inhibitors and activators of TEADs have been reported with decent in vitro potencies, a few exerted robust and compelling in vivo efficacies, and three that are undergoing clinical trials for the treatment of human cancers. Despite clinical advancement of the TEAD PBP inhibitors, development of other types TEAD inhibitors and activators generally lags behind. Information showcased herein might benefit discovery of next generation TEAD modulators for treatment of human oncological diseases and beyond.

Haze Occurrence Caused by High Gas-to-Particle Conversion in Moisture Air under Low Pollutant Emission in a Megacity of China.

Haze occurred in Zhengzhou, a megacity in the northern China, with the PM2.5 as high as 254 µg m-3 on 25 December 2019, despite the emergency response measure of restriction on the emission of anthropogenic pollutants which was implemented on December 19 for suppressing local air pollution. Air pollutant concentrations, chemical compositions, and the origins of particulate matter with aerodynamic diameter smaller than 2.5 µm (PM2.5) between 5-26 December were investigated to explore the reasons for the haze occurrence. Results show that the haze was caused by efficient SO2-to-suflate and NOx-to-nitrate conversions under high relative humidity (RH) condition. In comparison with the period before the restriction (5-18 December) when the PM2.5 was low, the concentration of PM2.5 during the haze (19-26 December) was 173 µg m-3 on average with 51% contributed by sulfate (31 µg m-3) and nitrate (57 µg m-3). The conversions of SO2-to-sulfate and NOx-to-nitrate efficiently produced sulfate and nitrate although the concentration of the two precursor gases SO2 and NOx was low. The high RH, which was more than 70% and the consequence of artificial water-vapor spreading in the urban air for reducing air pollutants, was the key factor causing the conversion rates to be enlarged in the constriction period. In addition, the last 48 h movement of the air parcels on 19-26 December was stagnant, and the air mass was from surrounding areas within 200 km, indicating weather conditions favoring the accumulation of locally-originated pollutants. Although emergency response measures were implemented, high gas-to-particle conversions in stagnant and moisture circumstances can still cause severe haze in urban air. Since the artificial water-vapor spreading in the urban air was one of the reasons for the high RH, it is likely that the spreading had unexpected side effects in some certain circumstances and needs to be taken into consideration in future studies.

Radiomics for Predicting Response of Neoadjuvant Chemotherapy in Nasopharyngeal Carcinoma: A Systematic Review and Meta-Analysis.

Purpose: This study examined the methodological quality of radiomics to predict the effectiveness of neoadjuvant chemotherapy in nasopharyngeal carcinoma (NPC). We performed a meta-analysis of radiomics studies evaluating the bias risk and treatment response estimation. Methods: Our study was conducted through a literature review as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We included radiomics-related papers, published prior to January 31, 2022, in our analysis to examine the effectiveness of neoadjuvant chemotherapy in NPC. The methodological quality was assessed using the radiomics quality score. The intra-class correlation coefficient (ICC) was employed to evaluate inter-reader reproducibility. The pooled area under the curve (AUC), pooled sensitivity, and pooled specificity were used to assess the ability of radiomics to predict response to neoadjuvant chemotherapy in NPC. Lastly, the Quality Assessment of Diagnostic Accuracy Studies technique was used to analyze the bias risk. Results: A total of 12 studies were eligible for our systematic review, and 6 papers were included in our meta-analysis. The radiomics quality score was set from 7 to 21 (maximum score: 36). There was satisfactory ICC (ICC = 0.987, 95% CI: 0.957-0.996). The pooled sensitivity and specificity were 0.88 (95% CI: 0.71-0.95) and 0.82 (95% CI: 0.68-0.91), respectively. The overall AUC was 0.91 (95% CI: 0.88-0.93). Conclusion: Prediction response of neoadjuvant chemotherapy in NPC using machine learning and radiomics is beneficial in improving standardization and methodological quality before applying it to clinical practice.

Rapid establishment of murine gastrointestinal organoids using mechanical isolation method.

