Erianin alleviates LPS-induced acute lung injury via antagonizing P-selectin-mediated neutrophil adhesion function.

ETHNOPHARMACOLOGICAL RELEVANCE: Dendrobium officinale Kimura et Migo, known as "Tiepi Shihu" in traditional Chinese medicine, boasts an extensive history of medicinal use documented in the Chinese Pharmacopoeia. "Shen Nong Ben Cao Jing" records D. officinale as a superior herbal medicine for fortifying "Yin" and invigorating the five viscera. Erianin, a benzidine compound, emerges as a prominent active constituent derived from D. officinale, with the pharmacological efficacy of D. officinale closely linked to the anti-inflammatory properties of erianin. AIM OF THE STUDY: Acute lung injury (ALI) is a substantial threat to global public health, while P-selectin stands out as a promising novel target for treating acute inflammatory conditions. This investigation aims to explore the therapeutic potential of erianin in ALI treatment and elucidate the underlying mechanisms. EXPERIMENTAL DESIGN: The effectiveness of erianin in conferring protection against ALI was investigated through comprehensive histopathological and biochemical analyses of lung tissues and bronchoalveolar lavage fluid (BALF) in an in vivo model of LPS-induced ALI in mice. The impact of erianin on fMLP-induced neutrophil chemotaxis was quantitatively assessed using the Transwell and Zigmond chamber, respectively. To determine the therapeutic target of erianin and elucidate their binding capability, a series of sophisticated assays were employed, including drug affinity responsive target stability (DARTS) assay, cellular thermal shift assay (CETSA), and molecular docking analyses. RESULTS: Erianin demonstrated a significant alleviation of LPS-induced acute lung injury, characterized by reduced total cell and neutrophil counts and diminished total protein contents in BALF. Moreover, erianin exhibited a capacity to decrease proinflammatory cytokine production in both lung tissues and BALF. Notably, erianin effectively suppressed the activation of NF-κB signaling in the lung tissues of LPS- challenged mice; however, it did not exhibit in vitro inhibitory effects on inflammation in LPS-induced human pulmonary microvascular endothelial cells (HPMECs). Additionally, erianin blocked the adhesion and rolling of neutrophils on HPMECs. While erianin did not influence endothelial P-selectin expression or cytomembrane translocation, it significantly reduced the ligand affinity between P-selectin and P-selectin glycoprotein ligand-1 (PSGL-1). CONCLUSIONS: Erianin inhibits P-selectin-mediated neutrophil adhesion to activated endothelium, thereby alleviating ALI. The present study highlights the potential of erianin as a promising lead for ALI treatment.

Effects of two commonly used antidepressants amitriptyline and fluoxetine on the pharmacokinetics of abrocitinib in rats.

Abrocitinib is approved to treat moderate-to-severe atopic dermatitis and eliminated mainly through cytochrome P450 (CYP450) enzyme. Two commonly used antidepressants, amitriptyline and fluoxetine, could inhibit the activities of CYP2C19 and CYP3A4. In this study, we developed a new and quick ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for quantitatively analyzing the plasma concentration of abrocitinib, and further investigated the effects of amitriptyline or fluoxetine on the pharmacokinetics of abrocitinib in rats. The selectivity, linearity, recovery, accuracy, precision, matrix effect and stability of UPLC-MS/MS assay were satisfied according to the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines. Our result showed that when co-administered with amitriptyline and fluoxetine, the CLz/F of abrocitinib was reduced by 44.4 % and 33.3 %, respectively, while the AUC(0-t) of abrocitinib was increased by 77.7 % and 49.4 %, respectively. It indicated that amitriptyline and fluoxetine could significantly increase the plasma concentration of abrocitinib in rats. Thus, dose adjustment of abrocitinib may be required when it is combined with amitriptyline or fluoxetine in ongoing clinical practice.

Simultaneous determination of iguratimod and its metabolite in rat plasma using a UPLC-MS/MS method: Application for drug-drug interaction.

