Uncovering the key pharmacodynamic material basis and possible molecular mechanism of extract of Epimedium against liver cancer through a comprehensive investigation.

ETHNOPHARMACOLOGICAL RELEVANCE: Liver cancer is a worldwide malignant tumor, and currently lacks effective treatments. Clinical studies have shown that epimedium (YYH) has therapeutic effects on liver cancer, and some of its prenylflavonoids have demonstrated anti-liver cancer activity through multiple mechanisms. However, there is still a need for systematic research to uncover the key pharmacodynamic material basis and mechanism of YYH. AIM OF THE STUDY: This study aimed to screen the anti-cancer material basis of YYH via integrating spectrum-effect analysis with serum pharmacochemistry, and explore the multi-target mechanisms of YYH against liver cancer by combining network pharmacology with metabolomics. MATERIALS AND METHODS: The anti-cancer effect of the extract of YYH (E-YYH) was first evaluated in mice with xenotransplantation H22 tumor cells burden and cultured hepatic cells. Then, the interaction between E-YYH compounds and the cytotoxic effects was revealed through spectrum-effect relationship analysis. And the cytotoxic effects of screened compounds were verified in hepatic cells. Next, UHPLC-Q-TOF-MS/MS was employed to identify the absorbed components of E-YYH in rat plasma to distinguish anti-cancer components. Subsequently, network pharmacology based on anti-cancer materials and metabolomics were used to discover the potential anti-tumor mechanisms of YYH. Key targets and biomarkers were identified and pathway enrichment analysis was performed. RESULTS: The anti-cancer effect of E-YYH was verified through in vitro and in vivo experiments. Six anti-cancer compounds in plasma (icariin, baohuoside Ⅰ, epimedin C, 2″-O-rhamnosyl icariside Ⅱ, epimedin B and sagittatoside B) were screened out by spectrum-effect analysis. Forty-five liver-cancer-related targets were connected with these compounds. Among these targets, PTGS2, TNF, NOS3 and PPARG were considered to be the potential key targets preliminarily verified by molecular docking. Meanwhile, PI3K/AKT signaling pathway and arachidonic acid metabolism were found to be associated with E-YYH's efficacy in network pharmacology and metabolomics analysis. CONCLUSIONS: Our research revealed the characteristics of multi-component, multi-target and multi-pathway mechanism of E-YYH. This study also provided an experimental basis and scientific evidence for the clinical application and rational development of YYH.

Intrinsic Mitochondrial Reactive Oxygen Species (ROS) Activate the In†Situ Synthesis of Trimethine Cyanines in Cancer Cells.

Environment-responsive in situ synthesis of molecular fluorescent dyes is challenging. Herein, we develop a photoextension strategy to make trimethine cyanines with decent conversion efficiency (up to 81 %) using 1-butyl 2,3,3-trimethyl 3H-indole derivatives as the sole precursors, and demonstrate a free radical mechanism. In the inducer-extension stage, free radicals and reactive oxygen species (ROS) were able to mediate similar reactions with no assistance of light. We explored a Mito-extension strategy to in situ synthesize trimethine cyanines in the living cells. The cellular ROS-dependence provided a foundation for preferential cyanine expression in cancer cells. Finally, we applied an iodized precursor as an intrinsic ROS-activated theranostic agent that integrated mitochondria-targeted cyanine synthesis, cell imaging and phototherapy.

Coal gangue modified bioretention system for runoff pollutants removal and the biological characteristics.

In this study, coal gangue (CG) was applied as media in bioretention system to remove runoff pollutant. CG modified bioretention systems show good removal efficiency towards runoff pollutant due to the high adsorption capacity of CG. The removal of total phosphorus (TP), total nitrogen (TN), ammonia (NH4+-N) and chemical oxygen demand (COD) by CG modified bioretention systems was influenced by diverse rainfall conditions including rainfall concentration, recurrence period and drying period, and their removal rate ranged 94-99%, 30-70%, 83-97% and 33-86%, respectively. The effluent concentration of Zn, Pb and Cu was as low as 3.14-10.99 µg/L, 0.66-2.56 µg/L and 0.60-3.15 µg/L, respectively. In addition, CG could promote the plant heavy metal uptake and thus decrease their accumulation in soil to a certain extent. Meanwhile, Malondialdehyde (MDA) content and peroxidases (POD) activities of plants in CG modified bioretention were lower than that in tradition bioretention, indicating that CG could help plants recovery and lessened the oxidative stress for the negative impact of high heavy metals accumulation. CG-based media alleviated the inhibitory effect of rainwater runoff pollutant accumulation (especially heavy metals) on microbial diversity and the enhancement of the dominant bacteria (such as Proteobacteria and Bacteroidota) could conduce the nutrients removal in the bioretention systems. In overall, this study demonstrated that the CG modified bioretention systems show an excellent removal performance combine with biological effects.