Gastrointestinal (GI) diseases, including pathological dysplasia, inflammation, neoplasia and injury, suffer millions of patients globally per year. Organoids, three-dimensional cell mass structures supported by biomaterials in dishes, are currently used as a research model for diseases of the small intestine. However, the traditional enzymatic-digestion method for establishing small-intestinal organoids (EnzyOs) is time consuming and often loses the bulk of crypts, a more efficient and reliable method needs to be developed. In this study, using mouse GI organoids as a model, we formulated a rapid mechanical isolation method that could efficiently isolate and culture villi-crypts into small intestinal organoids (MechOs). Primary duodenum organoids generated by MechOs displayed three types of morphology: spheroid, semi-budding and budding, while EnzyOs produced much less budding. Moreover, primary duodenum organoids from MechOs could be subcultured and presented similar gene expression profiles of small intestine specific markers as that from EnzyOs. Importantly, the MechOs method could also be used to generate other types of organoids derived from the stomach, jejunum-ileum, sigmoid-rectum and bile cysts. Taken together, the results show that MechOs could efficiently and economically generate digestive system organoids, providing a potential basis of epithelial organoids for the clinical treatment of gastroenterological diseases.

Structure-Based Discovery of MDM2/4 Dual Inhibitors that Exert Antitumor Activities against MDM4-Overexpressing Cancer Cells.

Despite recent clinical progress in peptide-based dual inhibitors of MDM2/4, small-molecule ones with robust antitumor activities remain challenging. To tackle this issue, 31 (YL93) was structure-based designed and synthesized, which had MDM2/4 binding Ki values of 1.1 and 642 nM, respectively. In three MDM4-overexpressing cancer cell lines harboring wild-type p53, 31 shows improved cell growth inhibition activities compared to RG7388, an MDM2-selective inhibitor in late-stage clinical trials. Mechanistic studies show that 31 increased cellular protein levels of p53 and p21 and upregulated the expression of p53-targeted genes in RKO cells with MDM4 amplification. In addition, 31 induced cell-cycle arrest and apoptosis in western blot and flow cytometry assays. Taken together, dual inhibition of MDM2/4 by 31 elicited stronger antitumor activities in vitro compared to selective MDM2 inhibitors in wild-type p53 and MDM4-overexpressing cancer cells.

Proteomic Profiling Identifies Kaposi's Sarcoma-Associated Herpesvirus (KSHV)-Encoded LANASIM-Associated Proteins in Hypoxia.

Hypoxia signaling is a key regulator in the development and progression of many types of human malignancies, including viral cancers. The latency-associated nuclear antigen (LANA), encoded by Kaposi's sarcoma-associated herpesvirus (KSHV) during latency, is a multifunctional protein that plays an essential role in viral episome maintenance and lytic gene silencing for inducing tumorigenesis. Although our previous studies have shown that LANA contains a SUMO-interacting motif (LANASIM), and hypoxia reduces SUMOylated KAP1 association with LANASIM, the physiological proteomic network of LANASIM-associated cellular proteins in response to hypoxia is still unclear. In this study, we individually established cell lines stably expressing wild-type LANA (LANAWT) and its SIM-deleted mutant (LANAdSIM) and treated them with or without hypoxia, followed by coimmunoprecipitation and mass spectrometry analysis to systemically identify the hypoxia-responsive profile of LANASIM-associated cellular proteins. We found that in hypoxia, the number of cellular proteins associated with LANAWT instead of LANAdSIM was dramatically increased. Functional network analysis revealed that two major pathways, which included cytoskeleton organization and DNA/RNA binding and processing pathways, were significantly enriched for 28 LANASIM-associated proteins in response to hypoxia. HNRNPU was one of the proteins consistently identified that interacted with LANASIM in different proteomic screening systems and responded to hypoxia. This study provides a proteomic profile of LANASIM-associated proteins in hypoxia and facilitates our understanding of the role of the collaboration between viral infection and the hypoxia response in inducing viral persistence and tumorigenesis. IMPORTANCE Kaposi's sarcoma-associated herpesvirus (KSHV) has been reported to be involved in the regulation of host proteins in response to hypoxic stress. LANA, one of the key latent proteins, contains a SUMO-interacting motif (LANASIM) and reduces the association with SUMOylated KAP1 upon hypoxic treatment. However, the physiological systematic network of LANASIM-associated cellular proteins in hypoxia is still unclear. Here, we revealed two major pathways, which included cytoskeleton organization and DNA/RNA binding and processing pathways, that were significantly enriched for 28 LANASIM-associated proteins in hypoxia. This discovery not only provides a proteomic profile of LANASIM-associated proteins in hypoxia but also facilitates our understanding of the collaboration between viral infection and hypoxic stress in inducing viral persistence and tumorigenesis.

Structural determination and in vitro tumor cytotoxicity evaluation of five new cycloartane glycosides from Asplenium ruprechtii Sa. Kurata.

