Tea polyphenol-derived nanomedicine for targeted photothermal thrombolysis and inflammation suppression.

Thrombotic diseases impose a significant global health burden, and conventional drug-based thrombolytic therapies are encumbered by the risk of bleeding complications. In this study, we introduce a novel drug-free nanomedicine founded on tea polyphenols nanoparticles (TPNs), which exhibits multifaceted capabilities for localized photothermal thrombolysis. TPNs were synthesized through a one-pot process under mild conditions, deriving from the monomeric epigallocatechin-3-gallate (EGCG). Within this process, indocyanine green (ICG) was effectively encapsulated, exploiting multiple intermolecular interactions between EGCG and ICG. While both TPNs and ICG inherently possessed photothermal potential, their synergy significantly enhanced photothermal conversion and stability. Furthermore, the nanomedicine was functionalized with cRGD for targeted delivery to activated platelets within thrombus sites, eliciting robust thrombolysis upon laser irradiation across diverse thrombus types. Importantly, the nanomedicine's potent free radical scavenging abilities concurrently mitigated vascular inflammation, thus diminishing the risk of disease recurrence. In summary, this highly biocompatible multifunctional nanomaterial holds promise as a comprehensive approach that combines thrombolysis with anti-inflammatory actions, offering precision in thrombosis treatment.

Rare ocular toxicity induced by pertuzumab/QL1209 in healthy chinese subjects: case reports and whole-exome sequencing analysis.

Pertuzumab is a recombinant anti-HER2 humanized monoclonal antibody widely used for the adjuvant treatment of HER2-positive breast cancer. Its safety is well established with the most common adverse effects being diarrhea and rash. To our knowledge, severe pertuzumab-induced ocular adverse events have never been reported. Herein, we describe several cases of pertuzumab/QL1209 (pertuzumab biosimilar)-induced blurred vision in healthy Chinese male subjects after a single injection of 420 mg pertuzumab/QL1209. Persistent optic nerve damage and vision loss occurred in the most severe case even after ophthalmic treatment. We conducted whole-exome sequencing (WES) of DNA samples from 5 cases and 13 controls to analyze the potential genetic factors and identified some associated variants (rs80303690 in RBM24, rs117375173 in CASR, rs1805097 in IRS2, and rs1227049 in CDH23). Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and Gene Ontology (GO) terms gene enrichment analyses were carried out for differentially expressed genes clustered in the PI3K/AKT/mTOR and Ras/Raf/MAPK signaling pathways, which were exactly activated by HER2 phosphorylation. In summary, this is the first report describing the occurrence of ocular toxicity induced by pertuzumab in the Chinese population and exploring the possible genetic mechanisms. These findings could provide evidence for clinicians to raise concerns about the risk of ocular toxicity with the clinical use of pertuzumab.

A pharmacokinetic study to comparatively evaluate the bioequivalence and safety of a humanized recombinant monoclonal antibody targeting human epidermal growth factor receptor-2 with the reference Herceptin in healthy Chinese subjects.

PURPOSE: This study aimed to compare the safety, tolerability, pharmacokinetics (PK), and bioequivalence of a test humanized recombinant monoclonal antibody targeting human epidermal growth factor receptor-2 (HER-2) with the reference Herceptin®. MATERIALS AND METHODS: The trial consisted of two parts (part I and part II). Part I was an open-label, sequential-cohort dose-escalation study, where 16 healthy subjects were either intravenously infused with QLHER2 (test) at single doses escalating from 0.2 to 6 mg/kg (0.2, 1, 2, 4, and 6 mg/kg) or given 4 mg/kg Herceptin (reference) for evaluating the safety, tolerability, and PK of QLHER2. Part II was a randomized, double-blind, parallel-group study to evaluate the bioequivalence of QLHER2 and Herceptin in 60 subjects. RESULTS: Following a 1.5-h intravenous infusion of single ascending doses of QLHER2 (1, 2, 4, or 6 mg/kg) in part I, Cmax and Tmax were 19.43-120.01 µg/mL and 68.91-157.87 h, respectively. AUC0-t and CL were 1.91-34.21 h·µg/mL and 0.54-0.12 mL/h/kg, indicating lower clearance at higher doses, with a greater than proportional increase in AUC0-t and t1/2 of 68.91-157.87 h. In part II, serum concentrations were comparable between QLHER2 and Herceptin over a 70-day sampling period, and the QLHER2/Herceptin ratios of Cmax and AUC0-t were 105.90% [90% confidence interval (CI): 95.69%-117.26%] and 95.79% (90% CI: 87.74%-106.40%), respectively. CONCLUSION: The 90% CI value of Cmax and AUC0-t for QLHER2/Herceptin ratio ranged between 80.0%-125.00%, indicating that QLHER2 was bioequivalent to Herceptin. These results support further evaluation of QLHER2. Trial registration number: ChiCTR2000041577 and ChiCTR2100041802. Date of registration: 30th December, 2020 and 5th January 2021.

