Comparative analysis of immunological changes following realgar and arsenic trioxide treatments in a murine model of myelodysplastic syndrome.

BACKGROUND: Myelodysplastic syndrome (MDS) is a prevalent hematological neoplastic disorder in clinics and its immunopathogenesis has garnered growing interest. Oral and intravenous arsenic agents have long been used to treat hematological malignancies. The main component of oral arsenic is realgar (arsenic disulfide), while arsenic trioxide is the main component of intravenous arsenic. METHODS: This study aimed to assess the effects of ATO and Realgar on the enhancement of peripheral blood, drug safety, and T cell immune status in the NUP98-HOXD13 (NHD13) mice model of MDS, specifically in the peripheral blood, spleen, and liver. RESULTS: The study findings indicate that realgar and arsenic trioxide (ATO) can improve peripheral hemogram in mice, whereas realgar promotes higher peripheral blood cell production than ATO. Furthermore, the clinical administration method and dose did not cause significant toxicity or side effects and thus can be considered safe. Coexistence and interconversion of hyperimmune function and immunosuppression in mice were also observed in this study. In addition, there were interactions between immune cells in the peripheral blood, spleen, and liver to regulate the immune balance of the body and activate immunity via T-cell activation. CONCLUSION: In summary, oral and intravenous arsenic agents are beneficial in improving peripheral hemogram and immunity in mice.

Determination of Cuproptosis-related Subtypes, Development of a Prognostic Model, and Characterization of Tumor Microenvironment Infiltration in Acute Myeloid Leukemia.

BACKGROUND/AIM: Acute myeloid leukemia (AML) is a severe malignancy of the bone marrow marked by an abnormal accumulation of bone marrow precursors. Cuproptosis is a recently identified type of copper-dependent regulatory cell apoptosis that relies on mitochondrial respiration. However, its participation in the development of AML remains unclear. This study analyzed the association between cuproptosis-related genes and the prognosis of AML patients. MATERIALS AND METHODS: Cases of AML were acquired from TCGA, GEO, and TARGET and the molecular subgroups characterized by genes associated with cuproptosis, besides the associated cell infiltration of the tumor microenvironment (TME) were investigated. The cuproptosis score was developed using the minor absolute shrinkage and selection operator (LASSO) tool to evaluate the cuproptosis features of a single tumor sample. RESULTS: Two distinct molecular subgroups related to cuproptosis were discovered in AML with different prognoses. The cellular infiltration assay of TME showed immunological heterogeneity between the two subtypes. The cuproptosis score predicted tumor subgroups, immunity, and prognosis. A small cuproptosis value was marked by a good prognosis, whereas the anti-PD-1/PD-L1 immunotherapy group suggested the same cuproptosis group was related to an elevated immunotherapy potency. CONCLUSION: The cuproptosis score is a biomarker important for determining the molecular subgroups, prognosis, TME cell infiltration features, and immunotherapeutic efficacy of individuals with leukemia.

Exploring underlying mechanism of artesunate in treatment of acute myeloid leukemia using network pharmacology and molecular docking

Background Acute myeloid leukemia (AML) is a highly heterogeneous hematological cancer. The current diagnosis and therapy model of AML has gradually shifted to personalization and accuracy. Artesunate, a member of the artemisinin family, has anti-tumor impacts on AML. This research uses network pharmacology and molecular docking to anticipate artesunate potential mechanisms of action in the therapy of AML. Methods Screening the action targets of artesunate through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), PubChem, and Swiss Target Prediction databases; The databases of Online Mendelian Inheritance in Man (OMIM), Disgenet, GeneCards, and Drugbank were utilized to identify target genes of AML, and an effective target of artesunate for AML treatment was obtained through cross-analysis. Protein–protein interaction (PPI) networks are built on the Cytoscape platform. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted on the relevant targets using R software. Finally, using molecular docking technology and Pymol, we performed verification of the effects of active components and essential targets. Results Artesunate 30 effective targets for treating AML include CASP3, EGFR, MAPK1, and STAT3, four targeted genes that may have a crucial function in disease management. The virus infection-related pathway (HeptatisB (HBV), Human papillomavirus (HPV), Epstein-Barr virus (EBV) infection and etc.), FoxO, viral carcinogenesis, and proteoglycans in cancer signaling pathways have all been hypothesized to be involved in the action mechanism of GO, which is enriched in 2044 biological processes, 125 molecular functions, 209 cellular components, and 106 KEGG pathways (AU)

Exploring underlying mechanism of artesunate in treatment of acute myeloid leukemia using network pharmacology and molecular docking.

