Wogonin attenuates inflammation and oxidative stress in lipopolysaccharide-induced mastitis by inhibiting Akt/NF-κB pathway and activating the Nrf2/HO-1 signaling.

Mastitis is a disease involved in inflammation of breast which affects human and animals. Wogonin is one bioactive compound from many Chinese herbal medicines, which have multiple properties, including anti-inflammatory activity. However, the roles of wogonin in mastitis progression are largely undefined. Mastitis models were established using LPS-treated mice and mammary epithelial cells (MECs). Infiltration of inflammatory cells was analyzed by hematoxylin-eosin staining and myeloperoxidase (MPO) activity. Inflammatory cytokine (TNF-α and IL-1ß) levels were detected via ELISA. The phosphorylation and total of Akt and NF-κB levels and content of Nrf2 and HO-1 were measured via western blot. Cell viability was examined by CCK-8 assay. Oxidative stress was assessed by ROS generation and levels of MDA, GSH, and SOD. Wogonin attenuated LPS-induced infiltration of inflammatory cells, increase of MPO activity and levels of TNF-α and IL-1ß, and activation of the Akt/NF-κB pathway in murine mammary gland tissues, and promoted activation of Nrf2/HO-1 signaling. Wogonin did not affect MEC viability, but mitigated LPS-induced inflammation in MECs by reducing TNF-α and IL-1ß levels. Wogonin relieved LPS-induced oxidative stress in MECs through decreasing ROS generation and MDA level and increasing GSH and SOD levels. Wogonin repressed LPS-induced activation of the Akt/NF-κB pathway in MECs and increased Nrf2/HO-1 signaling activation. Activated Akt/NF-κB signaling or Nrf2/HO-1 signaling inactivation reversed the suppressive effects of wogonin on LPS-induced inflammation and oxidative stress in MECs. Wogonin mitigates LPS-induced inflammation and oxidative stress of MECs via suppressing activation of the Akt/NF-κB signaling and activating Nrf2/HO-1 pathway, indicating the therapeutic potential of wogonin in mastitis.

Icariin alleviates ferroptosis-related atherosclerosis by promoting autophagy in xo-LDL-induced vascular endothelial cell injury and atherosclerotic mice.

Vascular endothelial cells (VECs) are located between the blood plasma and the vascular tissue, and the ferroptosis (iron-dependent programmed cell death) of VECs can lead to a range of cardiovascular diseases. Icariin is the main active ingredient of Epimedium brevicornum Maxim., which can improve endothelial cell dysfunction. In the present study, the protective effects of icariin on oxidised low-density lipoprotein (ox-LDL)-treated VECs and high-fat diet-fed Apolipoprotein E-deficient mice were investigated. Inflammatory fibrosis in tissues and inflammatory factors in serum and cell supernatants were detected, and mitochondrial membrane potential and the expression levels of ferroptosis-associated proteins were also detected. The results revealed that icariin reduced the endothelial atherosclerotic plaque area and collagen fibres in aortic sinus tissue, and increased the viability and mitochondrial membrane potential, whereas it reduced the reactive oxygen species levels of VECs. The nucleation of transcription factor EB (TFEB) and subsequent autophagy were negatively associated with ferroptosis in endothelial cells, and the more prominent the autophagy, the lower the levels of ferroptosis. Furthermore, by co-treating the cells with icariin and the two autophagy inhibitors, Bafilomycin A1 (blocking autophagosome and lysosome fusion) and 3-methyladenine (blocking autophagosome formation), respectively, the promoting effects of icariin on autophagy were found to be mediated through the process of autophagosome-lysosome fusion. In in vivo experiments, icariin reduced ferroptosis, alleviated atherosclerotic lesions and increased the rate of TFEB nucleation. Additionally, it was found that ARG304, THR308 and GLN311 were the optimal binding sites for the interaction between icariin and TFEB. Taken together, these results suggest that the fusion of autophagosomes and lysosomes promoted by icarrin enhances autophagy and thus reduces ferroptosis. Therefore, icariin may be a potential candidate for the prevention of ferroptosis of VECs and, thus, for the treatment of cardiovascular diseases.