Five new cycloartane glycosides, named aspleniumside A - E, were discovered and characterized by re-investigated the remaining extracts of the whole plant of Asplenium ruprechtii Sa. Kurata, a famous folk medicine for treating thromboangitis obliterans in China, Japan, and Korea. Compounds 3-5 possessed the 9,19-seco-cycloartane-9,11-en triterpene aglycone with 3,7(or 23),24,25,30-highly oxidized methylene, methylene or quaternary carbons, that was found in this species for the first time. The stereo-chemistry of all new compounds were fully discussed by extensive analysis of the 1D and 2D NMR data, and comparisons with those data of known compounds. 24R configuration was determined here which indicated the different growing areas of the same species could influence the secondary metabolic behavior, leading to the differences in chemical composition. All glycoside groups were determined as ß-d-glucopyranosyl by 1H coupling constant of anomeric protons and co-TLC of the acid hydrolysate with d-glucose. All the cycloartane glycosides were evaluated against HL-60 and HepG2 cells for cytotoxicity, compounds 1-3, showed potential cytotoxicity with the IC50 in range of 18-60 µM, while the standard sorafenib showed IC50 value of 10.61 ± 0.43 and 13.43 ± 1.12 µM against HL-60 and HepG2, respectively. The results attained in this study indicated that cycloartane glycosides should be the cytotoxicity substance in A. ruprechtii Sa. Kurata, and had the potential to be developed as tumor cytotoxicity agent applied in clinic.

Particle-induced oxidative damage by indoor size-segregated particulate matter from coal-burning homes in the Xuanwei lung cancer epidemic area, Yunnan Province, China.

Size-segregated samples of airborne particulate matter were collected at the coal-burning homes of the Hutou high lung cancer epidemic village and a comparison site Xize village of the Xuanwei County, Yuanan Province, by an Anderson Cascade Impact Sampler in winter and spring to study the toxicological characteristics of different-sized particles. The DNA damage caused by the water-soluble fractions of these size-segregated particles was analyzed by the plasmid scission assay, and the trace element compositions were determined by Inductively Coupled Plasma Mass Spectrometry. The DNA damage rate from the airborne particles in the high lung cancer incidence area was higher than that in Xize village. The different-sized particles have highly varying DNA damage rates, with the values being greater in the small size range than in the large size range. The particle-induced DNA damage rates had a significantly positive correlation with total water-soluble trace elements. Further analysis of the individual elements indicated that the water-soluble heavy metals Zn, Cu, Cd, Rb, Cs, and Sb had a positive correlation with the particle-induced DNA damage, implying that these water-soluble heavy metals played an important role in the DNA damage. The Sr had a negative correlation with the particle-induced DNA damage, suggesting that the water-soluble Sr might counter DNA damage. The mass concentrations of the total and individual water-soluble trace elements were mostly enriched in the small particle size ranges, thus implying the indoor airborne particles in the small size ranges would have a higher health risk.

Soluble Fe release from iron-bearing clay mineral particles in acid environment and their oxidative potential.

Soluble iron from atmospheric aerosol particles has toxicological effects on ambient environment due to their oxidative potential. However, the dissolution process and factors affecting this process are poorly understood. In this study, by solid phase characterization and aqueous dissolution experiments, we investigated the influence of acids, including HCl, H2SO4 and HNO3, and H+ concentration on iron dissolution rate, solubility and speciation of iron in chlorite, illite, kaolinite and pyrite. The dissolution of iron-bearing clay minerals, i.e. chlorite, illite and kaolinite, was a multi-stage process with a rapid rate in the initial stage and then decreasing rate in the following stages. In contrast, the regularly crystallized pyrite proceeded with an extremely rapid dissolution rate at very beginning and then remained almost constant. In all acid solutions, the dissolution rate was in the order of pyrite > illite > chlorite > kaolinite. H2SO4 was stronger than HCl and HNO3 in the destruction of mineral structures to release iron, while HNO3 dissolved more iron in pyrite (FeS2). High H+ concentration easily destroyed the mineral structures to release the structural or interlayer iron, whereas low H+ concentration increased the proportion of Fe (II) in clay minerals. Non-linear fitting of continuous dissolution models showed that the iron dissolution rates and iron redox speciation as functions of time were well predicted, with r2 > 0.99 for chlorite and illite, and r2 > 0.96 for kaolinite. Oxidative potential analysis proved that the dissolved iron possessed a considerable potential to generate reactive oxygen species.