Circ-ITCH overexpression promoted cell proliferation and migration in Hirschsprung disease through miR-146b-5p/RET axis.

BACKGROUND: Hirschsprung disease (HSCR) is a congenital intestinal disease caused by the abnormal proliferation and migration of enteric nerve cells (ENCC). Research suggested critical roles for circular RNA (circRNA) itchy E3 ubiquitin protein ligase (ITCH) in gastrointestinal malignancies progression. However, the function of circ-ITCH in HSCR remains poorly defined. METHODS: The related genes expression in 30 HSCR patients and 30 controls without HSCR were detected using qRT-PCR. Cell proliferation was assessed by CCK-8 assay and EdU assay. Cell migration was detected with wound-healing assay and transwell assay. The interactions among circ-ITCH, miR-146b-5p, and RET were confirmed by Dual luciferase reporter assay. RESULTS: Circ-ITCH and RET expressions were downregulated in HSCR patients and cells, while the miR-146b-5p expression was upregulated. Circ-ITCH overexpression facilitated cell proliferation, migration, and activated MAPK pathway, which were reversed by circRNA-ITCH knockdown. Circ-ITCH negatively regulated miR-146b-5p expression. MiR-146b-5p overexpression abolished the promoting effects of circ-ITCH overexpression on cell proliferation and migration. MiR-146b-5p inhibited RET expression. RET overexpression eliminated the inhibitory effects of miR-146b-5p overexpression on cell proliferation and migration. CONCLUSION: Circ-ITCH overexpression facilitated cell proliferation and migration in HSCR by regulating miR-146b-5p/RET/MAPK axis. IMPACT: The expressions of Circ-ITCH and RET were markedly reduced in HSCR, while miR-146b-5p expression was increased in HSCR. Circ-ITCH overexpression enhanced the proliferative and migratory abilities of SH-SY5Y and 293T cells. Circ-ITCH negatively regulated miR-146b-5p expression.

Bioequivalence studies of inhaled indacaterol maleate in healthy Chinese volunteers under gastrointestinal non-blocking or blocking with concomitant charcoal administration.

BACKGROUND: Indacaterol is one of the long-acting beta2-adrenergic agonists, referred as first-line monotherapy for Chronic obstructive pulmonary disease since 2011. Generic products are encouraged to benefit the large COPD patients in China, in which can provide more choices association with reduced cost and improve the quality of patient life. OBJECTIVE: The three-part study consists of two independent cohorts of thirty-six subjects, aimed to evaluate the bioequivalence (BE) of two indacaterol formulations in gastrointestinal (GI) absorption charcoal-block or non-block conditions. One pilot study performed in six healthy subjects to determine the blocking effect of a new charcoal-based regimen on GI absorption after orally inhalation of indacaterol. METHODS: Two BE studies were conducted with a randomized, open-label, 2-period crossover design in two independent 36-healthy-subject cohorts, equivalence in systemic and lung deposition was assessed after inhalation of a single dose of 150 µg indacaterol (test or reference formulation) alone or concomitant administration of charcoal. The charcoal-based regimen was improved by optimizing the dose and number of doses, and its blocking efficacy against GI absorption was assessed in a pilot study. Six healthy subjects received 9 g charcoal 10 min before, immediately after and 2 h after indacaterol (3 g/100 ml water × 3 times). Blood collected at predetermined time points up to 72 h. Plasma indacaterol concentrations were determined using HPLC-MS/MS. Pharmacokinetics parameters were calculated with non-compartment analysis. Equivalences were concluded if the 90% confidence interval (CI) for test: reference of Cmax and AUC0-t fell within the limits of 0.8-1.25. RESULTS: Indacaterol was undetectable in plasma samples in pilot study. The T/R ratio of the geometric mean Cmax and AUC0-t was 109.9% (90% CI, 106.1-113.8%) and 104.8% (90% CI, 101.5-108.1%) for charcoal-block subjects and 105.4% (90% CI, 99.8% ~ 111.3%), and 101.0% (90% CI, 97.7%-104.4%) for non-block subjects. No serious adverse events were reported. CONCLUSIONS: The results showed that 150 µg indacaterol (+/- 9 g charcoal) was well tolerated in all subjects. The two formulations are bioequivalent in terms of the rate and absorption both in charcoal-block and non-block conditions. The improved charcoal-based regimen demonstrated to be effective and fully blockade of GI absorption of indacaterol.