Uncovering the molecular mechanisms of Curcumae Rhizoma against myocardial fibrosis using network pharmacology and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Myocardial fibrosis leads to cardiac remodeling and dysfunction. Curcumae Rhizoma has been utilized in clinical trials to treat a variety of cardiovascular illnesses, although its role in myocardial fibrosis is unknown. AIM OF THE STUDY: The purpose of current study was to explore the potential mechanism action and anti-myocardial fibrosis effects of treatment with Curcumae Rhizoma. MATERIALS AND METHODS: The chemical components in the aqueous extract from Curcumae Rhizoma were identified using GC-MS analysis. A prediction network describing the relationship between Curcumae Rhizoma and MF was established based on information collected from multiple databases. Functional enrichment analysis was performed to investigate the specific functions and pathways involved in the candidate Curcumae Rhizoma targets acting on MF, which were further validated by vivo experiments. RESULTS: There were 444 targets obtained from the 39 active ingredients in Curcumae Rhizoma, and 5691 disease targets related to MF were identified. Then, 41 key targets were determined with the PPI interaction network, which was structured from 324 overlapping gene targets. GO and KEGG analyses revealed that the p38 MAPK/NF-κB and TGF-ß1/Smad2/3 signaling pathways might play crucial roles in the therapeutic mechanism of MF. According to the results of molecular docking, the binding activity between core components and targets was marvelous (affinity < -6 kcal/mol). Take it a step further, the experimental validation data affirmed that Curcumae Rhizoma substantially decreased myocardial fibrosis and recovered cardiac function in the ISO-induced rats. The associated proteins expression data implied that the p38 MAPK/NF-κB and TGF-ß1/Smad2/3 pathways might be vital in the anti-fibrosis effect of Curcumae Rhizoma. CONCLUSION: The findings suggested that Curcumae Rhizoma diminished myocardial fibrosis by suppressing fibrosis multiplication and collagen deposition through inhibiting p38 MAPK/NF-κB and TGF-ß1/Smad2/3 pathways, which might be a promising therapeutic medicament for alleviating myocardial fibrosis.

Effects of long-term phosphorus application on crop yield, phosphorus absorption, and soil phosphorus accumulation in maize-wheat rotation system.

In this study, we examined the effects of four phosphorus treatments on crop yields, and analyzed crop phosphorus uptake and phosphorus utilization efficiency, as well as changes in soil phosphorus deficit in maize-wheat rotation system, based on a 7-year field experiment in Baoding City, Hebei Province. The results showed that long-term phosphorus application significantly increased the yield and phosphorus uptake of maize and wheat. The yield and phosphorus uptake of maize and wheat showed a parabolic trend that first increased and then decreased with the increases of phosphorus application. The utilization efficiency of phosphorus fertilizer in the corn season was higher than that in the wheat season under various phosphorus application treatments. The cumulative utilization efficiency of phosphorus fertilizer in the wheat season showed a downward trend. The decline rate showed that optimized phosphorus application > 70% optimized phosphorus application >130% optimized phosphorus application. The cumulative utilization efficiency of phosphorus fertili-zer in the corn season showed an upward trend. For the rising rate, the optimized phosphorus application > 70% optimized phosphorus application > 130% optimized phosphorus application. Both the apparent phosphorus surplus and the accumulated phosphorus surplus of the soil without phosphorus application were under phosphorus deficiency. Under the treatment of phosphorus application, soil phosphorus showed a status of phosphorus surplus. The higher the phosphorus application rate, the longer the accumulation period, the higher the soil phosphorus surplus. Under the straw returning condition, phosphorus application rate for wheat of 105-150 kg·hm-2 and the phosphorus application rate for maize of 63-90 kg·hm-2 in Hebei fluvo-aquic soil could ensure the high crop yield, keep the phosphorus utilization efficiency at a high level, and reduce soil phosphorus accumulation and environmental risks.

[Effects of ecological factors on shape and ginsenoside of Panax ginseng].