Effect of Electroacupuncture on Bladder Dysfunction via Regulation of MLC and MLCK Phosphorylation in a Rat Model of Type 2 Diabetes Mellitus.

Previous studies observed have reported that electroacupuncture (EA) is effective in relieving diabetic bladder dysfunction (DBD); however, little is known about the mechanism. Therefore, we explored the effects and mechanisms of EA on DBD in streptozotocin-high-fat diet- (STZ-HFD-) induced diabetic rats. The Sprague-Dawley male rats were divided randomly into four groups: normal group, diabetes mellitus group (DM group), DM with EA treatment group (EA group), and DM with sham EA treatment group (sham EA group). After 8 weeks of EA treatment, the body weight, serum glucose, bladder weight, and cystometrogram were evaluated. The bladder wall thickness was examined by abdominal ultrasound imaging. After the transabdominal ultrasound measurements, hematoxylin-eosin (HE) staining was used to observe the bladder mucosa layer. The bladder detrusor smooth muscle cells (SMCs) and fibroblasts were observed under transmission electron microscopy (TEM). The phospho-myosin light chain (p-MLC), phospho-myosin light chain kinase (p-MLCK), and phospho-myosin phosphatase target subunit 1 (p-MYPT1) levels in the bladder were examined using Western blot. The bladder weight, serum glucose, bladder wall thickness, volume threshold for micturition, and postvoid residual (PVR) volume in the diabetic rats were significantly higher than those in the control animals. EA treatment significantly reduced the bladder weight, bladder wall thickness, volume threshold for micturition, and PVR volume in diabetic rats. EA caused a significant increase in the MLC dephosphorylation and MLCK phosphorylation levels in the group compared to the sham EA and model groups. EA reduced the infiltration of inflammatory cells in the bladder mucosa layer of diabetic rats. In addition, EA repaired the damaged bladder detrusor muscle of diabetic rats by reducing mitochondrial damage of the SMCs and fibroblasts. Therefore, EA could reduce the bladder hypertrophy to ameliorate DBD by reversing the impairment in the mucosa layer and detrusor SMCs, which might be mainly mediated by the regulation of p-MLC and p-MLCK levels.

Evaluation of modified permeable pavement systems with coal gangue to remove typical runoff pollutants under simulated rainfall.

Coal gangue (CG) as mineral waste was properly treated and applied as the filter media in permeable pavement systems due to its good sorption ability and mechanical strength. Batch experiments show the maximum adsorption capacity of calcined CG to phosphorus could reach 2.63 mg/g. To evaluate the removal effect of typical runoff pollutants including chemical oxygen demand (COD), total nitrogen (TN), total phosphorus (TP) and ammonia (NH4+-N), the gravel and sand in a traditional pavement system were replaced by CG respectively. The leaching behavior of the four pollutants in CG modified systems is limited and comparable with traditional system, indicating pretreated CG as filler would not cause environmental risk. CG-based pavement systems improved the removal efficiency of the four pollutants especially for TP. The removal mechanisms including interception, adsorption and microorganism degradation. The removal rates of COD, NH4+-N and TN by CG modified and traditional systems decreased with rainfall duration, while it is not obviously changed with rainfall recurrence period and drying period. Overall, the permeable pavement with CG layers that replaced both sand and gravel layers show best removal efficiency of all pollutants investigated especially for TP (>95%). This study provides a new way for CG utilization and gives the reference for the process design of permeable pavement.

A comparison of the growth status, rainfall retention and purification effects of four green roof plant species.

