Ginsenoside Compound K Reduces Psoriasis-related Inflammation by Activation of the Glucocorticoid Receptor in Keratinocytes.

AIM: To investigate the effects and mechanism of Ginsenoside Compound K (GCK) on psoriasis, focusing on the glucocorticoid receptor (GR) in keratinocytes. METHODS: An imiquimod (IMQ)-induced psoriasis-like dermatitis mouse model was generated to evaluate the anti-inflammatory effect of GCK. Hematoxylin and eosin (H&E) staining was used to assess skin pathological changes. Protein expression of K17 and p-p65 in mice skin was assayed by immunohistochemical. Protein expression and phosphorylation of p65 IκB were assayed by Western blot. Protein expression of K1, K6, K10, K16, K17, and GR were assayed by Western blot and immunofluorescence. Enzyme-linked immunosorbent assay (ELISA) was used to determine cytokine levels of TNF-α, IL-6, CXCL-8, and ICAM-1. Real-time polymerase chain reaction (RT-PCR) was used to quantify TNF-α, IL-6, IL-8, and ICAM-1 mRNA expression. Cell viability was determined by Cell Counting Kit-8(CCK-8) assay. A high-content cell-imaging system was used to assay cell proliferation. Nuclear translocation of p65 and GR was assayed by imaging flow cytometry and immunofluorescence microscopy. Small interfering RNA was used to confirm the role of GR in the anti-inflammatory and immunoregulatory effect of GCK in normal human epidermal keratinecytes (NHEKs). RESULTS: GCK reduced the psoriasis area, severity index, and epidermal thickening in IMQ-induced mice. GCK significantly attenuated the mRNA levels of IL-6, IL-8, TNF-α, and ICAM-1 and reduced epidermal hyperproliferation in the skin of IMQ-induced mice. GCK inhibited in vitro activation of NF-κB, leading to attenuated release of inflammatory mediators (IL-6, IL-8, TNF-α, and ICAM-1) and suppression of NHEK hyperproliferation and abnormal differentiation. These inhibitory effects of GCK were diminished by GR silencing in NHEKs. CONCLUSION: GCK suppressed psoriasis-related inflammation by suppressing keratinocyte activation, which may be related to promoting GR nuclear translocation and inhibiting NF-κB activation. In summary, GCK appears to be a GR activator and a promising therapeutic candidate for antipsoriatic agents.

Ginsenoside compound K exerts anti-inflammatory effects through transcriptional activation and transcriptional inhibition of glucocorticoid receptor in rheumatoid arthritis fibroblast-like synoviocytes.

Ginsenoside compound K (GCK) has anti-inflammatory and immunoregulatory effects, and glucocorticoid receptor (GR) has been considered as its potential target. But the mechanism by which GCK exerts its anti-inflammatory effects after GR activation remains unclear. In this study, molecular docking, isothermal titration calorimetry, siRNA of GR and GRA458T mutation were used to confirm the anti-inflammatory mechanism of GCK targeting GR in fibroblast-like synoviocytes (FLS). The results showed that the key binding sites of GR and GCK were identified as ASN564, MET560 and ASN638, with binding levels at the µm level. In addition, the inhibitory effect of GCK on the proliferation of FLS and the secretion of inflammatory cytokines (IL-6, IL-8, and IL-1ß) were mediated by transcriptional activation of GR, but on the migration, invasion, and TNF-α secretion of FLS were mediated by transcriptional inhibition of GR. These actions exert anti-inflammatory effects through indirect and direct inhibition of NF-κB transcriptional activity, respectively. In conclusion, this study elucidates that GCK can directly bind to and activate GR. Furthermore, after activation, GR mediates the anti-inflammatory effects of GCK through two mechanisms: transcriptional activation and transcriptional inhibition.

Polysorbate 80 as a possible allergenic component in cross-allergy to docetaxel and fosaprepitant: A literature review.