The ecological environment is closely related to the growth and quality of authentic medicinal materials. Ginseng is very strict with its natural environment and grows mostly in the damp valleys of forests, and the appearance and chemical composition of ginseng under different growth environments are very different. This article reviews the effects of different ecological factors(including light, temperature, altitude, moisture, soil factors, etc.)on the appearance and chemical composition(mainly ginsenosides) of ginseng. Through systematic review, it is found that soil physical factors are the most important ecological factors that affect the appea-rance of ginseng, and soil bulk density plays a key role; temperature affects ginsenosides in ginseng medicinal materials The dominant ecological factors for the accumulation of chemical ingredents; strong light, high altitude, high soil moisture, low soil nutrient and strong acid soil can influence the accumulation of secondary metabolites in ginseng. Environmental stress can also stimulate the formation and accumulation of secondary metabolites in medicinal plants. Appropriate low temperature stress, high or low water stress, acid or alkali stress can also promote the accumulation of ginsenosides. This article systematically reviews the ecological factors that affect the appearance and chemical composition of ginseng, and clarifies the dominant ecological factors and limiting factors for the formation of ginseng's appearance and quality, as well as beneficial environmental stress factors, in order to provide a theoretical basis for ginseng ecological planting and ginseng quality improvement.

Metformin attenuates hyperlipidaemia-associated vascular calcification through anti-ferroptotic effects.

Ferroptosis is a form of regulated cell death that involves metabolic dysfunction resulting from iron-dependent excessive lipid peroxidation. Elevated plasma levels of free fatty acids are tightly associated with cardiometabolic risk factors in patients with obesity, diabetes mellitus, and metabolic syndrome. Metformin (Met) is an antidiabetic drug with beneficial cardiovascular disease effects. The aim of this study was to determine the effects of Met on ferroptosis induced by lipid overload and the effects of these changes on vascular smooth muscle cells (VSMCs) calcification. We developed a hyperlipidaemia-related vascular calcification in vivo model with rats fed a high-fat diet combined with vitamin D3 plus nicotine, and palmitic acid (PA), the most abundant long-chain saturated fatty acid in plasma, was used to induce lipid overload and develop an oxidative stress-related calcification model in vitro. The results showed that Met inhibits hyperlipidaemia-associated calcium deposition in the rat aortic tissue. In vitro, treatment of VSMCs with PA stimulates ferroptosis concomitant with increased calcium deposition in VSMCs, while pretreatment with Met attenuates these effects. Furthermore, PA also promotes the protein expression of the extracellular matrix protein periostin (POSTN) and its secretion into the extracellular environment. More importantly, upregulation of POSTN increased the sensitivity of cells to ferroptosis. Mechanistically, upregulation of POSTN suppresses SLC7A11 expression through the inhibition of p53 in VSMCs, which contributes to a decrease in glutathione synthesis and therefore triggers ferroptosis. Interestingly, overexpression of p53 attenuates the inhibitory effect of POSTN on SLC7A11 expression, accompanied by increased Gpx4 expression. Furthermore, p53 knockdown suppresses Met-mediated anti-ferroptosis effects in PA-treated VSMCs, which may be related to the downregulation of SLC7A11 expression. In addition, supplementation of VSMCs with Met enhances the antioxidative capacity of VSMCs through Nrf2 signalling activation. Collectively, targeting POSTN in VSMCs may provide a new strategy for vascular calcification prevention or treatment.

PDK4 promotes vascular calcification by interfering with autophagic activity and metabolic reprogramming.