Vegetation is a key component of green roofs and one of the most important factors affecting the rainfall quantity and quality of green roofs. Four plant species (Sedum lineare Thunb., Sedum spurium 'Coccineum', Sedum aizoon L. and Sedum spectabile) and two planting methods (single-plant and mixed-plant) were tested on extensive green roofs (EGRs) in 2019. Plant growth status (plant height and vegetation coverage), rainfall volume control, nutrient concentration and load reduction were used to analyse the impact of the situation and the different plant growth conditions. The results showed that the growth status of Sedum lineare Thunb., Sedum aizoon L. and Sedum spectabile was great, and the vegetation coverage was more than 95% in summer. Each EGR with different sedum species had strong rainfall retention effects. The average retention rates of Sedum spectabile, Sedum lineare Thunb, mixed plants, Sedum aizoon L. and Sedum spurium 'Coccineum' were 90.98% and 91.38%, 88.51%, 83.42% and 84.17%, respectively. The average total nitrogen (TN) and nitrate nitrogen (NO3--N) concentrations of Sedum lineare Thunb. were 13.77 mg/L and 7.64 mg/L, which were higher than those of other sedum species, and the average concentrations of ammonia nitrogen (NH4+-N) and total phosphorus (TP) of mixed plants were 4.01 mg/L and 0.48 mg/L, which were higher than those of single plants. Different plant species had different effects on nutrient loads. The EGRs of single plants and mixed plants indicated sinks of TN and NH4-N and sources of TP, but the performance of NO3--N was inconsistent. Comprehensively, Sedum lineare Thunb., Sedum aizoon L. and Sedum spectabile were suitable for the green roofs. This study provides scientific support for the green roofs' application of actual projects and has a strong reference value for the development of green infrastructure.

Effects of Guizhi decoction for diabetic cardiac autonomic neuropathy: A protocol for a systematic review and meta-analysis.

BACKGROUND: Diabetic cardiac autonomic neuropathy (DCAN) is one of the serious complications of diabetes. The pathogenesis of DCAN has not been fully elucidated. There is currently no effective treatment for such chronic disease. Traditional Chinese medicine has a long clinical history for the prevention and treatment of diabetes and chronic complications, and it also shows certain advantages in the treatment of DCAN. Many clinical studies have confirmed that Chinese medicine Guizhi decoction can reduce the clinical symptoms and improve neuronal function of patients with DCAN. So we intend to conduct a systematic review further clarified the effectiveness and safety of Guizhi decoction for DCAN. METHODS: We will search each database from the built-in until July 2020. The English literature mainly searches Cochrane Library, PubMed, EMBASE, and Web of Science, while the Chinese literature comes from CNKI, CBM, VIP, and Wangfang database. Simultaneously we will retrieval clinical registration tests and grey literatures. In this study, only the clinical randomized controlled trials (RCTs) were selected to evaluate the efficacy and safety of Guizhi decoction in the treatment of DCAN. The 2 researchers independently conducted literature selection, data extraction, and quality assessment. Statistical heterogeneity among studies will be evaluated using the Cochran Q test (x) and the I statistical value. We will utilize the Review Manage software V5.3.0 (The Nordic Cochrane Center, The Cochrane Collaboration, 2014, Copenhagen, Denmark) to statistically analyze all data. ETHICS AND DISSEMINATION: This study is a protocol for a systematic review of Guizhi decoction as a treatment of DCAN patients. RESULTS: This study will provide high-quality synthesis of effectiveness and safety of Guizhi decoction for DCAN. CONCLUSION: This systematic review aims to provide new options for Guizhi decoction treatment of DCAN in terms of its efficacy and safety. REGISTRATION NUMBER: INPLASY202080018.

Vitamin D supplementation in the treatment of type 2 diabetic microangiopathy: A protocol for a systematic review and meta-analysis.