This aim of the work was to establish an acceptable sensitive assay based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) for quantitatively analyzing the plasma concentrations of iguratimod (IGR) and its metabolite M2 in rats, and to further investigate the effect of fluconazole on the pharmacokinetics of IGR and M2. The mobile phase consisted of acetonitrile and water with 0.1% formic acid, was used to separate IGR, M2 and internal standard (IS) fedratinib on a UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 µm) with the flow rate of 0.4 mL/min. Positive ion mode and multiple reaction monitoring (MRM) were used to construct the quantitative analysis. The calibration standard of IGR and M2 covered 2-10000 and 1-1000 ng/mL respectively, with the lower limit of quantification (LLOQ) as 2 ng/mL and 1 ng/mL respectively. In addition, selectivity, recovery, accuracy, precision, matrix effect and stability of the method validation program were well accepted in this work. Subsequently, this approach was used to assess the effect of fluconazole on the pharmacokinetics of IGR and M2 in rats. In the presence of 20 mg/kg fluconazole (experimental group), we found the main pharmacokinetic parameters were significantly altered when compared with 2.5 mg/kg IGR alone (control group). Among them, AUC(0-∞) and Cmax of IGR in the experimental group was 1.43 and 1.08 times higher than that of the control group, respectively. Moreover, we also found that the other main pharmacokinetic parameters of M2 had no significant changes, except t1/2z and Tmax. In conclusion, fluconazole significantly altered the main pharmacokinetics of IGR and M2 in rats. It implys that we should pay more attention to the adverse reaction of IGR when the concomitant use of fluconazole and IGR occur in the future clinical practice.

Development of an UPLC-MS/MS method for quantitative analysis of abexinostat levels in rat plasma and application of pharmacokinetics.

Broad-spectrum histone deacetylase inhibitors (HDACi) have excellent anti-tumor effects, such as abexinostat, which was a novel oral HDACi that was widely used in clinical treatment. The purpose of this study was to establish a rapid and reliable method for the detection of abexinostat concentrations in rat plasma using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The mobile phase we used was acetonitrile and 0.1% formic acid, and the internal standard (IS) was givinostat. Selective reaction monitoring (SRM) was used for detection with ion transitions at m/z 397.93 → 200.19 for abexinostat and m/z 422.01 → 186.11 for givinostat, respectively. The intra-day and inter-day precision of abexinostat were less than 11.5% and the intra-day and inter-day accuracy ranged from - 10.7% to 9.7% using this method. During the analysis process, the stability of the test sample was reliable. In addition, the recovery and matrix effects of this method were within acceptable limits. Finally, the method presented in this paper enabled accurate and quick determination of abexinostat levels in rat plasma from the pharmacokinetic study following gavage at a dose of 8.0 mg/kg abexinostat.

High-sensitivity immunoassay on interdigitated electrode to detect osteoporosis biological marker.

Osteoporosis is with porous bones, which refers to a decrease in the bone mineral density and weakens the bones to become brittle. Osteoporosis often progresses without any pain or symptoms until the bone fractures. Monitoring the condition of bone regularly helps to identify the bone that weakens at its earlier stages. In general, radiological techniques have been used to measure bone mineral density, are expensive, and the procedures are complicated. Therefore, researchers are focusing on the alternative method of biomarker quantification to identify bone mineral density. This research work was focused on quantifying the osteoporosis biomarker of C-terminal telopeptide of type I collagen (CTX-I) on an interdigitated electrode (IDE) sensor. Gold nanomaterial-modified anti-CTX-I antibody was attached to silica nanomaterial-decorated IDE and then identified by CTX-I interaction. Higher immobilization of antibodies was recorded on diamond-modified IDE through gold nanoparticles, and detected CTX-I as low as 0.5 pg/mL [y = 1.5507x - 0.9043 R2 = 0.9715], determined on a linear curve at the range 0.5-3.5 ng/mL. Further, specific identification of CTX-I was confirmed by control performances with osteopontin, IL-6, and anti-IgG antibody.

Development of a UPLC-MS/MS method for the determination of lacosamide and its metabolite and its application to drug-drug interaction.