Pyruvate dehydrogenase kinase 4 (PDK4) is an important mitochondrial matrix enzyme in cellular energy regulation. Previous studies suggested that PDK4 is increased in the calcified vessels of patients with atherosclerosis and is closely associated with mitochondrial function, but the precise regulatory mechanisms remain largely unknown. This study aims to investigate the role of PDK4 in vascular calcification and the molecular mechanisms involved. Using a variety of complementary techniques, we found impaired autophagic activity in the process of vascular smooth muscle cells (VSMCs) calcification, whereas knocking down PDK4 had the opposite effect. PDK4 drives the metabolic reprogramming of VSMCs towards a Warburg effect, and the inhibition of PDK4 abrogates VSMCs calcification. Mechanistically, PDK4 disturbs the integrity of the mitochondria-associated endoplasmic reticulum membrane, concomitantly impairing mitochondrial respiratory capacity, which contributes to a decrease in lysosomal degradation by inhibiting the V-ATPase and lactate dehydrogenase B interaction. PDK4 also inhibits the nuclear translocation of the transcription factor EB, thus inhibiting lysosomal function. These changes result in the interruption of autophagic flux, which accelerates calcium deposition in VSMCs. In addition, glycolysis serves as a metabolic adaptation to improve VSMCs oxidative stress resistance, whereas inhibition of glycolysis by 2-deoxy-D-glucose induces the apoptosis of VSMCs and increases the calcium deposition in VSMCs. Our results suggest that PDK4 plays a key role in vascular calcification through autophagy inhibition and metabolic reprogramming.

[Cultivation strategy on cluster brand of ecological agriculture of Dao-di herbs].

The cluster brand is the embodiment of the core competitiveness of an industry. Developing and cultivating cluster brand of ecological agriculture of Dao-di herbs not only helps to optimize the value chain of the Chinese medicinal materials(CMMs) industry cluster, realize the value-added of the CMMs industry cluster, but also enhance the visibility and influence of the industrial cluster, enhance the core competitiveness of the industrial cluster. This has important practical significance for promoting the "orderly" "safe" and "effective" development of the Dao-di herbs. Based on the industry development status of CMMs, this article introduces several concepts related to cluster brands and their relationships, and focuses on the cultivation models and strategies of cluster brand in the CMMs industry. Based on the current status of the development of the CMMs industry, this article introduces several concepts related to cluster brands and their interrelationships. It discusses the cultivation models and strategies of cluster brands in the CMMs industry, industry associations, Chinese medicine companies and individual growers as the support, insists on the ecological cultivation of authentic medicinal materials and the cultivation of cluster brands. Finally, it points out the direction for the high-quality development of the ecological agriculture of CMMs.

Exploring Future Food Provision Scenarios for China.

Developing sustainable food systems is essential, especially for emerging economies, where food systems are changing rapidly and affect the environment and natural resources. We explored possible future pathways for a sustainable food system in China, using multiple environmental indicators linked to eight of the Sustainable Development Goals (SDGs). Forecasts for 2030 in a business as usual scenario (BAU) indicate increases in animal food consumption as well as increased shortages of the land available and the water needed to produce the required food in China. Associated greenhouse gas emissions and nitrogen and phosphorus losses could become 10-42% of global emissions in 2010. We developed three main pathways besides BAU [produce more and better food (PMB), consume and waste less food (CWL), and import more food (IMF)] and analyzed their impacts and contributions to achieving one or more of the eight SDGs. Under these scenarios, the demand for land and water and the emissions of GHG and nutrients may decrease by 7-55% compared to BAU, depending on the pathway followed. A combination of PMB and CWL was most effective, while IMF externalizes impacts to countries exporting to China. Modestly increasing feed or food imports in a selective manner could ease the pressure on natural resources. Our modeling framework allows us to analyze the effects of changes in food production-consumption systems in an integrated manner, and the results can be linked to the eight SDGs. Despite formidable technological, social, educational, and structural barriers that need to be overcome, our study indicates that the ambitious targets of China's new agricultural and environmental strategy appear to be achievable.

Restoring mitochondrial biogenesis with metformin attenuates ß-GP-induced phenotypic transformation of VSMCs into an osteogenic phenotype via inhibition of PDK4/oxidative stress-mediated apoptosis.