Effect of postdose fasting duration on hetrombopag olamine pharmacokinetics and pharmacodynamics in healthy volunteers.

AIMS: Hetrombopag olamine is a novel small-molecule, nonpeptide thrombopoietin receptor agonist developed for immune thrombocytopenia treatment. This study aims to determine the safety and the effect of fasting duration after administration of hetrombopag on pharmacokinetics and pharmacodynamics in Chinese healthy subjects. METHODS: A randomized, open-label, single-dose, 3-period crossover, self-control trial was conducted. 15 eligible subjects were enrolled and received hetrombopag 7.5 mg at day 1 of each period followed by a standard meal 4 hours postdose (treatment A/fasting condition), or a high-calorie, high-fat meal 1 hour postdose (treatment B), or a high-calorie, high-fat meal 2 hours postdose (treatment C). The plasma concentrations of hetrombopag were determined by validated liquid chromatography-tandem mass spectrometry, platelet counts were quantified by blood test. Analysis was performed using a mixed model, including treatment, period as fixed effects and participant as a random effect. RESULTS: Compared with treatment A, peak concentration and area under concentration-time curve extrapolated to infinity decreased by 56 and 74.6%, and 44 and 61% in treatments B and C, respectively. The mean platelet number on day 6 increased by 15.8, 6.96 and 10.26%, respectively, in treatments A, B and C in comparison with baseline platelet level. No severe adverse events happened in any of the 3 treatments. CONCLUSION: Hetrombopag was well tolerated in healthy male subjects under fasted/fed conditions. The shorter fasting duration resulted in lower hetrombopag exposure, corresponding to a lower level of platelet elevation. Therefore, we recommended oral administration of hetrombopag on an empty stomach (fasting condition) or at least 2 hours before a meal to achieve maximum bioavailability.

Exploration of suitable pharmacodynamic parameters for acarbose bioequivalence evaluation: A series of clinical trials with branded acarbose.

AIMS: To determine deficiencies in the Food and Drug Administration (FDA)'s guidance for assessing acarbose bioequivalence (BE) and to explore optimal pharmacodynamic (PD) metrics for better evaluation of acarbose BE. METHODS: Three clinical trials with branded acarbose were conducted in healthy subjects, including a pilot study (Study I, n = 11, 50 and 100 mg), a 2×2 crossover BE study (Study II, n = 36, 100 mg) and a 4×4 Williams study (Study III, n = 16, 50/100/150 mg). Serum glucose concentrations were measured by the glucose oxidase method. RESULTS: In Study I, compared with 50 mg acarbose, only 100 mg acarbose had a significantly lower Cmax0-4h than that of sucrose administration alone (7.96 ± 0.83 mmol/L vs 6.78 ± 1.02 mmol/L, P < .05). In Study II, the geometric mean ratios of the test formulation to the reference formulation (both formulations were the branded drug) for FDA PD metrics, ΔCmax0-4h and ΔAUC0-4h , were 0.903 and 0.776, respectively, and the 90% confidence intervals were 67.44-120.90 and 53.65-112.13, respectively. The geometric mean ratios (confidence interval) for possible optimal evaluation PD metrics (Cmax0-2h and AUC0-2h ) were 1.035 (94.23-112.68) and 0.982 (89.28-107.17), respectively. Further, Cmax0-2h and AUC0-2h also met the sensitivity requirements for BE evaluation in Study III. CONCLUSION: Considering the mechanisms of action of acarbose, the PD effect was shown to be dose independent during the 2-4 hours postadministration of acarbose. Hence PD metrics based on the serum glucose concentration from 0 to 2 hours (Cmax0-2h and AUC0-2h ) are more sensitive than the FDA-recommended PD metrics for acarbose BE evaluation from 0-4 hours (ΔCmax0-4h and ΔAUC0-4h ). The trial has been registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn, ChiCTR1800015795, ChiCTR-IIR-17013918, ChiCTR-IIR-17011903). All subjects provided written informed consent before screening.