BACKGROUND: Acute myeloid leukemia (AML) is a highly heterogeneous hematological cancer. The current diagnosis and therapy model of AML has gradually shifted to personalization and accuracy. Artesunate, a member of the artemisinin family, has anti-tumor impacts on AML. This research uses network pharmacology and molecular docking to anticipate artesunate potential mechanisms of action in the therapy of AML. METHODS: Screening the action targets of artesunate through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), PubChem, and Swiss Target Prediction databases; The databases of Online Mendelian Inheritance in Man (OMIM), Disgenet, GeneCards, and Drugbank were utilized to identify target genes of AML, and an effective target of artesunate for AML treatment was obtained through cross-analysis. Protein-protein interaction (PPI) networks are built on the Cytoscape platform. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted on the relevant targets using R software. Finally, using molecular docking technology and Pymol, we performed verification of the effects of active components and essential targets. RESULTS: Artesunate 30 effective targets for treating AML include CASP3, EGFR, MAPK1, and STAT3, four targeted genes that may have a crucial function in disease management. The virus infection-related pathway (HeptatisB (HBV), Human papillomavirus (HPV), Epstein-Barr virus (EBV) infection and etc.), FoxO, viral carcinogenesis, and proteoglycans in cancer signaling pathways have all been hypothesized to be involved in the action mechanism of GO, which is enriched in 2044 biological processes, 125 molecular functions, 209 cellular components, and 106 KEGG pathways. Molecular docking findings revealed that artesunate was critically important in the therapy of AML due to its high affinity for the four primary disease targets. Molecular docking with a low binding energy yields helpful information for developing medicines against AML. CONCLUSIONS: Consequently, artesunate may play a role in multi-targeted, multi-signaling pathways in treating AML, suggesting that artesunate may have therapeutic potential for AML.

Anthropocene microplastic stratigraphy of Xiamen Bay, China: A history of plastic production and waste management.

Microplastics (MPs) are considered one of the significant stratigraphic markers of the onset of the Anthropocene Epoch; however, the interconnections between historic plastic production, waste management as well as social-economic and timing of MP accumulation are not well understood. Here, stratigraphic data of MPs from a sediment core from Xiamen Bay, China, was used to reconstruct the history of plastic pollution. Generalized Additive Modeling indicates a complex temporal evolution of MP accumulation. The oldest MPs deposited in 1952 was 30,332 ± 31,457 items/kg•dw, coincide with the infancy of the plastic industry and onset of the Anthropocene. The Cultural Revolution (1966-1976) curtailed these initial increases. Subsequent rapid growth in MPs during the late 1970s was peaked at 189,241 ± 29,495 items/kg•dw in 1988 and was followed by a drastic decline in the late 1980s to a low value in 1996 (16,626 ± 26,371 items/kg•dw), coinciding with proliferation of MP sources, coupled with evolution of plastic production, consumption, and regulation. Increasing MPs over the past decades implies that previous mitigation measures have been compromised by the escalated influx of MPs from increasing plastics production, legacy MPs remaining in circulation and insufficient waste management for a growing population. The present methodology and results represent a conceptual advance in understanding how changes in policy and economics over time correlate to changes in MP records in Anthropocene strata, which may help make decisions on plastic pollution mitigation strategies worldwide.

Biofunctionalized graphene oxide nanosheet for amplifying antitumor therapy: Multimodal high drug encapsulation, prolonged hyperthermal window, and deep-site burst drug release.

Biofunctional surface-modification surpassed critical limitation of graphene oxide (GO) in biocompatibility and drug delivery efficiency, contributing to versatile biomedical applications. Here, a protein corona-bridged GO nanoplatform with high drug loading, longstanding hyperthermia, and controllable drug release, was engineered for amplified tumor therapeutic benefits. Structurally, GO surface was installed with phenylboronic acid (PBA) layer, on which iRGD conjugated apolipoprotein A-I (iRGD-apoA-I) was coordinated via boron electron-deficiency, to form the sandwich-like GO nanosheet (iAPG). The GO camouflaging by iRGD-apoA-I corona provided multimodal high doxorubicin (DOX) loading by π-π stacking and coordination, and generated a higher photothermal transformation efficiency simultaneously. In vitro studies demonstrated that iAPG significantly improved drug penetration and internalization, then achieved tumor-targeted DOX release through near-infrared (NIR) controlled endo/lysosome disruption. Moreover, iAPG mediated site-specific drug shuttling to produce a 3.53-fold enhancement of tumor drug-accumulation compared to the free DOX in vivo, and induced deep tumor penetration dramatically. Primary tumor ablation and spontaneous metastasis inhibition were further demonstrated with negligible side effects under optimal NIR. Taken together, our work provided multifunctional protein corona strategy to inorganic nanomaterials toward advantageous biomedical applications.

South China Sea documents the transition from wide continental rift to continental break up.

During extension, the continental lithosphere thins and breaks up, forming either wide or narrow rifts depending on the thermo-mechanical state of the extending lithosphere. Wide continental rifts, which can reach 1,000 km across, have been extensively studied in the North American Cordillera and in the Aegean domain. Yet, the evolutionary process from wide continental rift to continental breakup remains enigmatic due to the lack of seismically resolvable data on the distal passive margin and an absence of onshore natural exposures. Here, we show that Eocene extension across the northern margin of the South China Sea records the transition between a wide continental rift and highly extended (<15 km) continental margin. On the basis of high-resolution seismic data, we document the presence of dome structures, a corrugated and grooved detachment fault, and subdetachment deformation involving crustal-scale nappe folds and magmatic intrusions, which are coeval with supradetachment basins. The thermal and mechanical weakening of this broad continental domain allowed for the formation of metamorphic core complexes, boudinage of the upper crust and exhumation of middle/lower crust through detachment faulting. The structural architecture of the northern South China Sea continental margin is strikingly similar to the broad continental rifts in the North American Cordillera and in the Aegean domain, and reflects the transition from wide rift to continental breakup.

