A Novel Network Pharmacology Strategy Based on the Universal Effectiveness-Common Mechanism of Medical Herbs Uncovers Therapeutic Targets in Traumatic Brain Injury.

Purpose: Many herbs can promote neurological recovery following traumatic brain injury (TBI). There must lie a shared mechanism behind the common effectiveness. We aimed to explore the key therapeutic targets for TBI based on the common effectiveness of the medicinal plants. Material and methods: The TBI-effective herbs were retrieved from the literature as imputes of network pharmacology. Then, the active ingredients in at least two herbs were screened out as common components. The hub targets of all active compounds were identified through Cytohubba. Next, AutoDock vina was used to rank the common compound-hub target interactions by molecular docking. A highly scored compound-target pair was selected for in vivo validation. Results: We enrolled sixteen TBI-effective medicinal herbs and screened out twenty-one common compounds, such as luteolin. Ten hub targets were recognized according to the topology of the protein-protein interaction network of targets, including epidermal growth factor receptor (EGFR). Molecular docking analysis suggested that luteolin could bind strongly to the active pocket of EGFR. Administration of luteolin or the selective EGFR inhibitor AZD3759 to TBI mice promoted the recovery of body weight and neurological function, reduced astrocyte activation and EGFR expression, decreased chondroitin sulfate proteoglycans deposition, and upregulated GAP43 levels in the cortex. The effects were similar to those when treated with the selective EGFR inhibitor. Conclusion: The common effectiveness-based, common target screening strategy suggests that inhibition of EGFR can be an effective therapy for TBI. This strategy can be applied to discover core targets and therapeutic compounds in other diseases.

Buyang huanwu decoction promotes remyelination via miR-760-3p/GPR17 axis after intracerebral hemorrhage.

ETHNOPHARMACOLOGICAL RELEVANCE: The repairment of myelin sheaths is crucial for mitigating neurological impairments of intracerebral hemorrhage (ICH). However, the current research on remyelination processes in ICH remains limited. A representative traditional Chinese medicine, Buyang Huanwu decoction (BYHWD), shows a promising therapeutic strategy for ICH treatment. AIM OF THE STUDY: To investigate the pro-remyelination effects of BYHWD on ICH and explore the underlying mechanisms. MATERIALS AND METHODS: The collagenase-induced mice ICH model was created for investigation. BYHWD's protective effects were assessed by behavioral tests and histological staining. Transmission electron microscopy was used for displaying the structure of myelin sheaths. The remyelination and oligodendrocyte differentiation were evaluated by the expressions of myelin proteolipid protein (PLP), myelin basic protein (MBP), MBP/TAU, Olig2/CC1, and PDGFRα/proliferating cell nuclear antigen (PCNA) through RT-qPCR and immunofluorescence. Transcriptomics integrated with disease database analysis and experiments in vivo and in vitro revealed the microRNA-related underlying mechanisms. RESULTS: Here, we reported that BYHWD promoted the neurological function of ICH mice and improved remyelination by increasing PLP, MBP, and TAU, as well as restoring myelin structure. Besides, we showed that BYHWD promoted remyelination by boosting the differentiation of PDGFRα+ oligodendrocyte precursor cells into olig2+/CC1+ oligodendrocytes. Additionally, we demonstrated that the remyelination effects of BYHWD worked by inhibiting G protein-coupled receptor 17 (GPR17). miRNA sequencing integrated with miRNA database prediction screened potential miRNAs targeting GPR17. By applying immunofluorescence, RNA in situ hybridization and dual luciferase reporter gene assay, we confirmed that BYHWD suppressed GPR17 and improved remyelination by increasing miR-760-3p. CONCLUSIONS: BYHWD improves remyelination and neurological function in ICH mice by targeting miR-760-3p to inhibit GPR17. This study may shed light on the orchestration of remyelination mechanisms after ICH, thus providing novel insights for developing innovative prescriptions with brain-protective properties.

Large-Scale Observations Support Aboveground Vegetation as an Important Biological Mercury Sink in the Tibetan Plateau.