Impact of polymorphisms in angiogenesis-related genes on clinical outcomes of radiotherapy in patients with nasopharyngeal carcinoma.

The purpose of this paper is to assess the relationship between gene polymorphism in angiogenesis-related genes and radiation responses in nasopharyngeal carcinoma (NPC) patients. The genotypes of 180 NPC patients were analyzed by Sequenom MassARRAY. The response evaluation criteria in solid tumours were used for assessing efficacies, and the criteria of the Radiation Therapy Oncology Group or European Organization for Research & Treatment of Cancer were utilized for evaluating acute toxic reactions in response to radiation. Statistical methods included chi-square test, uni- and multivariate logistic regression analyses. Genotypic carriers of rs1800541 GT were at an elevated risk of developing grade 3+ oral mucositis, and a genetic variant of rs5333 was a predictor for a lower occurring risk of grade 2+ radiation-induced xerostomia. EDN1 rs1800541, rs2071942 and rs5370 variants were associated with a significantly higher risk of severe myelosuppression. SNPs in such angiogenesis-related genes as EDN1 rs1800541, rs2071942 & rs5370 and EDNRA rs5333 may serve as useful biomarkers for predicting the outcomes of NPC patients.

A preclinical evaluation of a novel multikinase inhibitor, SKLB-329, as a therapeutic agent against hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a serious life-threatening malignant disease of liver. Molecular targeted therapies are considered a promising strategy for the treatment of HCC. Sorafenib is the first, and so far the only targeted drug approved by the US Food and Drug Administration (FDA) for clinical therapy of HCC. Despite being effective in some HCC patients, some demerits of sorafenib in the treatment of HCC, such as modest survival benefits, and drug resistance, have also been reported, which highlights the unmet medical need among patients with HCC. Here, we report a novel multikinase inhibitor discovered by us, SKLB-329, which potently inhibits angiogenesis-related kinases including VEGFR1/2/3, and FGFR2, and the Src kinase. SKLB-329 significantly inhibited endothelial cell growth, migration, invasion and tube formation. It showed potent anti-angiogenic activity in a transgenic zebrafish model. Moreover, SKLB-329 could efficiently restrain the proliferation of HCC cells through down-regulation of Src-mediated FAK and Stat3 activity. In vivo, oral administration of SKLB-329 considerably suppressed the tumor growth in HCC xenograft models (HepG2 and SMMC7721) in a dose-dependent manner. In all of the in vitro and in vivo assays of this investigation, sorafenib was used as a positive control, and in most assays SKLB-329 exhibited a higher potency compared with the positive control. In addition, SKLB-329 also bears favorable pharmacokinetic properties. Collectively, the results of preclinical studies presented here demonstrate that SKLB-329 is a promising drug candidate for HCC treatment.

Association evaluations of oral anticoagulants with dementia risk based on genomic and real-world data.

BACKGROUND: Several observational studies have suggested that oral anticoagulants (OACs) might reduce the risk of dementia in the elderly, but the evidence is inconclusive. And the consistency of this relationship across different OAC classes and dementia subtypes is still uncertain. METHODS: To comprehensively evaluate this association, we applied Mendelian randomization (MR) combined with pharmacovigilance analysis. MR was used to assess the associations between genetic proxies for three target genes of OACs (VKORC1, F2, and F10) and dementia, including Alzheimer's disease (AD) and vascular dementia (VaD). This genetic analysis was supplemented with real-world pharmacovigilance data, employing disproportionality analysis for more reliable causal inference. RESULTS: Increased expression of the VKORC1 gene was strongly associated with increased risk of dementia, especially for AD (OR = 1.28, 95% CI = 1.14-1.43; p value < 0.001). Based on pharmacovigilance data, vitamin K antagonists (VKAs, inhibitors targeting VKORC1) exhibited a protective effect against dementia risk (ROR = 0.43, 95% CI = 0.28-0.67). Additional sensitivity analyses, including different MR models and cohorts, supported these results. Conversely, no strong causal associations of genetically proxied F2 and F10 target genes with dementia and its subtypes were found. CONCLUSIONS: This study reveals that the inhibition of genetically proxied VKORC1 expression or VKAs exposure is associated with a reduced risk of Alzheimer's dementia. However, there is little evidence to support similar associations with direct oral anticoagulants (F2 inhibitors and F10 inhibitors). Further research is warranted to clinically validate our findings.