Seafloor hydrothermal activity along mid-ocean ridge with strong melt supply: study from segment 27, southwest Indian ridge.

Continuous tow investigations have shown that the present vent field inventory along fast to intermediate spreading ridges may be underestimated by at least 3-6 times, while the limited towed line investigations of venting sites along slow to ultra-slow spreading ridges make it impossible to determine their distribution. The Chinese Dayang cruise has conducted detailed towed line surveys of hydrothermal activity on segment 27 of the ultra-slow spreading southwest Indian ridge in 2015. The results have identified as many as 9 hydrothermal fields along 85-km-long segment, including one confirmed hydrothermal field, three inferred hydrothermal fields and five suspected fields. Hydrothermal activities are not only limited along-axis but also found approximately 10 km away from the axis. These vent fields are likely powered by a seismically identified axial magma chamber, including melt migration along normal faults to flank areas. The calculated hydrothermal activity frequency on segment 27 is approximately 3.6-8 times higher than that calculated from the Interridge database, suggesting that careful system exploration can reveal more hydrothermal activities even on ultra-slow spreading ridges effected by hotspot.

Microplastic abundance, characteristics, and removal in wastewater treatment plants in a coastal city of China.

Studying the abundance, characteristics, and removal of microplastics (MPs) in wastewater treatment plants (WWTPs) in coastal cities is of great significance for understanding the impacts of human activities on the marine environment, but currently, little information on this topic is available in China. Therefore, the abundance, characteristics, and removal of MPs in seven WWTPs of Xiamen, a typical coastal city in China, are studied. Sixty samples were collected using an improved sampling method involving an electromagnetic flowmeter and a fast digital camera. The influent MPs concentration is 1.57-13.69 items/L, and it is reduced to 0.20-1.73 items/L in the effluent, indicating that 79.3-97.8% MPs is removed. Based on the daily effluent discharge and MPs removal rate, it is estimated that ∼6.5 × 108 MPs are released from the seven WWTPs into the Xiamen Bay each day. The light microscopic and micro-Raman spectroscopic analysis indicates that ∼62.68% of particles are plastic polymers, including polypropylene (31.6%), polyethylene (21.9%), polystyrene (10.1%), propylene/ethylene copolymer (9.2%), and polyethylene terephthalate (7.5%). The color of MPs is mainly composed of white (27.3%) and clears (25.8%). Our results show that granules (41.1%) are the dominant shape of MPs, followed by fragments (31.3%), fibers (23.7%), and pellet (3.9%). The characteristics of MPs such as sizes, shapes, and types affect the MPs removal in WWTPs. Our findings show that MPs concentration in the influent is positively correlated with the suspended solids (SS), however, in the effluent, it is associated with the WWTPs operating load, as reflected by obviously higher MP abundance in overloaded ones.

Effects of arsenic disulfide on apoptosis, histone acetylation, toll like receptor 2 activation, and erythropoiesis in bone marrow mononuclear cells of myelodysplastic syndromes patients in vitro.

OBJECTIVE: As the main component of traditional Chinese medicine realgar, arsenic disulfide (As2S2) is widely used in treating myelodysplastic syndromes (MDS). The goal of the current study is to assess the effects of As2S2 on bone marrow mononuclear cells (BMMNC) of MDS. METHODS: BMMNCs were obtained from 10 lower risk MDS patients, 5 higher risk MDS patients, and 3 healthy controls. Then, the cells were treated with As2S2 for 48h, using vorinostat (also known as SAHA) as control. Cell proliferation and apoptosis were detected. mRNA and protein levels of histone deacetylase-1 (HDAC1), Toll-like receptor 2 (TLR2), and erythroid transcription factor (GATA-1) were detected by quantitative real-time PCR and western blot analysis. RESULTS: After As2S2 treatment in concentrations ranging from 3.125 to 100µmol/L, cell proliferation was inhibited in both lower risk and higher risk MDS. Fifty percent inhibitory concentrations were 24.4µmol/L and 23.6µmol/L, respectively, for lower and higher risk MDS. Apoptotic cells significantly increased in both types of MDS. mRNA and protein levels of HDAC1 and TLR2 were reduced, whereas GATA-1 was increased in both types of MDS. CONCLUSIONS: As2S2 could inhibit cell proliferation and induce apoptosis through histone acetylation modulation in MDS. Similar to SAHA, As2S2 could reduce TLR2 activation and increase GATA-1 expression. Current data suggest epigenetic and immunological alternations are involved in therapeutic mechanisms of realgar in the treatment of MDS.