BACKGROUND: The number of people with diabetes is growing exponentially.Human studies have shown that vitamin D supplementation is beneficial for type 2 diabetic microangiopathy. However, owing to the low quality, small sample size, and methodological heterogeneity of these studies, this conclusion is not convincing. Consequently, in order to determine whether vitamin D supplementation is effective and safe in type 2 diabetic microangiopathy, it is necessary to conduct a meta-analysis of high-quality clinical trials. METHODS: We will search each database from the built-in until March 2020. The English literature mainly searches Cochrane Library, PubMed, EMBASE, and Web of Science, while the Chinese literature comes from CNKI, CBM, VIP, and Wangfang database. Simultaneously we will retrieval clinical registration tests and grey literatures. In this study, only the clinical randomized controlled trials were selected to evaluate the efficacy and safety of vitamin D in the treatment of type 2 diabetic microangiopathy. The two researchers independently conducted literature selection, data extraction and quality assessment. Statistical heterogeneity among studies will be evaluated using the Cochran Q test (x) and the I statistical value. We will utilize the Review Manage software V5.3.0 (The Nordic Cochrane Center, The Cochrane Collaboration, 2014, Copenhagen, Denmark) to statistically analyze all data. ETHICS AND DISSEMINATION: Ethics and dissemination: This study is a systematic review of vitamin D supplementation as a treatment of type 2 diabetic microangiopathy. RESULTS: This study will provide high-quality synthesis of effectiveness and safety of vitamin D supplementation for type 2 diabetic microangiopathy. CONCLUSION: This systematic review aims to provide new options for vitamin D treatment of type 2 diabetic microangiopathy in terms of its efficacy and safety. REGISTRATION NUMBER: LNPLASY202050055.

Vitamin D supplementation for nonalcoholic fatty liver disease in type 2 diabetes mellitus: A protocol for a systematic review and meta-analysis.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is strongly associated with type 2 diabetes mellitus (T2DM), and low vitamin D levels are positively associated with NAFLD and T2DM. But there is absence of convincing evidence-based medicine to confirm the efficacy of vitamin D supplementation for T2DM with NAFLD. Thus, we aimed to conduct this meta-analysis to summarize the efficacy of vitamin D supplementation for T2DM combined with NAFLD, and help to further clarify its beneficial action on diabetic patients with NAFLD. METHODS: The study only selects clinical randomized controlled trials of vitamin D supplementation for T2DM combined with NAFLD. We will search each database from the built-in until July 2020. The English literature mainly searches Cochrane Library, Pubmed, EMBASE, and Web of Science. While the Chinese literature comes from CNKI, CBM, VIP, and Wangfang database. Meanwhile, we will retrieve clinical trial registries and grey literature. Two researchers worked independently on literature selection, data extraction, and quality assessment. The dichotomous data is represented by relative risk (RR), and the continuous is expressed by mean difference (MD) or standard mean difference (SMD), eventually the data is synthesized using a fixed effect model (FEM) or a random effect model (REM) depending on the heterogeneity. The imaging markers of liver, biomarkers of hepatic steatosis, serological indexes of hepatic fibrosis, serum NAFLD liver fat score were evaluated as the main outcomes. While several secondary outcomes were also evaluated in this study. The statistical analysis of this meta-analysis was conducted by RevMan software version 5.3. RESULTS: This meta-analysis will further determine the beneficial efficacy of vitamin D supplementation for T2DM combined with NAFLD. CONCLUSION: This study determines the positive efficacy of vitamin D supplementation for diabetic patients with NAFLD.

Characterization and Therapeutic Application of Mesenchymal Stem Cells with Neuromesodermal Origin from Human Pluripotent Stem Cells.

Rationale: Mesenchymal stem cells (MSC) hold great promise in the treatment of various diseases including autoimmune diseases, inflammatory diseases, etc., due to their pleiotropic properties. However, largely incongruent data were obtained from different MSC-based clinical trials, which may be partially due to functional heterogeneity among MSC. Here, we attempt to derive homogeneous mesenchymal stem cells with neuromesodermal origin from human pluripotent stem cells (hPSC) and evaluate their functional properties. Methods: Growth factors and/or small molecules were used for the differentiation of human pluripotent stem cells (hPSC) into neuromesodermal progenitors (NMP), which were then cultured in animal component-free and serum-free induction medium for the derivation and long-term expansion of MSC. The resulted NMP-MSC were detailed characterized by analyzing their surface marker expression, proliferation, migration, multipotency, immunomodulatory activity and global gene expression profile. Moreover, the in vivo therapeutic potential of NMP-MSC was detected in a mouse model of contact hypersensitivity (CHS). Results: We demonstrate that NMP-MSC express posterior HOX genes and exhibit characteristics similar to those of bone marrow MSC (BMSC), and NMP-MSC derived from different hPSC lines show high level of similarity in global gene expression profiles. More importantly, NMP-MSC display much stronger immunomodulatory activity than BMSC in vitro and in vivo, as revealed by decreased inflammatory cell infiltration and diminished production of pro-inflammatory cytokines in inflamed tissue of CHS models. Conclusion: Our results identify NMP as a new source of MSC and suggest that functional and homogeneous NMP-MSC could serve as a candidate for MSC-based therapies.