Evolution and speciation transformation of chlorine during automobile shredder residue pyrolysis.

Disposal of automobile shredder residue (ASR) via pyrolysis enables the recovery of valuable products; however, the production of hazardous pollutants and low-value products is inevitable due to its high chlorine content. In this work, chlorine evolution behavior and the conversion mechanism during ASR pyrolysis between 480 and 600 °C were systematically studied. The experimental results for organic chlorine (Org-Cl) showed that released chlorinated gases were complex, and HCl only accounted for 35% of the gas phase products, while short-chain hydrocarbons with carbon atoms between two and four accounted for 52%. Chlorine was predominantly retained in the char, and Org-Cl was the primary contributor to the residual chlorine, accounting for over 50% of the char. The content of inorganic chlorine (InO-Cl) was low in the raw sample but significantly increased in the char. Through the distinction between organic and inorganic chlorine content in char, it was confirmed that Org-Cl could be converted to InO-Cl due to complex secondary reactions with metallic compounds. The conversion was favored by increasing the Org-Cl content and the temperature. Our findings clarified the evolution mechanism of chlorine and the transformation from Org-Cl to InO-Cl, thus providing guidance for chlorine regulation and the efficient recycling of metal resources.

Effect of Ticagrelor versus Clopidogrel on All-Cause and Cardiovascular Mortality in Acute Coronary Syndrome Patients with Hyperuricemia.

BACKGROUND AND OBJECTIVE: The relationship between hyperuricemia and mortality in patients with acute coronary syndrome (ACS) is considerably controversial. Additionally, the strategy of dual antiplatelet therapy (DAPT) has not been evaluated in patients with ACS with hyperuricemia. This study aims to evaluate the impact of hyperuricemia on the prognosis of ACS and explore the efficacy of ticagrelor compared with clopidogrel in patients with hyperuricemia. METHODS: The study enrolled 4319 patients divided into hyperuricemia (HUA, n = 1060) and normouricemia (NUA, n = 3259) groups. The inverse probability of treatment weighting (IPTW)-adjusted Cox regression analysis was used to evaluate the impact of ticagrelor versus clopidogrel on all-cause and cardiovascular mortality. RESULTS: Hyperuricemia significantly increased the risk of all-cause death compared with patients with NUA at 7 days [adjusted hazard ratio (HR): 4.292, 95% confidence interval (CI) 1.727-10.67]; P = 0.002), 14 days (adjusted HR: 2.871, 95% CI 1.326-6.219; P = 0.0074), 30 days (adjusted HR: 2.168, 95% CI 1.056-4.453; P = 0.035), 3 months (adjusted HR: 2.018, 95% CI 1.152-3.533; P = 0.0144) and 1 year (adjusted HR: 1.702, 95% CI 1.137-2.548; P = 0.009). No significant difference was found between ticagrelor and clopidogrel in 1-year all-cause mortality [7.0% versus 5.5%, adjusted HR: 1.114 (95% CI 0.609-2.037), P = 0.725] among patients with concomitant hyperuricemia. CONCLUSION: Hyperuricemia was independently related to an increased risk of all-cause and cardiovascular death in patients with ACS undergoing PCI. At 1-year follow-up, there were no significant differences between ticagrelor and clopidogrel concerning all-cause and cardiovascular death in patients with hyperuricemia.

The adsorption mechanism of arsenic in flue gas over the P-doped carbonaceous adsorbent: Experimental and theoretical study.

The utilization of carbon-based sorbent has gained extensive attention for arsenic removal from flue gas due to their high specific surface area, sufficient active sites and abundant sources. This study proposes that the addition of phosphorous could be used as an effective promoter for the activation and modification of carbonaceous sorbent to enhance their arsenic fixation capacity. Both experimental and density functional theory (DFT) methods were employed to systematically investigate the adsorption characteristics of arsenic over different carbon based sorbents. The results reveal that the modification of H3PO4 generated C-O-P, C-P-O, and C3-P-O functional groups on the surface of activated carbon, and the adsorption ability of H3PO4-modified activated carbon for gaseous arsenic was significantly improved compared with the untreated activated carbon. DFT calculations indicate that unsaturated C atoms on carbonaceous surface served as active sites during arsenic adsorption, the electronegativity of which could be enhanced by phosphorous functional group, thereby facilitating the adsorption of gaseous arsenic species. Additionally, the positive effect of the phosphorous functional group on arsenic adsorption is more pronounced on zigzag carbonaceous surface than on armchair carbonaceous surface. This work provides a theoretical basis of the development of high-performance biochar preparation for arsenic adsorption by explaining the promoting effect of phosphorous functional group on gaseous arsenic adsorption on carbonaceous surface.