Mercury, a pervasive global pollutant, primarily enters the atmosphere through human activities and legacy emissions from the land and oceans. A significant portion of this mercury subsequently settles on land through vegetation uptake. Characterizing mercury storage and distribution within vegetation is essential for comprehending regional and global mercury cycles. We conducted an unprecedented large-scale aboveground vegetation mercury survey across the expansive Tibetan Plateau. We find that mosses (31.1 ± 0.5 ng/g) and cushion plants (15.2 ± 0.7 ng/g) outstood high mercury concentrations. Despite exceptionally low anthropogenic mercury emissions, mercury concentrations of all biomes exceeded at least one-third of their respective global averages. While acknowledging the role of plant physiological factors, statistical models emphasize the predominant impact of atmospheric mercury on driving variations in mercury concentrations. Our estimations indicate that aboveground vegetation on the plateau accumulates 32-12+21 Mg (interquartile range) mercury. Forests occupy the highest biomass and store 82% of mercury, while mosses, representing only 3% of the biomass, disproportionally contribute 13% to mercury storage and account for 43% (2.5-1.4+3.0 Mg/year) of annual mercury assimilation by vegetation. Additionally, our study underscores that extrapolating aboveground vegetation mercury storage from lower-altitude regions to the Tibetan Plateau can lead to substantial overestimation, inspiring further exploration in alpine ecosystems worldwide.

A novel microbial and hepatic biotransformation-integrated network pharmacology strategy explores the therapeutic mechanisms of bioactive herbal products in neurological diseases: the effects of Astragaloside IV on intracerebral hemorrhage as an example.

BACKGROUND: The oral bioavailability and blood-brain barrier permeability of many herbal products are too low to explain the significant efficacy fully. Gut microbiota and liver can metabolize herbal ingredients to more absorbable forms. The current study aims to evaluate the ability of a novel biotransformation-integrated network pharmacology strategy to discover the therapeutic mechanisms of low-bioavailability herbal products in neurological diseases. METHODS: A study on the mechanisms of Astragaloside IV (ASIV) in treating intracerebral hemorrhage (ICH) was selected as an example. Firstly, the absorbed ASIV metabolites were collected by a literature search. Next, the ADMET properties and the ICH-associated targets of ASIV and its metabolites were compared. Finally, the biotransformation-increased targets and biological processes were screened out and verified by molecular docking, molecular dynamics simulation, and cell and animal experiments. RESULTS: The metabolites (3-epi-cycloastragenol and cycloastragenol) showed higher bioavailability and blood-brain barrier permeability than ASIV. Biotransformation added the targets ASIV in ICH, including PTK2, CDC42, CSF1R, and TNF. The increased targets were primarily enriched in microglia and involved in cell migration, proliferation, and inflammation. The computer simulations revealed that 3-epi-cycloastragenol bound CSF1R and cycloastragenol bound PTK2 and CDC42 stably. The In vivo and in vitro studies confirmed that the ASIV-derived metabolites suppressed CDC42 and CSF1R expression and inhibited microglia migration, proliferation, and TNF-α secretion. CONCLUSION: ASIV inhibits post-ICH microglia/macrophage proliferation and migration, probably through its transformed products to bind CDC42, PTK2, and CSF1R. The integrated strategy can be used to discover novel mechanisms of herbal products or traditional Chinses medicine in treating diseases.

Transport of mercury in a regulated high-sediment river and its input to marginal seas.

Seafood is a major source of Hg exposure for humans, and rivers are an important source of Hg for adjacent seas. The Yellow River is an extremely high-sediment river that is heavily influenced by anthropogenic water facilities, especially sediment regulations, which might result in significant intra- and inter- year flux variations on pollutants. Overestimations of Hg flux were found in previous studies on high-sediment rivers, and a comprehensive study of Hg transport along such a river has not yet been attempted. In this study, we quantified the fates of Hg and methylmercury (MeHg) in the Yellow River and its main branches, as well as the impacts of anthropogenic activities, including deposition of contaminants in the reservoirs, diversion in the downstream, and sediment regulation, by sampling in 2017 and 2018,and comparing the two typical years with and without sediment regulation. The total Hg (THg) and MeHg concentrations in the Yellow River and its tributaries were high, and extremely high MeHg/THg ratios were found in the three sampled reservoirs. The river discharges substantial amounts of THg and MeHg into the Bohai Sea, and particulate Hg in the humid period accounts for a large proportion. A significant increase in Hg flux into the ocean was found in 2018 compared with that in 2017, which was primarily attributed to the altered hydrology caused by sediment regulation. Substantial amounts of Hg were impounded in the reservoirs, and only a small fraction was discharged downstream of the reservoir in the non-regulation years. Moreover, Hg fluxes to the coastal ocean were impacted by downstream water diversion in non-regulation years, whereas the contributions of diversions in regulation years were small. In conclusion, models showed that in recent 15 years, sediment regulation can enhance the Hg burden and risk to coastal ecosystem of Bohai Sea.