The effect of different surface materials on runoff quality in permeable pavement systems.

To investigate the effect of different permeable pavement surface materials on the removal of pollutants from urban storm-runoff, six commonly surface materials (porous asphalt, porous concrete, cement brick, ceramic brick, sand base brick, and shale brick) were selected in this study and the research was carried out by column experiments. Except the concentrations of total suspended solids (TSS), chemical oxygen demand (COD), ammonia nitrogen (NH4-N), nitrate nitrogen (NO3-N), total nitrogen (TN), and total phosphorus (TP) in the influent and effluent that were measured, the removal mechanism of pollutants was discussed further. The results indicate that the surface materials influence the removal efficiency of pollutants greatly and have different effects on certain pollutant. Furthermore, the physical interception and adsorption would be the main mechanism for the removal of pollutants from runoff. For example, for all surface materials, the average removal efficiency of TSS is nearly about 90.0% because of physical interception. Due to the amount of iron oxide, the removal efficiency of COD, NO3-N, and TN of shale brick was 88.2, 35.1, and 17.5%, respectively. NH4-N and TN can be easily removed by porous asphalt due to the high content of organic matter. By lacking of useful adsorption sites, all the surface materials had little effect on the removal of TP from runoff. This research could offer useful guidelines for the better design of permeable pavement system and promote the insight into the removal mechanism of pollutants in permeable pavement system. Graphical abstract Different types of materials for the different types of pollutants in the runoff purification capacity were significantly different, overall, shale brick and porous asphalt Shale bricks and porous asphalt have a better purification effect according to the six kinds of materials.

The Arabidopsis transcription factor IIB-related protein BRP4 is involved in the regulation of mitotic cell-cycle progression during male gametogenesis.

Male gametogenesis in angiosperms involves two rounds of mitosis that are essential for the generation of two sperm cells to achieve double fertilization, a distinct event in the sexual reproduction of flowering plants. Precise regulation of mitosis during male gametogenesis is critically important for the establishment of the male germline. However, the molecular mechanisms underlying mitotic division during male gametophyte development have not been characterized fully. Here, we report that the Arabidopsis transcription initiation factor TFIIB-related protein BRP4 is involved in the regulation of mitotic cell-cycle progression during male gametogenesis. BRP4 was expressed predominately in developing male gametophytes. Knockdown expression of BRP4 by a native promoter-driven RNA interference construct in Arabidopsis resulted in arrest of the mitotic progression of male gametophytes, leading to a defect in pollen development. Moreover, we showed that the level of expression of a gene encoding a subunit of the origin recognition complex, ORC6, was decreased in BRP4 knockdown plants, and that the ORC6 knockdown transgenic plants phenocopied the male gametophyte defect observed in BRP4 knockdown plants, suggesting that ORC6 acts downstream of BRP4 to mediate male mitotic progression. Taken together, our results reveal that BRP4 plays an important role in the regulation of mitotic cell-cycle progression during male gametogenesis.

Auraptenol attenuates vincristine-induced mechanical hyperalgesia through serotonin 5-HT1A receptors.