Mitochondrial abnormalities have long been observed in the development of vascular calcification. Metformin, a member of the biguanide class of antidiabetic drugs, has recently received attention owing to new findings regarding its protective role in cardiovascular disease. Since the precise control of mitochondrial quantity and quality is critical for the survival and function of vascular smooth muscle cells (VSMCs), maintaining mitochondrial homeostasis may be a potential protective factor for VSMCs against osteoblast-like phenotypic transition. However, limited studies have been reported in this area. Here, we investigated the role of metformin in the phenotypic transformation of VSMCs, as well as its intracellular signal transduction pathways. We demonstrated that supplementation with metformin restored the ß-glycerophosphate (ß-GP)-mediated impairment of mitochondrial biogenesis in VSMCs, as evidenced by an increased mitochondrial DNA copy number, a restored mitochondrial membrane potential (MMP), and upregulated mitochondrial biogenesis-related gene expression, whereas the AMP-activated protein kinase (AMPK) inhibitor compound C suppressed these effects. We also observed that overexpression of pyruvate dehydrogenase kinase 4 (PDK4), an important mitochondrial matrix enzyme in cellular energy metabolism, exacerbated ß-GP-induced oxidative stress and subsequent apoptosis in VSMCs but that these effects were suppressed by dichloroacetate, a widely reported PDK4 inhibitor. More importantly, enhanced mitochondrial biogenesis attenuated the ß-GP-induced phenotypic transformation of VSMCs into an osteogenic phenotype through inhibition of the PDK4/oxidative stress-mediated apoptosis pathway, whereas disruption of mitochondrial biogenesis by zidovudine aggravated ß-GP-induced apoptosis in VSMCs. In addition, inhibition of autophagy by small interfering RNA targeting Atg5 reduced mitochondrial biogenesis in VSMCs. In summary, we uncovered a novel mechanism by which metformin attenuates the phenotypic transformation of VSMCs into an osteogenic phenotype via inhibition of the PDK4/oxidative stress-mediated apoptosis pathway, and mitochondrial homeostasis is involved in this process.

China's livestock transition: Driving forces, impacts, and consequences.

China's livestock industry has experienced a vast transition during the last three decades, with profound effects on domestic and global food provision, resource use, nitrogen and phosphorus losses, and greenhouse gas (GHG) emissions. We provide a comprehensive analysis of the driving forces around this transition and its national and global consequences. The number of livestock units (LUs) tripled in China in less than 30 years, mainly through the growth of landless industrial livestock production systems and the increase in monogastric livestock (from 62 to 74% of total LUs). Changes were fueled through increases in demand as well as, supply of new breeds, new technology, and government support. Production of animal source protein increased 4.9 times, nitrogen use efficiency at herd level tripled, and average feed use and GHG emissions per gram protein produced decreased by a factor of 2 between 1980 and 2010. In the same period, animal feed imports have increased 49 times, total ammonia and GHG emissions to the atmosphere doubled, and nitrogen losses to watercourses tripled. As a consequence, China's livestock transition has significant global impact. Forecasts for 2050, using the Shared Socio-economic Pathways scenarios, indicate major further changes in livestock production and impacts. On the basis of these possible trajectories, we suggest an alternative transition, which should be implemented by government, processing industries, consumers, and retailers. This new transition is targeted to increase production efficiency and environmental performance at system level, with coupling of crop-livestock production, whole chain manure management, and spatial planning as major components.

Hotspots for Nitrogen and Phosphorus Losses from Food Production in China: A County-Scale Analysis.

Food production in China results in large losses of nitrogen (N) and phosphorus (P) to the environment. Our objective is to identify hotspots for N and P losses to the environment from food production in China at the county scale. To do this, we used the NUFER (Nutrient flows in Food chains, Environment and Resources use) model. Between 1990 and 2012, the hotspot area expanded by a factor of 3 for N, and 24 for P. In 2012 most hotspots were found in the North China Plain. Hotspots covered less than 10% of the Chinese land area, but contributed by more than half to N and P losses to the environment. Direct discharge of animal manure to rivers was an important cause of N and P losses. Food production was found to be more intensive in hotspots than in other counties. Synthetic fertilizer use and animal numbers in hotspots were a factor of 4-5 higher than in other counties in 2012. Also the number of people working in food production and the incomes of farmers are higher in hotspots than in other counties. This study concludes with suggestions for region-specific pollution control technologies for food production in China.

Harvesting more grain zinc of wheat for human health.