Lacosamide, a third-generation novel antiepileptic drug, was first approved in 2008 as an adjunct to partial seizures. In 2014, the U.S. Food and Drug Administration (FDA) approved it as a single agent for partial seizures. Since epilepsy is a chronic condition, most patients need long-term antiepileptic medicinal products, so it is even more important to consider the drug-drug interactions (DDIs). For the purpose of this experiment, an ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay with accuracy and simplicity was optimized and fully validated for the simultaneous quantitative determination of lacosamide and O-Desmethyl-lacosamide (ODL), and DDIs between lacosamide and nisoldipine in vivo and in vitro was researched. The protein was precipitated with acetonitrile, the analytes were eluted with acetonitrile and a 0.1% formic acid solution in a gradient program, and lacosamide, ODL, and lamotrigine (Internal Standard, IS) were successfully separated by chromatography. The findings of the biological analysis revealed that the lower limit of quantification (LLOQ) for lacosamide in samples was 2 ng/mL and the linearity ranged from 2 to 10000 ng/mL. The LLOQ for ODL was 1 ng/mL, while the linearity range for this substance was 1-1,000 ng/mL. In rat liver microsomes (RLM), the LLOQ of ODL was 80 ng/mL and the linear range was 80-40000 ng/mL. The selectivity, stability, matrix effect and recovery rate were all satisfied with the need of quantitative analysis of samples. Then, the UPLC-MS/MS assay was employed successfully on the interactions of lacosamide and nisoldipine in vivo and in vitro. The half-maximal inhibitory concentration (IC50) was 3.412 µM in RLM, where nisoldipine inhibited the metabolism of lacosamide with a mixture of inhibition mechanism. In rat pharmacokinetic experiments, it was found that nisoldipine could significantly change the pharmacokinetic characteristics of lacosamide, including AUC(0-t), AUC(0-∞), Tmax, CLz/F and Cmax, but had no significant effect on ODL. In summary, the UPLC-MS/MS method could accurately and sensitively quantify lacosamide and ODL, and could be used for the interaction between nisoldipine and lacosamide in vivo and in vitro.

Impact assessment of human activities on resources of juvenile horseshoe crabs in Hainan coastal areas, China.

The booming coastal zone economy poses increasing anthropogenic threats to marine life and habitats. Using the endangered living fossil horseshoe crab (HSC) as an example, we quantified the intensity of various anthropogenic pressures along the coast of Hainan Island, China, and for the first time assessed their impact on the distribution of juvenile HSCs through a field survey, remote sensing, spatial geographic modeling, and machine learning methods. The results indicate that the Danzhou Bay needs to be protected as a priority based on species and anthropogenic pressure information. Aquaculture and port activities dramatically impact the density of HSCs and therefore be managed priority. Finally, a threshold effect between total, coastal residential, and beach pressure and the density of juvenile HSCs were detected, which indicates the need for a balance between development and conservation as well as the designation of suitable sites for the construction of marine protected areas.

A novel cadmium detoxification pathway in Tri-spine horseshoe crab (Tachypleus tridentatus): A 430-million-years-ago organism.

Marine and intertidal heavy metal pollution has been a major concern in recent years. Tachypleus tridentatus has existed on earth for more than 430 million years. It has suffered a sharp decline in population numbers caused by environmental pollution and anthropogenic disturbance for almost 40 years. However, the effects of heavy metal pollution on juvenile T. tridentatus have not been reported. Here we show the mechanism of cadmium (Cd) detoxification in juvenile T. tridentatus using integrated antioxidant indexes and transcriptomic and metabolomic analysis. High Cd2+ concentration caused oxidative stress in juvenile T. tridentatus. The hazards increase with increasing Cd2+ concentration in juvenile T. tridentatus. Transcriptomics and metabolomics analyses concluded that high Cd2+ concentration resulted in the imbalance of glycerophospholipid metabolism in juvenile T. tridentatus to detoxify Cd. Our results offer a rationale for protective measures and further studies of heavy metal stress in T. tridentatus.

Improving cleaner production of human activities to mitigate total petroleum hydrocarbons accumulation in coastal environment.

The marine coast is an important ecological transitional boundary but easily suffers from human intervention. Total petroleum hydrocarbons (TPHs) are ubiquitous along the coast. However, the influence of anthropogenic and natural factors on TPHs distribution remains unclear. This study sampled surficial sediment (N = 243) from the coasts of the largest peninsula-Leizhou Peninsula, in Southern China. We found that land-based discharge, sea traffic, and sediment type significantly (p < 0.05) drive the accumulation of TPHs. We observed that TPHs increased by 1.036 µg · g-1 (exp[αi] = exp. [0.0355]) of its original value with the addition of one more boat on the wharf. Although the average TPHs were at a moderate level (124.68, ND-1536.14, µg · g-1) and risk, 'Blue Carbon' ecosystems, i.e., mangroves (224.84, ND - 1441.13, µg · g-1, p < 0.001) were more severely polluted. Cleaner production policy should be applied to mitigate TPHs discharging trend from coastal areas.