Common chemotherapeutic agents such as vincristine often cause neuropathic pain during cancer treatment in patients. Such neuropathic pain is refractory to common analgesics and represents a challenging clinical issue. Angelicae dahuricae radix is an old traditional Chinese medicine with demonstrated analgesic efficacy in humans. However, the active component(s) that attribute to the analgesic action have not been identified. This work described the anti-hyperalgesic effect of one coumarin component, auraptenol, in a mouse model of chemotherapeutic agent vincristine-induced neuropathic pain. We reported that auraptenol dose-dependently reverted the mechanical hyperalgesia in mice within the dose range of 0.05-0.8 mg/kg. In addition, the anti-hyperalgesic effect of auraptenol was significantly blocked by a selective serotonin 5-HT1A receptor antagonist WAY100635 (1 mg/kg). Within the dose range studied, auraptenol did not significantly alter the general locomotor activity in mice. Taken together, this study for the first time identified an active component from the herbal medicine angelicae dahuricae radix that possesses robust analgesic efficacy in mice. These data support further studies to assess the potential of auraptenol as a novel analgesic for the management of neuropathic pain.

Cord blood vitamin D status impacts innate immune responses.

OBJECTIVES: Our objectives were to 1) assess cord blood vitamin D concentrations from healthy term newborns, 2) ascertain whether cord blood vitamin D insufficiency precludes optimal induction of the Toll-like receptor (TLR) antimicrobial pathway in monocytes, and 3) determine whether in vitro supplementation with 25-hydroxyvitamin D(3) [25(OH)D(3)] and/or 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] restores TLR-induced antimicrobial responses. STUDY DESIGN: Plasma concentrations of 25(OH)D and 1,25(OH)(2)D were measured from cord blood of 23 newborns. Human monocytes were cultured in cord blood plasma and stimulated with TLR2 and TLR4 ligands, and then antimicrobial gene expression was analyzed using quantitative PCR. RESULTS: Cord blood 25(OH)D and 1,25(OH)(2)D concentrations were positively correlated to each other (r = 0.78; P <0.0001). Compared with those conditioned in vitamin D-sufficient plasma [25(OH)D > 75 nmol/liter], monocytes cultured in severely vitamin D-deficient plasma [25(OH)D < 30 nmol/liter] exhibited decreased TLR-induced cathelicidin expression (P <0.05). Supplementation in vitro of vitamin D-deficient plasma with 25(OH)D(3) increased antimicrobial peptide gene expression. CONCLUSIONS: Cord blood vitamin D deficiency, by its effects on TLR-induced antimicrobial production, altered in vitro monocyte responses. The observation that exogenous 25(OH)D(3) in vitro recovered TLR-induced antimicrobial responses suggests the need for additional prospective investigations to further delineate the role of vitamin D in the newborn immune response.

Subinhibitory concentrations of perilla oil affect the expression of secreted virulence factor genes in Staphylococcus aureus.

BACKGROUND: The pathogenicity of staphylococcus aureus is dependent largely upon its ability to secrete a number of virulence factors, therefore, anti-virulence strategy to combat S. aureus-mediated infections is now gaining great interest. It is widely recognized that some plant essential oils could affect the production of staphylococcal exotoxins when used at subinhibitory concentrations. Perilla [Perilla frutescens (L.) Britton], a natural medicine found in eastern Asia, is primarily used as both a medicinal and culinary herb. Its essential oil (perilla oil) has been previously demonstrated to be active against S. aureus. However, there are no data on the influence of perilla oil on the production of S. aureus exotoxins. METHODOLOGY/PRINCIPAL FINDINGS: A broth microdilution method was used to determine the minimum inhibitory concentrations (MICs) of perilla oil against S. aureus strains. Hemolysis, tumour necrosis factor (TNF) release, Western blot, and real-time RT-PCR assays were performed to evaluate the effects of subinhibitory concentrations of perilla oil on exotoxins production in S. aureus. The data presented here show that perilla oil dose-dependently decreased the production of α-toxin, enterotoxins A and B (the major staphylococcal enterotoxins), and toxic shock syndrome toxin 1 (TSST-1) in both methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA). CONCLUSIONS/SIGNIFICANCE: The production of α-toxin, SEA, SEB, and TSST-1 in S. aureus was decreased by perilla oil. These data suggest that perilla oil may be useful for the treatment of S. aureus infections when used in combination with ß-lactam antibiotics, which can increase exotoxins production by S. aureus at subinhibitory concentrations. Furthermore, perilla oil could be rationally applied in food systems as a novel food preservative both to inhibit the growth of S. aureus and to repress the production of exotoxins, particularly staphylococcal enterotoxins.