Influence of climate and land use on watershed anthropogenic phosphorus inputs and riverine phosphorus export dynamics: A global analysis.

Many studies have found predictive relationships between riverine phosphorus (P) export and net anthropogenic P inputs (NAPI) at the watershed scale, but the global or regional extent of these relationships has not been empirically quantified. Herein, we present a data-driven global assessment of the response of riverine total P (TP) fluxes to NAPI based on 358 watersheds. NAPI exhibited high spatial heterogeneity (2-12,085 kg P km-2 yr-1) and was well correlated with riverine TP fluxes. Riverine TP export fractions of NAPI were primarily regulated by NAPI components, hydroclimate factors, and land-use as determined through a random-forest meta-analysis. In watersheds dominated by disturbed land-use (e.g., agricultural and developed lands), runoff emerged as pivotal climate-related factors influencing riverine export fractions of NAPI. In watersheds dominated by natural land-use, runoff, precipitation and temperature were identified as the most critical factors. We developed a mixed-effects meta-regression model (R2 = 0.63-0.70, RMSE = 19-78 %, n = 87-202) to examine the quantitative relationship between riverine TP fluxes and NAPI, which avoids subjectivity in selecting influencing factors and regression forms. The model estimated that legacy P contributed 14-17 % of annual riverine TP fluxes in Chinese watersheds, 25 % in North American watersheds and 11-27 % in European watersheds. Annual NAPI contributions to annual riverine TP flux were 83-86 % in China, 75 % in North America and 73-89 % in Europe. The model forecasted 52-67 %, 69-71 % and 74-77 % reductions in riverine TP fluxes across Chinese, North American, and European watersheds by 2050 under five shared socio-economic pathway scenarios compared to 2010 baseline conditions, respectively. This study provides a straightforward and reliable method for quantifying anthropogenic P input and riverine P export dynamics within an acceptable error range. It provides guidance for developing phosphorus pollution control strategies to counter potential increases in phosphorus inputs due to expected changes in climate and land use.

Unravelling hidden threats of water disinfection: Toxicity evaluation and toxic products identification during diclofenac degradation.

Diclofenac (DCF) is a widely-used nonsteroidal anti-inflammatory drug that is routinely found in surface water bodies. While ozonation and ultraviolet (UV) radiation are commonly employed as disinfection methods in water treatment processes, the degradation of DCF in these processes occurs due to the strong oxidizing activity of the reactive oxygen species produced during both ozonation and UV radiation. Despite extensive studies reporting the removal and transformation of DCF through ozone and UV treatments, the potential hidden hazards of toxicity arising from these processes as well as the identification of the toxic transformation products have often been overlooked. In this study, various toxicities including microtoxicity, genotoxicity and antiestrogenicity were evaluated using multiple in-vitro bioassays. The transformation products were identified via ultra-performance liquid chromatography equipped with mass spectrometry (UPLC-MS). Correlation analysis was employed to gain deeper insight into the contributions of degradation products to overall toxicity. The results revealed that DCF possessed significant genotoxic and antiestrogenic effects, but displayed minimal microtoxicity. Microtoxic products such as those containing carbazole were generated during DCF degradation with ozone, UVA and UVC. Antiestrogenic products with dichloroaniline structures were observed in DCF ozonation but not in photodegradation by UVA and UVC. These findings highlighted the hidden risks associated with the disinfection of water containing micropollutants such as DCF.

Evaluation of three prevalent global riverine nutrient transport models.