Migration and emission characteristics of trace elements in coal-fired power plant under deep peak load regulation.

The trace elements (TEs) have caused great harm to the environment due to the large consumption of coal, and their emission from the coal-fired power plant (CFPP) has become a hot issue. The deep peak load regulation (DPLR) become a trend in the CFPP, which will affect the migration and emission of TEs. To explore the effect of the DLPR on the migration and emission characteristics of typical TEs in a 330 MW CFPP, the TEs field tests were carried out during the regulation period. Results showed that a higher load enhanced the migration of Pb, Mn, and Cr from bottom ash to fly ash, while it had little effect on the other TEs. More importantly, >99 % of TEs (93 % of Se) could be captured by air pollution control devices (APCDs), and the emission risk of Se and Mn increased with the load. Compared with the other TEs, it is particularly noteworthy that Se has a higher gaseous proportion in the flue gas, and the emission factor sharply increased from 165 MW to 297 MW. In addition, part of the particulate selenium transformed into a gaseous state across the ESP. This work contributes to understanding the migration characteristic of TEs during the DPLR process of CFPP and provides guidance for TEs control in the CFPP.

CpG-Conjugated Silver Nanoparticles as a Multifunctional Nanomedicine to Promote Macrophage Efferocytosis and Repolarization for Atherosclerosis Therapy.

Atherosclerosis (AS) is a major contributor to cardiovascular diseases, necessitating the development of novel therapeutic strategies to alleviate plaque burden. Macrophage efferocytosis, the process by which macrophages clear apoptotic and foam cells, plays a crucial role in plaque regression. However, this process is impaired in AS lesions due to the overexpression of CD47, which produces a "do not eat me" signal. In this study, we investigated the potential of CpG, a toll-like receptor 9 agonist, to enhance macrophage efferocytosis for AS therapy. We demonstrated that CpG treatment promoted the engulfment of CD47-positive apoptotic cells and foam cells by macrophages. Mechanistically, CpG induced a metabolic shift in macrophages characterized by enhanced fatty acid oxidation and de novo lipid biosynthesis, contributing to its pro-efferocytic effect. To enable in vivo application, we conjugated CpG on silver nanoparticles (AgNPs) to form CpG-AgNPs, which could protect CpG from biological degradation, promote its cellular uptake, and release CpG in response to intracellular glutathione. Combining the intrinsic antioxidative and anti-inflammatory abilities of AgNPs, such nanomedicine displayed multifunctionalities to simultaneously promote macrophage efferocytosis and repolarization. In an ApoE-/- mouse model, intravenous administration of CpG-AgNPs effectively targeted atherosclerotic plaques and exhibited potent therapeutic efficacy with excellent biocompatibility. Our study provides valuable insights into CpG-induced macrophage efferocytosis and highlights the potential of CpG-AgNPs as a promising therapeutic strategy for AS.

Study on pharmacokinetic interactions between SHR2554 and itraconazole in healthy subjects: A single-center, open-label phase I trial.