OBJECTIVE: Patients had allergies to both fosaprepitant and docetaxel with similar signs and symptoms. To explore the possible causes of allergy and whether there is cross-allergy between fosaprepitant and docetaxel, we conducted a literature review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. METHODS: A systematic search of the following databases was performed: Pubmed, Embase, Cochrane Library, CINAHL, Scopus, Web of Science and Taylor & Francis. The final search was on 12 November 2022. Two investigators independently selected eligible studies and extracted data according to inclusion and exclusion criteria and assessed the methodological quality of included studies. Any disagreement was resolved by a third researcher. RESULTS: The main cause of fosaprepitant and docetaxel allergy is polysorbate 80. Fosaprepitant and docetaxel have similar allergic symptoms, mainly facial flushing (19.0%, 18.5%); erythema/dermatitis (17.2%, 1.9%); fluid retention (17.2%, 22.2%); and dyspnea, bronchospasm, shortness of breath and coughing (15.5%, 16.7%). Hypotension (1.7%, 7.4%) and decreased oxygen saturation (1.7%, 1.9%) are rare. The treatments for both allergies are similar: stop injection, oxygen, glucocorticoid, antihistamines and symptomatic treatments. CONCLUSION: Polysorbate 80 is the same allergenic component of docetaxel and fosaprepitant. The symptoms and treatments caused by the two drugs are similar. Most allergic reactions are not serious. Medications containing the same allergy ingredient need to be used with caution for patients with severe allergies to polysorbate 80.

One-Pot Assembly of Dual-Site-Specific Antibody-Drug Conjugates via Glycan Remodeling and Affinity-Directed Traceless Conjugation.

The drug-to-antibody ratio (DAR) value and dual-drug combination greatly influence the therapeutic index of antibody-drug conjugates (ADCs). The reported approaches usually require multifunctional branched linkers, a combination of complicated technologies, or protein-protein ligation, which may incorporate multihydrophobic fragments or result in low coupling efficiency. Herein, we developed a facile and efficient one-pot method to assemble dual-site-specific ADCs with defined DARs at both the N-glycosylation site and K248 site, either with the same payloads or with two types of payloads. The constructed dual-site ADCs showed acceptable homogeneity, excellent buffer stability, and enhanced in vitro and in vivo efficiency.

Enhanced antibody-defucosylation capability of α-L-fucosidase by proximity-based protein fusion.

Up to date, the reported fucosidases generally show poor activities toward the IgG core-fucose, which limits the efficiency of ENGase-catalyzed glycoengineering process. However, EndoS or EndoS2 owns excellent activity and great selectivity towards the N-glycosylation of IgGs, and their non-catalytic domains are deduced to have specific interactions to IgG Fc domain that result in the great activity and selectivity. Herein, we constructed a series fusion protein of AlfC (an α-l-fucosidase from Lactobacillus casei BL23) with EndoS/S2 non-catalytic domain by replacing the catalytic GH (glycan hydrolase) domain of EndoS/S2 with the AlfC. We found that all these fused AlfCs showed significantly enhanced defucosylation activity toward the deglycosylated IgGs (Fucα1,6GlcNAc-IgG). We also performed the kinetic study of these fusion enzymes, and our results tend to tell that the EndoS-based fusion proteins have higher kcat values while the EndoS2-based ones possess lower Km values other than higher kcat. Conclusively, our research provides an effective approach to improve the activity of AlfC and remarkably shortened the defucosylation process within several minutes, which will significantly promote the development of glycoengineered antibodies in the future.

Evaluation of river longitudinal connectivity based on landscape pattern and its application in the middle and lower reaches of the Yellow River, China.