Global riverine nitrogen (N) and phosphorus (P) transport models offer important insights into basin nutrient cycling. However, appropriate model selection for a given research objective remains ambiguous. This study conducted a meta-analysis to evaluate the performance and applicability of three prevalent global riverine nutrient transport models: Global NEWS, IMAGE-GNM, and WorldQual. According to performance criteria (satisfactory: R2 > 0.50 and NSE > 0.50), the Global NEWS model performs satisfactorily in simulating dissolved organic nitrogen (DON; n = 101, R2 = 0.58, NSE = 0.57) and dissolved organic phosphorus loads (DOP; n = 80, R2 = 0.59, NSE = 0.59). The model falls short in simulating dissolved inorganic nitrogen (DIN; n = 644, R2 = 0.56, NSE = - 0.80) and dissolved inorganic phosphorus loads (DIP; n = 450, R2 = 0.33, NSE = - 0.12). The IMAGE-GNM model shows satisfactory accuracies in simulating riverine total nitrogen (TN; n = 831, R2 = 0.56, NSE = 0.53) and total phosphorus (TP; n = 902, R2 = 0.59, NSE = 0.48) concentrations, particularly in European basins. The WorldQual model presented unsatisfactory performance in simulating riverine TN (n = 11, R2 = 0.76, NSE = 0.34) and TP (n = 13, R2 = 0.71, NSE = - 0.25) concentrations. Using a two-segment linear model, we recommend the Global NEWS model for basins larger than 2.2 × 104 km2 for DIN and 3.2 × 104 km2 for DIP. The IMAGE-GNM model is best suited for basins with long-term datasets and high latitudes (TN > 21 years and > 53.8 °N; TP > 22 years and > 54.5 °N). For model improvements, both the Global NEWS and WorldQual models could benefit from enhanced in-stream nutrient retention/release modules. The Global NEWS model could be further improved with a better chemical weathering module. For the IMAGE-GNM model, refining the soil erosion module is warranted to enhance model performance. Addressing legacy nutrient effects is crucial for all three models. This study provides valuable guidance for selecting and improving nutrient transport models based on specific research needs.

Nano-composite system of traditional Chinese medicine for ocular applications: molecular docking and three-dimensional modeling insight for intelligent drug evaluation.

The absorption of drugs was impeded in the posterior part of the eye due to the special structure. In addition, it was crucial to comprehend transport laws of molecules in ocular drug delivery for designing effective strategies. However, the current quality evaluation methods of the eye were backward and lack of dynamic monitoring of drug processes in vivo. Herein, nano-drug delivery system and three-dimensional (3D) model were combined to overcome the problems of low bioavailability and diffusion law. The model drugs were screened by molecular docking. The flexible nano-liposome (FNL) and temperature-sensitive gel (TSG) composite formulation was characterized through comprehensive evaluation. COMSOL software was utilized to build 3D eyeball to predict the bioavailability of drugs. The size of the preparation was about 98.34 nm which is relatively optimal for the enhanced permeability of the eyes. The formulation showed a stronger safety and non-irritant. The pharmacokinetics results of aqueous humor showed that the AUC of two drugs in this system increased by 3.79 and 3.94 times, respectively. The results of 3D calculation model proved that the concentrations of drugs reaching the retina were 1.90×10-5 mol/m3 and 6.37×10-6 mol/m3. In conclusion, the FNL-TSG markedly improved the bioavailability of multiple components in the eye. More importantly, a simplified 3D model was developed to preliminarily forecast the bioavailability of the retina after drug infusion, providing technical support for the accurate evaluation of ocular drug delivery. It provided new pattern for the development of intelligent versatile ophthalmic preparations.

An in silico and in vitro integrated analysis method to reveal the curative mechanisms and pharmacodynamic substances of Bufei granule on chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a common respiratory disease with high disability and mortality. Clinical studies have shown that the Traditional Chinese Medicine Bufei Granule (BFG) has conspicuous effects on relieving cough and improving lung function in patients with COPD and has a reliable effect on the treatment of COPD, whereas the therapeutic mechanism is vague. In the present study, the latent bronchodilators and mechanism of BFG in the treatment of COPD were discussed through the method of network pharmacology. Then, the molecular docking and molecular dynamics simulation were performed to calculate the binding efficacy of corresponding compounds in BFG to muscarinic receptor. Finally, the effects of BFG on bronchial smooth muscle were validated by in vitro experiments. The network pharmacology results manifested the anti-COPD effect of BFG was mainly realized via restraining airway smooth muscle contraction, activating cAMP pathways and relieving oxidative stress. The results of molecular docking and molecular dynamics simulation showed alpinetin could bind to cholinergic receptor muscarinic 3. The in vitro experiment verified both BFG and alpinetin could inhibit the levels of CHRM3 and acetylcholine and could be potential bronchodilators for treating COPD. This study provides an integrating network pharmacology method for understanding the therapeutic mechanisms of traditional Chinese medicine, as well as a new strategy for developing natural medicines for treating COPD.

A strategy based on gene sequencing and molecular docking for analysis and prediction of bioactive peptides in Shuxuetong injection.