BACKGROUND: SHR2554, a novel oral Enhancer of Zeste Homolog 2 inhibitor, shows broad-spectrum anti-tumor efficacy in preclinical studies. As SHR2554 is mainly metabolized by CYP3A4, it is helpful to conduct research on the effects of itraconazole, a strong inhibitor of CYP3A4-metabolizing enzymes, on the pharmacokinetic characteristics and safety of SHR2554. METHODS: We conducted a single-center, open-label pharmacokinetic study of itraconazole on SHR2554 in 18 healthy Chinese subjects. Subjects were orally administrated SHR2554 50 mg on Day 1, itraconazole 200 mg Quaque Die (QD) from Days 4 to 7, SHR2554 50 mg co-administrated with itraconazole 200 mg on Day 8, and itraconazole 200 mg QD from Days 9 to 12. Then, 4 ml of venous blood was collected at predetermined time points. Plasma SHR2554 concentrations were analyzed using a validated high-performance liquid chromatography tandem mass spectrometry method. Pharmacokinetic parameters were calculated using Phoenix WinNonlin v8.1. RESULTS: The Cmax of SHR2554 alone and in combination was 10.197 ± 7.0262 ng·ml-1 versus 70.538 ± 25.0219 ng·ml-1 , AUC0-∞ was 50.99 ± 19.358 h·ng·ml-1 versus 641.53 ± 319.538 h·ng·ml-1 , and AUC0-t was 28.70 ± 18.913 h·ng·ml-1 versus 612.13 ± 315.720 h·ng·ml-1 . Co-administration of SHR2554 and itraconazole caused 7.73-, 12.47-, and 23.75-fold adjusted geometric mean ratios increases in SHR2554 Cmax , AUC0-∞ and AUC0-t respectively. The co-administration regimen was well tolerated and had a good safety profile. CONCLUSIONS: Compared with a single dose of SHR2554 50 mg, the exposure of SHR2554 in vivo was significantly affected by the combined administration of itraconazole.

A Phase I Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Novel Intravenous Formulation of Meloxicam (QP001) in Healthy Chinese Subjects.

Background: Meloxicam is a selective cyclooxygenase-2 inhibitor used for pain relief, but its poor solubility limits its clinical applications. QP001 is a novel intravenous formulation of meloxicam developed with PEG and pH regulator to improve its solubility. This study aimed to evaluate the safety, tolerability, and pharmacokinetics of QP001 in Chinese healthy subjects. Methods: The trial consisted of three parts. Part I was a two-period crossover study to evaluate bioavailability, in which 10 healthy were either intravenously infused with 15mg QP001 (test) or orally given 15mg MobicⓇ (reference). Part II was a single-arm design to assess the pharmacokinetic (PK) characteristics after 30 mg single- and multiple-dose QP001 in 10 subjects. In part III, we investigated the PKs and tolerability of QP001 at a high dose (60 mg) in another 10 subjects. The PK parameters and treatment-emergent adverse events (TEAEs) were evaluated. Results: A total of 30 subjects were enrolled in the study. QP001 was well tolerated and safe without significant TEAEs in all three study parts. The PK characteristics of QP001 were linear following a single-dose range of 15-60 mg (Cmax and AUC0-t were 5.82-17.66 µg/mL and 58.08-251.17 µg∙h/mL, respectively). After five consecutive daily 30 mg doses, the accumulation index was around 1.98, which indicated a minimal accumulation of QP001. Compared to the tablet dosage form, the relative bioavailability of QP001 reached 116.85%. Additionally, the PK profile of QP001 showed no gender difference. Conclusion: QP001 was well tolerated in healthy Chinese subjects after single ascending doses up to 60 mg and multiple-dose of 30 mg. Based on the PK and safety results, QP001 is a promising once-daily intravenous COX-2 inhibitor candidate for managing pain. Trial Registration: The trial is registered at chinadrugtrials.org.cn (ChiCTR2100047884).

Effects of molten salt thermal treatment on the properties improvement of waste tire pyrolytic char.

Pyrolysis is a technical means for waste tires recycling, which can promote the enrichment of carbon black and facilitate the subsequent recovery. However, carbon black particles aggregated and the inorganic impurities tended to be enriched in pyrolytic char during the waste tire pyrolysis process, which is not conducive to the substitution of commercial carbon black by pyrolytic char. In the present study, a novel method using molten salts thermal treatment was proposed for the impurities removal from pyrolytic chars with different characteristics. In addition, the proper thermal treatment conditions were further estimated to obtain better performance for the physical-chemical properties improvement of pyrolytic char. Six kinds of char samples were chosen to conduct molten salts thermal treatment (MSTT) experiments at 350, 400, and 450 °C. The experimental results show that MSTT can effectively remove the impurities of different pyrolytic chars, and the most optimum reaction conditions are at 400 °C, 2 h of reaction time, and molten salt/char ratio of 10:1. In addition, after MSTT, the pyrolytic char was depolymerized, and the average particle size reduced from 36.63 µm to 19.08 µm, the specific surface area increased from 49 m2/g to 73 m2/g. At the same time, the graphite carbon content of the pyrolytic char increased from 24.41% to 70.90%, and the hydroxyl content on the pyrolytic char surface increased significantly. In summary, the physical-chemical properties of waste tire pyrolytic char were improved by MSTT, which is close to the carbon black N550 level.