River connectivity plays an essential role in maintaining the health and stability of river basin ecosystems. It is of great significance to protect river ecosystems to clarify the effect of water conservancy project construction and operation on river hydrological connectivity. The longitudinal connectivity is affected by the landscape patterns of river, such as the convergence and dispersion of the mid-channel bars and the river areas. This study aims to analyze the impacts of construction and regulation of Xiaolangdi Dam on the connectivity of the middle and lower reaches of the Yellow River from the perspective of landscape pattern. An improved longitudinal river connectivity evaluation method was proposed by accounting for the influence of the landscape pattern represented by mid-channel bars based on barrier coefficient method, and then was applied to analyze the connectivity pre- and post-dam construction. The results show that the amplitude and frequency of the oscillation of the river were greatly reduced and tended to be stable. The aggregation degree of mid-channel bars was reduced, and the distribution of mid-channel bars was more dispersed. The river longitudinal connectivity before and after the construction of the Xiaolangdi Dam were 1.35 and 1.50 respectively, indicating an increased river longitudinal connectivity. Overall, there are differences in connectivity before and after Xiaolangdi Dam construction, and connectivity fluctuates after dam construction. Because of the dam regulation of water and sediment, the river connectivity during the flood season increased significantly, and was greater than that before and after the flood season. The longitudinal connectivity evaluation method established in this study is accurate and efficient, and provides an intuitive and reliable new method for quantitatively analyzing the changing laws and characteristics of river connectivity.

Flow and turbulence in unevenly obstructed channels with rigid and flexible vegetation.

The pattern of vegetation along the cross-section of macrophyte-dominated shallow waters is generally uneven, which affects water velocity and turbulence. This study examined the velocity and turbulence in the open channel with an uneven transverse distribution of vegetation in laboratory flume experiments. Two vegetation patterns were tested: emergent vegetation which covered part of the channel, and a symmetrical combination of submerged and emergent vegetation canopies along the lateral direction of the flume. The flow was measured using a three-dimensional Acoustic Doppler Velocimeter. The velocity and turbulence characteristics were analyzed under three vegetation densities and five discharge scenarios. Results showed that the longitudinal mean velocity changed with vegetation density and flow discharge when vegetation was unevenly distributed in a lateral direction. The strong variation in shear stress at the emergent vegetation-open water intersections and submerged-emergent vegetation intersections resulted in large-scale vortices at the interfaces. The formation processes of stem-scale turbulence and shear-scale turbulence under different vegetation scenarios were discussed. A turbulent kinetic energy model within partly obstructed vegetation canopies was established, which helped to identify the development of horizontal and vertical coherent vertices.

Hiding Payload Inside the IgG Fc Cavity Significantly Enhances the Therapeutic Index of Antibody-Drug Conjugates.

The inadequate understanding of the structure-activity relationship (SAR) of glycosite-specific antibody-drug conjugates (ADCs) hinders its design and development. Herein, we revealed the systemic SAR and structure-toxicity relationship (STR) of gsADCs by constructing 50 gsADC structures bearing three glycan subtypes and diverse linker-drug combinations. According to the results, extra hydrophilic linkers are indispensable for the intact glycan-based gsADCs to achieve better in vivo efficacy. Meanwhile, the gsADCs that conjugate linker-drug complexes onto the terminal sialic acid are more stable and potent than the ones conjugated onto the terminal galactose in vivo. Notably, the LacNAc-based gsADCs, which shortened the spacer and located the linker-drug more inside the immunoglobulin class G (IgG) Fc cavity, showed excellent hydrophilicity, in vivo activity, pharmacokinetics, and safety. Conclusively, we found that hiding the linker-toxin into the Fc cavity can significantly enhance the therapeutic index of LacNAc-based gsADCs, which will benefit the further design of ADCs with optimal druggability.

Paeoniflorin-6'-O-benzene sulfonate protected the intestinal epithelial barrier by restoring the inhibitory effect of GRK2 and ß-arrestin 2 on ERK1/2-NF-κB.

Peoniflorin-6'-O-benzene sulfonate (CP-25) inhibited the activity of GRK2 to exert anti-inflammatory and immunomodulatory effects. This study aimed to investigate the effect of CP-25 the intestinal epithelial barrier and the mechanism. CaCO-2 cell monolayer and dextran sulfate salt (DSS)-induced colitis mouse model was used to evaluate intestinal epithelial barrier function in vitro and in vivo, respectively. Results showed that CP-25 prevented dysfunction of the intestinal epithelial barrier and inhibited NF-κB p65 activation in TNF-α-induced CaCO-2 cells. The colon structure destroyed in DSS-induced colitis mice was improved by CP-25. CP-25 has a role in inhibition membrane translocation of GRK2-ß-arrestin 2 complex, stabilization of the binding of GRK2 and ß-arrestin 2 to ERK1/2 in cytoplasm. Subsequently down-regulated the nuclear transcription and transactivation of NF-κB p65 via inhibiting its phosphorylation of Ser536, and Ser276, respectively and restored the epithelial barrier function. In conclusion, CP-25 inhibited ERK1/2-NF-κB activation and thereby protected the intestinal epithelial barrier, which was associated with restoring the inhibition of GRK2 and ß-arrestin 2 on ERK1/2.