Peptides are a class of protein fragments with relatively high biological activity and intense specificity, which play crucial role in the treatment of Shuxuetong injection (SXT). However, the extraordinary complexity of Chinese medicinal formulates and the lack of systematic identification methods are primary challenges for study of pharmacodynamic peptides. In addition, infinitesimal peptides contents further hinder the identification and structural characterization of polypeptide by traditional means. In this paper, we described a strategy that LC-MS combined with molecular docking to systematically illustrate the peptide components of SXT. The key to this research was used of gene sequencing to establish a SXT protein database to further achieve the separation and enrichment of chemical methods. Moreover, the ADRA2A, PAR4 and DRD3 were precisely docked with the identified peptides. The result indicated that 12 compounds had stable binding ability and were speculated to be the latent bioactive monomers for the treatment of stroke. Additionally, 12 peptides were verified by cell-based experiment. The results showed that only YLKTT could indeed protect astrocytes from oxygen glucose deprivation/reoxygenation (OGD/R). The YLKTT showed higher activity than the others in vitro. It might be a completely new compound that has never been reported before, providing the basis for further research and a new paradigm for stroke.

Targeted drug delivery vehicles mediated by nanocarriers and aptamers for posterior eye disease therapeutics: barriers, recent advances and potential opportunities.

Nanomedicine and aptamer have excellent potential in giving play to passive and active targeting respectively, which are considered to be effective strategies in the retro-ocular drug delivery system. The presence of closely adjoined tissue structures in the eye makes it difficult to administer the drug in the posterior segment of the eye. The application of nanomedicine could represent a new avenue for the treatment, since it could improve penetration, achieve targeted release, and improve bioavailability. Additionally, a novel type of targeted molecule aptamer with identical objective was proposed. As an emerging molecule, aptamer shows the advantages of penetration, non-toxicity, and high biocompatibility, which make it suitable for ocular drug administration. The purpose of this paper is to summarize the recent studies on the effectiveness of nanoparticles as a drug delivery to the posterior segment of the eye. This paper also creatively looks forward to the possibility of the combined application of nanocarriers and aptamers as a new method of targeted drug delivery system in the field of post-ophthalmic therapy.

A Comprehensive Review of Pharmacokinetics and Pharmacodynamics in Animals: Exploration of Interaction with Antibiotics of Shuang-Huang- Lian Preparations.

As a traditional Chinese medicine (TCM), Shuang-Huang-Lian (SHL) has been widely used for treating infectious diseases of the respiratory tract such as encephalitis, pneumonia, and asthma. During the past few decades, considerable research has focused on pharmacological action, pharmacokinetic interaction with antibiotics, and clinical applications of SHL. A huge and more recent body of pharmacokinetic studies support the combination of SHL and antibiotics have different effects such as antagonism and synergism. SHL has been one of the best-selling TCM products. However, there is no systematic review of SHL preparations, ranging from protection against respiratory tract infections to interaction with antibiotics. Since their important significance in clinical therapy, the pharmacodynamics, pharmacokinetics, and interactions with antibiotics of SHL were reviewed and discussed. In addition, this review attempts to explore the possible potential mechanism of SHL preparations in the prevention and treatment of COVID-19. We are concerned about the effects of SHL against viruses and bacteria, as well as its interactions with antibiotics in an attempt to provide a new strategy for expanding the clinical research and medication of SHL preparations.

Study on the Mechanism of Prunella Vulgaris L on Diabetes Mellitus Complicated with Hypertension Based on Network Pharmacology and Molecular Docking Analyses.

The role of traditional Chinese medicine Prunella vulagaris L in the treatment of tumors and inflammation has been widely confirmed. We found that some signaling pathways of Prunella vulgaris L action can also regulate diabetes and hypertension, so we decided to study the active ingredients, potential targets and signaling pathway of Prunrlla vulgaris L, and explore the "multi-target, multi-pathway" molecular mechanism of Prunella vulgaris L on diabetes mellitus complicated with hypertension(DH). Methods. Based on TCMSP(Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform) and CNKI(China National Knowledge Infrastructure), the components and action targets related to Prunella vulgaris L were screened. The OMIM(Online Mendelian Inheritance in Man) and GeneCards (The human gene database) were used to search for targets related to DH. The "gene - drug - disease" relationship map was drawn by Cytoscape_v3.7.2 plug-in. The target was amplified by the STRING platform, and the "protein - protein" interaction relationship (PPI) network of the interacting target was obtained by the STRING online analysis platform and the Cytoscape_v3.7.2 plug-in. Finally, GO enrichment analysis and KEGG pathway enrichment analysis were conducted on David and Metascape platform to study the co-acting targets. Results. 11 active components, 41 key targets and 16 significant signaling pathways were identified from Prunella vulgaris L. The main active components of Prunella vulgaris L against DH were quercetin and kaumferol, etc, and potential action targets were IL-6 and INS, etc and signaling pathways were AGE-RAGE signaling pathway, TNF signaling pathway, MAPK signaling pathway, PI3K-AKT signaling pathway, etc. It involves in biological processes such as cell proliferation, apoptosis and inflammatory response. Conclusions. The main molecular mechanism of Prunella vulgaris L against DH is that sterols and flavonoids play an active role by affecting TNF signaling pathway, AGE-RAGE signaling pathway, MAPK pathway, PI3K-Akt pathway related targets such as IL-6 and INS.