CASPorter: A Novel Inducible Human CASP1/NALP3/ASC Inflammasome Biosensor.

BACKGROUND: Following our 2015 elucidation of the CASP1/NALP3 inflammasome mechanism of glucocorticoid (GC)-resistance in pediatric acute lymphoblastic leukemia (ALL) patients, we engineered a cell-based CASP1/NALP3 reporter system suitable for high-throughput screening (HTS) of small molecule libraries, with the purpose of identifying compounds capable of inhibiting the CASP1/NALP3 inflammasome and synergizing with GC drugs for the treatment of GC-resistant ALL patients and various autoinflammatory diseases. METHODS: A Dox-controlled system was utilized to induce the expression of the ASC transgene in HEK293 cells while simultaneously overexpressing NLRP3 and CASP1. ASC/CASP1/NALP3 inflammasome complex formation was confirmed by co-immunoprecipitation (co-IP) experiments. Next, a LV fluorescence-based biosensor (CASPorter) was transduced in the HEK293-iASC-NLRP3/CASP1 cell line to monitor the real-time activation of CASP1/NALP3 inflammasome in live cells. The applicability and effectiveness of the CASPorter cell line were tested by co-treatment with Dox and four known CASP1/NLRP3 inhibitors (MCC950, Glyburide, VX-765 and VRT-043198). Inflammasome activation and inhibitions were assessed by Western blotting, fluorescence microscopy and flow cytometry (FC) methods. RESULTS: Dox treatment significantly induced ASC expression and increased levels of cleaved and catalytically active CASP1, co-IPs further demonstrated that CASP1 was pulled-down with NLRP3 in HEK293-iASC-NLRP3/CASP1 cells after induction of ASC by Dox treatment. In HEK293-iASC-NLRP3/CASP1-CASPorter cell system, cleavage of the CASP1 consensus site (YVAD) in the CASPorter protein after Dox treatment causing excitation/emission of green fluorescence and the 71% GFP+ cell population increase quantified by FC (78.1% vs 6.90%). Dox-induced activation of the NLRP3 inflammasome was dose-dependently inhibited by Dox co-treatment with four known CASP1/NLRP3 inhibitors. CONCLUSION: We have established a cell-based CASP1/NLRP3 inflammasome model, utilizing a fluorescence biosensor as readout for qualitatively observing and quantitatively determining the activation of caspase 1 and NLRP3 inflammasomes in living cells and easily define the inhibitory effect of inhibitors with high efficacy.

Fine particulate-bound arsenic and selenium from coal-fired power plants: Formation, removal and bioaccessibility.

The arsenic (As) and selenium (Se) in fine particulate matter (PM10) have attracted increasing attentions due to their health effects. However, the emission control of fine particulate-bound arsenic and selenium (fine particulate-bound As/Se) from coal-fired power plants still faces various challenges. Understanding the formation and characteristics of fine particulate-bound As/Se is crucial for developing specific control technologies. This study clarifies the formation mechanism, removal characteristics, and inhalation bioaccessibility of fine particulate-bound As/Se from industrial coal-fired power plants through methods including aerosol generation, As/Se speciation determination, and in vitro bioaccessibility testing. The findings demonstrated that PM1 from pulverized coal-fired (PC) boilers was enriched with As/Se in terms of concentration and mass distribution. Instead, As/Se was mainly distributed in PM2.5-10 from circulating fluidized bed (CFB) boilers. Limestone injection in CFB boilers promoted As/Se enrichment in coarse PM. Fine particulate-bound As was mainly formed by chemical adsorption of As vapors by Ca-minerals, while the formation of fine particulate-bound Se was closely related to active Ca-minerals and Fe-minerals. Furthermore, Ca-bound As was easy to remove by electrostatic precipitator (ESP) and the removal of physically adsorbed SeO2(s) was difficult, which was caused by the specific resistivity of different mineral components. Importantly, finer particulate-bound As/Se posed higher inhalation bioaccessibility, following the order of PM1 ≥ PM1-2.5 > PM2.5-10. In particular, Ca-bound Se in fine PM owned high bioaccessibility. Based on these findings, measures were proposed to suppress the formation of fine particulate-bound As/Se in the furnace and/or strengthen its removal in the post-combustion stage.