Linking human activity to spatial accumulation of microplastics along mangrove coasts.

Microplastics (MP) in mangrove coasts are threating ecological health and seafood safety. However, quantitative evidence on the effects of different coastal human activities on microplastic accumulation in mangrove sediments is lacking, thereby impeding the policy development of evidence-based waste management. In this study, continuous geographical sampling (N = 50) was applied to collect sediments from the largest mangrove coast, namely the Leizhou Peninsula in China. Similar worldwide research data (16 mangrove coasts) were collected from the Science Citation Index Expanded (SCIE) database of the Web of Science. The connections between human drivers and microplastic accumulation were evaluated by spatial comparison, multi-correspondence analysis, and multiple differences analysis. The microplastic abundance fluctuated widely along the mangrove coasts (average value was 51.24, ranged from 6.40 to 255.57 items·kg-1 dry weight; coefficient of variation = 97%) with a globally lower-middle concentration in sediments of the Leizhou Peninsula. Densely populated urban residents and the floating population of tourists largely contributed to the high abundance of microplastics in mangrove sediments, of which large-sized (1-5 mm) white foams were the dominant type. Although suburbs had less crowds, both onshore and offshore fishery production could cause high accumulation of microplastics in neighboring mangrove coasts, which were characterized by small-sized (<1 mm) fragments with fresh color. Small microplastics (80%) with fresh color (44%) were dominant. Weathering may break down more toxic particles in urban areas neighboring mangrove coasts. Larger mangrove patches could partly block ocean-based microplastics; however, coasts surrounded by more geographical barriers had intensified pollutant accumulation. It was suggested that foam packaging of commodities for urban residents and tourists in popular tourism areas should be reduced and restrictions of fishery waste plastics are needed along shores with mangroves, especially in coasts surrounded by more geographic barriers.

Association between LEKR1-CCNL1 and IGSF21-KLHDC7A gene polymorphisms and diabetic retinopathy of type 2 diabetes mellitus in the Chinese Han population.

BACKGROUND: Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes. The present study aimed to identify a possible connection between gene polymorphisms and the risk of developing DR. MATERIALS AND METHODS: A total of 319 patients with type 2 diabetes mellitus (T2DM) were selected. All patients underwent a complete eye examination. Based on this, the patients with T2DM were divided into two subgroups: 175 patients with retinopathy (DR) and 144 patients without retinopathy (NDR). We calculated the genotype frequencies of case and control subjects using the chi-squares test. The odds ratio (OR) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression adjusted for age and sex. RESULTS: The finding by analysis is that the mean of duration of diabetes, total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), glomerular filtration rate and C-peptide were significantly different between DR and NDR. We found significant differences in cystatin-C concentrations with LEKR1-CCNL1 rs13064954 and NOS3 rs3918227 of different genotypes. Significant differences in serum TG levels were seen among the three genotypes of MTHFR rs1537516. Subjects carried the T allele of IGSF21-KLHDC7A rs3007729 had higher serum LDL concentrations (p = 0.015). In the allele model, LEKR1-CCNL1 rs13064954 decreased the risk of DR (OR =0.57, 95% CI = 0.34-0.96, p = 0.032). Under the dominant model, the IGSF21-KLHDC7A rs3007729 CT-TT genotype increased the risk of DR (OR =1.84, 95% CI = 1.14-2.99, p = 0.013). CONCLUSIONS: Our results suggest that LEKR1-CCNL1 and IGSF21-KLHDC7A influence the development of DR.

MicroRNA-29 regulates high-glucose-induced apoptosis in human retinal pigment epithelial cells through PTEN.