Human Methylmercury Exposure and Potential Impacts in Central Tibet: Food and Traditional Tibetan Medicine.

Methylmercury presents potent neurotoxicity to humans. Fish consumption is the leading source of human exposure to methylmercury worldwide. However, the exposure source in Tibet remains poorly understood because of the scarcity of observational data on most Tibetan foods, although high mercury levels were recently detected in some traditional Tibetan medicines. Here, the results of field investigations show that the joint consumption of traditional Tibetan medicines (TTMs), fish, and rice constitutes a primary exposure pathway to methylmercury in Tibetans and that the probable daily intake of methylmercury is close to that for many coastal regions. People who are young and high-income may have higher methylmercury exposure levels mainly because of economic development and cultural exchanges among regions. Our analysis indicates that a large proportion of the Tibetan population are likely to face a high methylmercury exposure risk and that mercury-susceptible populations in Tibet should be attentive to consuming TTMs with fish.

Biotransport of mercury and human methylmercury exposure through crabs in China - A life cycle-based analysis.

Exposure to methylmercury (MeHg) has various toxic effects on humans. The evaluation of human MeHg exposure has previously focused on fish consumption. However, in this study, we found that MeHg levels in domestic crabs in China were also relatively high (range: 50-1400 ng/g, dry weight). The high MeHg levels in crabs and their high consumption do not match the risk assessment of MeHg, indicating an underestimated exposure risk, especially in MeHg-sensitive groups such as pregnant women. The annual crab MeHg content output in China was estimated to be 30 ± 27 kg. A total of 6.8% of the country's land area contributes 71% of the MeHg output. However, 66% of the output is redistributed to non-crab-producing regions via interregional food trade, posing risks to the population on a national scale. The daily intake of MeHg from crabs could easily exceed the reference dose (0.1 µg/kg of body weight per day) suggested by the United States Environmental Protection Agency with consideration of coexposure from fish, rice, and other food sources. We suggest that future MeHg exposure analysis includes crab MeHg as a coexposure pathway to estimate the dietary MeHg limit accurately and emphasize the influence of interregional food trade on MeHg exposure.

Mercury and methylmercury in China's lake sediments and first estimation of mercury burial fluxes.

Lake sediments are key materials for mercury deposition and methylation. To understand the mercury concentrations in China's lakes, 100 lake surface sediment samples were collected from 35 lakes in 2014. Total mercury (THg), methylmercury (MeHg) concentrations and the annual Hg burial rates in lake sediments were measured. THg and MeHg concentrations in the sediment ranged from 13.6 to 1488 ng‧g-1 and 0.05 to 1.70 ng‧g-1, respectively, and urban lakes reported most high values, indicating direct anthropogenic inputs. The Inner Mongolia-Xinjiang Region (MX) and Qinghai-Tibet Plateau Region (QT) reported relatively lower mercury burial rates, while the Eastern Plain Region (EP), Northeast Mountain and Plain Region (NE), and Yunnan-Guizhou Plateau Region (YG) reported higher mercury burial rates. Regional variances of THg burial fluxes were dominated by atmospheric deposition, terrestrial input, and sediment accumulation rates in different lakes. In 2014, the estimated average THg burial rate in China's lakes was 139 µg‧m-2‧yr-1, comparable to the average in mid-latitude North America in recent years; however, due to China's much smaller lake area relative to NA, the annual THg burial flux in China was much lower than that in North America. EP and NE, where most freshwater aquatic products in China are harvested, accounted for 58.2% and 22.9%, respectively, of the THg burial flux. High sedimentary MeHg concentrations and MeHg:THg ratios were reported in most of the NE but low MeHg concentrations and MeHg:THg ratios were reported in EP. MeHg concentrations and MeHg:THg ratios were positively correlated with water COD levels and negatively correlated with average temperature. The results of this study indicate that in addition to the adjacent seas, lake sediments are an important mercury sink in China's aquatic environment, which could cause health risks due to MeHg intake, especially in NE.