A comprehensive application: Molecular docking and network pharmacology for the prediction of bioactive constituents and elucidation of mechanisms of action in component-based Chinese medicine.

Traditional Chinese medicine (TCM) has been used for more than 2000 years in China. TCM has received wide attention recently due to its unique charm. At the same time, its main obstacles have attracted wide attention, including vagueness of drug composition and treatment mechanism. With the development of virtual screening technology, more and more Chinese medicine compounds have been studied to discover the potential active components and mechanisms of action. Molecular docking is a computer technology based on structural design. Network pharmacology establishes powerful and comprehensive databases to understand the relationship between TCM and disease network. In this review, emergent uses and applications of two techniques and further superiorities of the two techniques when embarked to boil down into a tidy system were illustrated. A combination of the two provides a theoretical basis and technical support for the construction of modern TCM based on the compatibility of components and accelerates the realization of two basic elements as well, including the clearness of the pharmacodynamic substances and explanation of the effect of TCM.

Advances in Pharmacological Actions and Mechanisms of Flavonoids from Traditional Chinese Medicine in Treating Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a common respiratory disease with high morbidity and mortality. The conventional therapies remain palliative and have various undesired effects. Flavonoids from traditional Chinese medicine (TCM) have been proved to exert protective effects on COPD. This review aims to illuminate the poly-pharmacological properties of flavonoids in treating COPD based on laboratory evidences and clinical data and points out possible molecular mechanisms. Animal/laboratory studies and randomised clinical trials about administration of flavonoids from TCM for treating COPD from January 2010 to October 2020 were identified and collected, with the following terms: chronic obstructive pulmonary disease or chronic respiratory disease or inflammatory lung disease, and flavonoid or nature product or traditional Chinese medicine. Pharmacokinetic studies and external application treatment were excluded. A total of 15 flavonoid compounds were listed. Flavonoids could inhibit inflammation, oxidative stress, and cellular senescence, restore corticosteroid sensitivity, improve pulmonary histology, and boost pulmonary function through regulating multiple targets and signaling pathways, which manifest that flavonoids are a group of promising natural products for COPD. Nevertheless, most studies remain in the research phase of animal testing, and further clinical applications should be carried out.

Randomized controlled trial on adjunctive cognitive remediation therapy for chronically hospitalized patients with schizophrenia.

BACKGROUND: Cognitive remediation therapy (CRT) is one of the promising new non-drug approaches to reducing cognitive deficits of patients with schizophrenia that has not yet been fully evaluated in China. AIM: Assess the efficacy of CRT in improving the cognitive functioning, social functioning and insight of patients with chronic schizophrenia. METHODS: 126 clinically stable inpatients with chronic schizophrenia were randomly allocated to an intervention group (with CRT) and a treatment as usual group (TAU) (which used standard occupational and recreational therapy methods). The treatment frequency and duration were the same for the two groups: five times per week for three months. The Wisconsin Card Sorting Test (WCST) was used to evaluate before versus after changes in cognitive function, the Scale of Social Skills of chronic schizophrenia Inpatients (SSSI) was used to assess social functioning, and the Insight and Treatment Attitude Questionnaire (ITAQ) was use to assess insight. RESULTS: Four patients dropped out during the study leaving 60 in the CRT group and 62 in the TAU group in the final analysis. Both groups showed significant improvement in WCST measures over the three-month trial but the improvement in the CRT group was significantly greater than that for the TAU group on all of the WCST measures assessed. The total SSSI score improved significantly in both groups over the three months, but the improvement in the two groups was not significantly different. The total ITAQ score also showed significant improvement in both groups over the three months and the degree of improvement was significantly greater in the CRT group than in the TAU group. CONCLUSION: As an adjunctive treatment to antipsychotic medication, a three month course of CRT is more effective at improving the cognitive functioning and insight of hospitalized patients with chronic schizophrenia than routine occupational and recreational therapy.