Anticancer activity of oleanolic acid and its derivatives modified at A-ring and C-28 position.

Oleanolic acid (OA) is a five-ring triterpenoid compound, which is widely present in plants. Due to a wide range of pharmacological activities, oleanolic acid has attracted more and more attention. However, oleanolic acid is insoluble in water and has low bioavailability, which limits its clinical application. In this review, we focus on summarizing the anti-cancer activity and mechanism of the A ring or C-28 carboxyl modified derivatives of OA since 2015, to determine the strength of its anti-cancer effectiveness and evaluate whether it could be used as a clinical anti-cancer drug.

19F MRI-fluorescence imaging dual-modal cell tracking with partially fluorinated nanoemulsions.

As a noninvasive "hot-spot" imaging technology, fluorine-19 magnetic resonance imaging (19F MRI) has been extensively used in cell tracking. However, the peculiar physicochemical properties of perfluorocarbons (PFCs), the most commonly used 19F MRI agents, sometimes cause low sensitivity, poor cell uptake, and misleading results. In this study, a partially fluorinated agent, perfluoro-tert-butyl benzyl ether, was used to formulate a 19F MRI-fluorescence imaging (FLI) dual-modal nanoemulsion for cell tracking. Compared with PFCs, the partially fluorinated agent showed considerably improved physicochemical properties, such as lower density, shorter longitudinal relaxation times, and higher solubility to fluorophores, while maintaining high 19F MRI sensitivity. After being formulated into stable, monodisperse, and paramagnetic Fe3+-promoted nanoemulsions, the partially fluorinated agent was used in 19F MRI-FLI dual imaging tracking of lung cancer A549 cells and macrophages in an inflammation mouse model.

A Traceless Site-Specific Conjugation on Native Antibodies Enables Efficient One-Step Payload Assembly.

Direct chemical modification of native antibodies in a site-specific manner remains a great challenge. Ligand-directed conjugation can achieve the selective modification of antibodies, but usually requires multiple extra steps for ligand release and cargo assembly. Herein, we report a novel, traceless strategy to enable the facile and efficient one-step synthesis of site-specific antibody-drug conjugates (ADCs) by harnessing a thioester-based acyl transfer reagent. The designed reagent, consisting of an optimized Fc-targeting ligand, a thioester bridge and a toxin payload, directly assembles the toxin precisely onto the K251 position of native IgGs and simultaneously self-releases the affinity ligand in one step. With this method, we synthesized a series of K251-linked ADCs from native Trastuzumab. These ADCs demonstrated excellent homogeneity, thermal stability, and both in vitro and in vivo anti-tumor activity. This strategy is equally efficient for IgG1, IgG2, and IgG4 subtypes.

The nexuses between carbon emissions, agriculture production efficiency, research and development, and government effectiveness: evidence from major agriculture-producing countries.

Agriculture production efficiency and carbon emissions have become the challenge for the sustainable world. Therefore, this study explores the relationships between agriculture production and carbon emissions in major (seventeen) agriculture-producing countries over the time period of 1996-2018. Data envelopment analysis is applied to estimate the efficiency of agriculture sector production. The results suggested that the USA, Russia, Korea, Japan, and Italy were efficient agriculture production. Among BRICS countries, China (0.183), India (0.378), and Brazil (0.382) are far off to Russia in Agriculture production efficiency. Growth of research and development investment by 1% increases agriculture production efficiency by 0.0773 (full panel), 0.119 (developing), and 0.0245(developed), respectively. Carbon emissions are also significantly decreased by research and development investment. However, the effectiveness of the government on carbon emissions can be both positive and negative in developed and developing countries' cases. Nevertheless, both developed and developing governments are concerned about increasing agriculture production efficiency. The shape validity of the environmental Kuznets curve is also varied between the developed and developing groups. From the policy perspective, it is suggested that the government should reform its policies to avoid carbon activities and enhance the agricultural sector on a priority basis to increase the efficiency of current raw resources, generate jobs, and reap a variety of other advantages.