Significant elevation of human methylmercury exposure induced by the food trade in Beijing, a developing megacity.

Methylmercury (MeHg) poses health risks to humans worldwide. The investigation of a longer chain of biogeochemical MeHg transport from production to consumption than that addressed in previous studies could provide additional scientific foundation for the reduction of risks. The main objective of this study is to identify the impacts of the interregional food trade along with the age, gender and socioeconomic status of people on human MeHg exposure in a developing megacity. Based on a field investigation, sampling and measurements, we provide experimental evidence regarding the substantial displacement of human MeHg exposure from production areas to consumption areas induced by the food trade. In 2018, 20% and 64% of the exposure in Beijing originated from the international and interprovincial food trade, respectively. Meanwhile, the ingestion of fish contributed 79% to the total exposure, followed by rice (4.4%), crab (3.8%) and shrimp (2.7%), and the exposure risk in urban districts was higher than that in rural areas by a factor of 2.2. A significantly higher contribution of imported deep-sea species to exposure among young people than among older people was observed (P < 0.01**), and a larger contribution of the international food trade to the MeHg exposure risk for women of childbearing age (average: 27%) than that among other groups (average: 10%) was found. Overall, our efforts demonstrate the dramatic impact of the food trade on MeHg exposure in a developing megacity, and we suggest that MeHg-susceptible populations in China should choose indigenous fish species (e.g., hairtail, yellow croaker and carp species) rather than imported deep-sea species as their dietary protein source.

Rice life cycle-based global mercury biotransport and human methylmercury exposure.

Protecting the environment and enhancing food security are among the world's greatest challenges. Fish consumption is widely considered to be the single significant dietary source of methylmercury. Nevertheless, by synthesizing data from the past six decades and using a variety of models, we find that rice could be a significant global dietary source of human methylmercury exposure, especially in South and Southeast Asia. In 2013, globalization caused 9.9% of human methylmercury exposure via the international rice trade and significantly aggravated rice-derived exposure in Africa (62%), Central Asia (98%) and Europe (42%). In 2016, 180 metric tons of mercury were generated in rice plants, 14-fold greater than that exported from oceans via global fisheries. We suggest that future research should consider both the joint ingestion of rice with fish and the food trade in methylmercury exposure assessments, and anthropogenic biovectors such as crops should be considered in the global mercury cycle.

Traditional Tibetan Medicine Induced High Methylmercury Exposure Level and Environmental Mercury Burden in Tibet, China.

Highly elevated concentrations of total mercury (THg) and methylmercury (MeHg) were found in the municipal sewage in Tibet. Material flow analysis supports the hypothesis that these elevated concentrations are related to regular ingestion of Hg-containing Traditional Tibetan Medicine (TTM). In Tibet in 2015, a total of 3600 kg of THg was released from human body into the terrestrial environment as a result of TTM ingestion, amounting to 45% of the total THg release into the terrestrial environment in Tibet, hence substantially enhancing the environmental Hg burden. Regular ingestion of TTM leads to chronic exposure of Tibetans to inorganic Hg (IHg) and MeHg, which is 34 to 3000-fold and 0-12-fold higher than from any other known dietary sources, respectively. Application of a human physiology model demonstrated that ingestion of TTM can induce high blood IHg and MeHg levels in the human body. Moreover, 180 days would be required for the MeHg to be cleared out of the human body and return to the initial concentration i.e. prior to the ingestion of 1 TTM pill. Our analysis suggests that high Hg level contained in TTM could be harmful to human health and elevate the environmental Hg burden in Tibet.