Evidence for immortality and autonomy in animal cancer models is often not provided, which causes confusion on key issues of cancer biology.

Modern research into carcinogenesis has undergone three phases. Surgeons and pathologists started the first phase roughly 250 years ago, establishing morphological traits of tumors for pathologic diagnosis, and setting immortality and autonomy as indispensable criteria for neoplasms. A century ago, medical doctors, biologists and chemists started to enhance "experimental cancer research" by establishing many animal models of chemical-induced carcinogenesis for studies of cellular mechanisms. In this second phase, the two-hit theory and stepwise carcinogenesis of "initiation-promotion" or "initiation-promotion-progression" were established, with an illustrious finding that outgrowths induced in animals depend on the inducers, and thus are not authentically neoplastic, until late stages. The last 40 years are the third incarnation, molecular biologists have gradually dominated the carcinogenesis research fraternity and have established numerous genetically-modified animal models of carcinogenesis. However, evidence has not been provided for immortality and autonomy of the lesions from most of these models. Probably, many lesions had already been collected from animals for analyses of molecular mechanisms of "cancer" before the lesions became autonomous. We herein review the monumental work of many predecessors to reinforce that evidence for immortality and autonomy is essential for confirming a neoplastic nature. We extrapolate that immortality and autonomy are established early during sporadic human carcinogenesis, unlike the late establishment in most animal models. It is imperative to resume many forerunners' work by determining the genetic bases for initiation, promotion and progression, the genetic bases for immortality and autonomy, and which animal models are, in fact, good for identifying such genetic bases.

An anti-inflammatory C-stiryl iridoid from Camptosorus sibiricus Rupr.

A new iridoid glycoside, named camptoside (1), together with three known compounds as dehydrodiconiferyl alcohol-9'-O-ß-d-glucopyranoside (2), aesculetin (3) and vajicoside (4), have been isolated from Camptosorus sibiricus Rupr. (Aspleniaceae). Their structures were established on the basis of spectroscopic analysis, especially 1D- and 2D-NMR data, and by comparison of their spectroscopic and physical data with those reported in the literature. Compounds 1-3 exhibited inhibitions of nitric oxide production in lipopolysaccharide-induced RAW 264.7 macrophages with IC50 values of 11.2, 8.3 and 9.4 µM, respectively.

Determination of S-Allylmercaptocysteine in Rat Plasma by LC-MS/MS and its Application to a Pharmacokinetics Study.

In this work, a rapid, simple, sensitive and specific LC-MS/MS method was developed and validated for the quantification of S-Allylmercaptocysteine (SAMC) in plasma. After a simple sample procedure by one step protein precipitation with acetontrile, the samples were separated on Gemini-NX C18 column (2.1 mm i.d. 150 mm, 3 µm, Phenomenex). The mobile phase was composed of water-acetonitrile (20:80, v/v) at an isocratic flow rate of 0.3 mL/min. The developed method was validated based on the International Conference on Harmonization (ICH) guidelines. The results show that the method had satisfactory specificity, precision and accuracy in a linear range of 50-3,000 ng/mL for SAMC. The precision conformed to the acceptance criteria, and the lower limit of quantification was 50 ng/mL for the analyte. The plasma samples stored for 10 days or after two freeze-thaw cycles (-80°C) were stable. This method was successfully applied to a pharmacokinetics study of SAMC in rats. It was found that SAMC metabolized very quickly in rats and its plasma half-life was less than 5 min.

Air pollution-aerosol interactions produce more bioavailable iron for ocean ecosystems.

It has long been hypothesized that acids formed from anthropogenic pollutants and natural emissions dissolve iron (Fe) in airborne particles, enhancing the supply of bioavailable Fe to the oceans. However, field observations have yet to provide indisputable evidence to confirm this hypothesis. Single-particle chemical analysis for hundreds of individual atmospheric particles collected over the East China Sea shows that Fe-rich particles from coal combustion and steel industries were coated with thick layers of sulfate after 1 to 2 days of atmospheric residence. The Fe in aged particles was present as a "hotspot" of (insoluble) iron oxides and throughout the acidic sulfate coating in the form of (soluble) Fe sulfate, which increases with degree of aging (thickness of coating). This provides the "smoking gun" for acid iron dissolution, because iron sulfate was not detected in the freshly emitted particles and there is no other source or mechanism of iron sulfate formation in the atmosphere.