Hyperglycemia or high-glucose (HG)-induced apoptosis in human retinal pigment epithelial (RPE) cells is a characteristic process in diabetic retinopathy. In our study, we examined whether microRNA-29 (miR-29) may regulate HG-induced RPE cell apoptosis. Human RPE cell line, ARPE-19 cells, was treated with various high concentration of glucose in vitro. HG-induced RPE cell apoptosis was examined by terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL) assay and miR-29 gene expression by quantitative RT-PCR (qRT-PCR). miR-29 was then downregulated in RPE cells, and its effect on HG-induced apoptosis was examined by TUNEL assay and western blot assay on caspase-7 protein. Association of miR-29 on its downstream target, PTEN, in HG-induced RPE cell apoptosis was evaluated by dual-luciferase assay and qRT-PCR. PTEN was silenced in RPE cells. The effects of PTEN downregulation on miR-29-mediated HG-induced RPE cell apoptosis were also examined by TUNEL and western blot assays. HG induced significant apoptosis in RPE cells in a dose-dependent manner. miR-29 was upregulated by HG in RPE cells. miR-29 downregulation protected HG-induced apoptosis and reduced the production of caspase-7 protein in RPE cells. PTEN was shown to be directly downregulated by HG and then upregulated by miR-29 downregulation in RPE cells. Small interfering RNA (siRNA)-mediated PTEN downregulation reversed the protective effect of miR-29 downregulation on HG-induced RPE cell apoptosis. This study demonstrates that miR-29, through inverse association of PTEN, plays an important role in the process of HG-induced apoptosis in RPE cells.

Greenhouse gas emissions from landfill leachate treatment plants: a comparison of young and aged landfill.

With limited assessment, leachate treatment of a specified landfill is considered to be a significant source of greenhouse gas (GHG) emissions. In our study, the cumulative GHG emitted from the storage ponds and process configurations that manage fresh or aged landfill leachate were investigated. Our results showed that strong CH4 emissions were observed from the fresh leachate storage pond, with the fluxes values (2219-26,489 mg Cm(-2)h(-1)) extremely higher than those of N2O (0.028-0.41 mg Nm(-2)h(-1)). In contrast, the emission values for both CH4 and N2O were low for the aged leachate tank. N2O emissions became dominant once the leachate entered the treatment plants of both systems, accounting for 8-12% of the removal of N-species gases. Per capita, the N2O emission based on both leachate treatment systems was estimated to be 7.99 g N2O-N capita(-1)yr(-1). An increase of 80% in N2O emissions was observed when the bioreactor pH decreased by approximately 1 pH unit. The vast majority of carbon was removed in the form of CO2, with a small portion as CH4 (<0.3%) during both treatment processes. The cumulative GHG emissions for fresh leachate storage ponds, fresh leachate treatment system and aged leachate treatment system were 19.10, 10.62 and 3.63 Gg CO(2) eq yr(-1), respectively, for a total that could be transformed to 9.09 kg CO(2) eq capita(-1)yr(-1).

Budd-Chiari syndrome: diagnosis with three-dimensional contrast-enhanced magnetic resonance angiography.

AIM: To evaluate the role of three-dimensional contrast-enhanced magnetic resonance angiography (3D CE MRA) in the diagnosis of Budd-Chiari syndrome (BCS). METHODS: Twenty-three patients with BCS underwent 3D CE MRA examination, in which 13 cases were secondary to either hepatocellular carcinoma (11 cases), right adrenal carcinoma (1 case) or thrombophlebitis (1 case) and 10 suffered from primary BCS. The patency of the inferior vena cava (IVC), hepatic and portal veins as well as the presence of intra- and extrahepatic collaterals, liver parenchymal abnormalities and porto-systemic varices were evaluated. Inferior vena cavography was performed in 10 cases. The diagnosis of IVC obstruction by 3D CE MRA was compared with that demonstrated by inferior vena cavography. RESULTS: The major features of BCS could be clearly displayed on 3D CE MRA. Positive hepatic venous signs included tumor thrombosis (9 cases), tumor compression (2 cases), nonvisualization (4 cases) and focal stenosis (2 cases). Positive IVC findings were noted as severe stenosis or occlusion (10 cases), tumor invasion (2 cases), thrombosis (3 cases), thrombophlebitis (1 case) and septum formation (3 cases). Intrahepatic collaterals were shown in 9 patients, 2 of them with "spider web" sign. The displayed extrahepatic collaterals included dilated azygos and hemi-azygos veins (13 cases) and left renal-inferior phrenic-pericardiophrenic veins (2 cases). The occlusion of the left intrahepatic portal veins was found in 2 cases. Porto-systemic varices were detected in 10 patients. Liver parenchymal abnormalities displayed by 3D CE MRA were enlargement of the caudate lobe (7 cases), heterogenous enhancement (18 cases) and complicated tumors (13 cases). Compared with the inferior vena cavography performed in 10 cases, the accuracy of 3D CE MRA was 100 % in the diagnosis of IVC obstruction. CONCLUSION: 3D CE MRA can display the major features of BCS and provide an accurate diagnosis.