Increasing grain zinc (Zn) concentration of cereals for minimizing Zn malnutrition in two billion people represents an important global humanitarian challenge. Grain Zn in field-grown wheat at the global scale ranges from 20.4 to 30.5 mg kg-1, showing a solid gap to the biofortification target for human health (40 mg kg-1). Through a group of field experiments, we found that the low grain Zn was not closely linked to historical replacements of varieties during the Green Revolution, but greatly aggravated by phosphorus (P) overuse or insufficient nitrogen (N) application. We also conducted a total of 320-pair plots field experiments and found an average increase of 10.5 mg kg-1 by foliar Zn application. We conclude that an integrated strategy, including not only Zn-responsive genotypes, but of a similar importance, Zn application and field N and P management, are required to harvest more grain Zn and meanwhile ensure better yield in wheat-dominant areas.

Nitrogen, Phosphorus, and Potassium Flows through the Manure Management Chain in China.

The largest livestock production and greatest fertilizer use in the world occurs in China. However, quantification of the nutrient flows through the manure management chain and their interactions with management-related measures is lacking. Herein, we present a detailed analysis of the nutrient flows and losses in the "feed intake-excretion-housing-storage-treatment-application" manure chain, while considering differences among livestock production systems. We estimated the environmental loss from the manure chain in 2010 to be up to 78% of the excreted nitrogen and over 50% of the excreted phosphorus and potassium. The greatest losses occurred from housing and storage stages through NH3 emissions (39% of total nitrogen losses) and direct discharge of manure into water bodies or landfill (30-73% of total nutrient losses). There are large differences among animal production systems, where the landless system has the lowest manure recycling. Scenario analyses for the year 2020 suggest that significant reductions of fertilizer use (27-100%) and nutrient losses (27-56%) can be achieved through a combination of prohibiting manure discharge, improving manure collection and storages infrastructures, and improving manure application to cropland. We recommend that current policies and subsidies targeted at the fertilizer industry should shift to reduce the costs of manure storage, transport, and application.

Environmental assessment of management options for nutrient flows in the food chain in China.

The nitrogen (N) and phosphorus (P) costs of food production have increased greatly in China during the last 30 years, leading to eutrophication of surface waters, nitrate leaching to groundwater, and greenhouse gas emissions. Here, we present the results of scenario analyses in which possible changes in food production-consumption in China for the year 2030 were explored. Changes in food chain structure, improvements in technology and management, and combinations of these on food supply and environmental quality were analyzed with the NUFER model. In the business as usual scenario, N and P fertilizer consumption in 2030 will be driven by population growth and diet changes and will both increase by 25%. N and P losses will increase by 44 and 73%, respectively, relative to the reference year 2005. Scenarios with increased imports of animal products and feed instead of domestic production, and with changes in the human diet, indicate reductions in fertilizer consumption and N and P losses relative to the business as usual scenario. Implementation of a package of integrated nutrient management measures may roughly nullify the increases in losses in the business as usual scenario and may greatly increase the efficiency of N and P throughout the whole food chain.

Phosphorus flows and use efficiencies in production and consumption of wheat, rice, and maize in China.

Increasing fertilizer phosphorus (P) application in agriculture has greatly contributed to the increase of crop yields during the last decades in China but it has also increased P flows in food production and consumption. The relationship between P use efficiency and P flow is not well quantified at national level. In present paper we report on P flows and P use efficiencies in rice, wheat, and maize production in China using the NUFER model. Conservation strategies for P utilization and the impact of these strategies on P use efficiency have been evaluated. Total amounts of P input to wheat, rice, and maize fields were 1095, 1240, and 1128 Gg, respectively, in China, approximately 80% of which was in chemical fertilizers. The accumulation of P annually in the fields of wheat, rice, and maize was 29.4, 13.6, and 21.3 kg ha(-1), respectively. Phosphorus recovered in the food products of wheat, rice, and maize accounted for only 12.5%, 13.5%, and 3.8% of the total P input, or 3.2%, 2.6%, and 0.9% of the applied fertilizer P, respectively. The present study shows that optimizing phosphorus flows and decreasing phosphorus losses in crop production and utilization through improved nutrient management must be considered as an important issue in the development of agriculture in China.