Health risk assessment of heavy metals in fish and accumulation patterns in food web in the upper Yangtze River, China.

This study aims to concern the distribution of As, Cr, Cd, Hg, Cu, Zn, Pb and Fe in surface sediment, zoobenthos and fishes, and quantify the accumulative ecological risk and human health risk of metals in river ecological system based on the field investigation in the upper Yangtze River. The results revealed high ecological risk of As, Cd, Cu, Hg, Zn and Pb in sediment. As and Cd in fish presented potential human health risk of metals by assessing integrated target hazard quotient results based on average and maximum concentrations, respectively. No detrimental health effects of heavy metals on humans were found by daily fish consumption. While, the total target hazard quotient (1.659) exceeding 1, it meant that the exposed population might experience noncarcinogenic health risks from the accumulative effect of metals. Ecological network analysis model was established to identify the transfer routes and quantify accumulative effects of metals on river ecosystem. Control analysis between compartments showed large predator fish firstly depended on the omnivorous fish. Accumulative ecological risk of metals indicated that zoobenthos had the largest metal propagation risk and compartments located at higher trophic levels were not easier affected by the external environment pollution. CAPSULE: A potential accumulative ecological risk of heavy metal in the food web was quantified, and the noncarcinogenic health risk of fish consumption was revealed for the upper reach of the Yangtze River.

Ecological risk assessment of heavy metals in sediment in the upper reach of the Yangtze River.

Heavy metal pollution in China's Yangtze River basin has been of high concern. The concentrations of heavy metals (Cr, Cd, Hg, Cu, Zn, Pb, and As) in the sediment were investigated in the upper reaches of the river, China. Sediment quality guidelines (SQGs), an enrichment factor (EF), an index of geo-accumulation (I geo), and potential ecological risk were used to evaluate the extent of contamination from the heavy metal concentrations in the sediment. Among the seven metals, a noticeable degree of pollution was seen only in the case of Cd and Cd posed a considerable ecological risk at some sample sites. The Pearson correlation analysis was implemented to determine the relationships among the heavy metals, and principal component analysis (PCA) was performed to determine the most common pollution sources. The elements As, Cd, Pb, and Zn were grouped together, and the anthropogenic sources of these heavy metals were closely related. The sites with higher Cd concentrations were mainly confined to the river's reach near industrial areas. Controlling the pollution sources will effectively reduce the pollutant concentrations in the sediment.

Risk analysis of emergent water pollution accidents based on a Bayesian Network.

To guarantee the security of water quality in water transfer channels, especially in open channels, analysis of potential emergent pollution sources in the water transfer process is critical. It is also indispensable for forewarnings and protection from emergent pollution accidents. Bridges above open channels with large amounts of truck traffic are the main locations where emergent accidents could occur. A Bayesian Network model, which consists of six root nodes and three middle layer nodes, was developed in this paper, and was employed to identify the possibility of potential pollution risk. Dianbei Bridge is reviewed as a typical bridge on an open channel of the Middle Route of the South to North Water Transfer Project where emergent traffic accidents could occur. Risk of water pollutions caused by leakage of pollutants into water is focused in this study. The risk for potential traffic accidents at the Dianbei Bridge implies a risk for water pollution in the canal. Based on survey data, statistical analysis, and domain specialist knowledge, a Bayesian Network model was established. The human factor of emergent accidents has been considered in this model. Additionally, this model has been employed to describe the probability of accidents and the risk level. The sensitive reasons for pollution accidents have been deduced. The case has also been simulated that sensitive factors are in a state of most likely to lead to accidents.