Cornus officinalis var. koreana Kitam extracts alleviate cadmium-induced renal fibrosis by targeting matrix metallopeptidase 9.

ETHNOPHARMACOLOGICAL RELEVANCE: Cornus officinalis var. koreana Kitam (Cornus officinalis) is a commonly used Chinese herbal medicine and has a good clinical efficacy in kidney and liver diseases. Recent years, a number of studies reported the significant effects of Cornus officinalis on renal fibrosis. However, it is still unclear about the underlying specific mechanism, the bioactive ingredients, and the target gene regulatory network. AIM OF THE STUDY: We investigated the impact of Cornus officinalis extract on cadmium-induced renal fibrosis, screened the bioactive ingredients of Cornus officinalis using a pharmacological sub-network analysis, and explored the regulatory effects of Cornus officinalis extracts on target gene matrix metallopeptidase 9 (MMP9). METHODS: Male C57BL/6N mice were treated with single or combinatorial agents such as saline, cadmium chloride, Cornus officinalis, Isoginkgetin and FSL-1. Isoginkgetin is a compound with anti-MMP9 activity. FSL-1 can induce MMP9 expression. Masson staining and Western blot and immunohistochemistry analyses were used for assessing renal fibrosis. In addition, wound healing model was established using BUMPT (Boston university mouse proximal tubular) cells to investigate how Cornus officinalis affected cadmium-induced cell migration. The main Cornus officinalis bioactive compounds were identified by UHPLC-MS (Ultra-high-performance liquid chromatography - mass spectrometry). The MMP9 target for Cornus officinalis active ingredients were confirmed through a pharmacological sub-network analysis. RESULTS: Aqueous extracts of Cornus officinalis protected from renal dysfunction and kidney fibrosis induced by cadmium chloride in mice. In vitro experiments validated that Cornus officinalis extracts inhibited cell migration ability especially in cadmium chloride condition. The sub-network analysis and chemical components profiling technique revealed the active compounds of Cornus officinalis. Cellular thermal shift assay verified the binding abilities of three active components Daidzein, N-Acetyl-L-tyrosine or Swertisin with matrix metalloproteinase-9. Gelatin zymography assay revealed that the activity of MMP9 was inhibited by the three active components. We further confirmed that MMP9 was involved in the process of Cornus officinalis extracts reducing renal fibrosis. Cornus officinalis attenuated the cadmium-induced renal fibrosis was correlated with decreased expression of MMP9, collagen I, α-SMA (alpha-smooth muscle actin) and vimentin. CONCLUSIONS: This study demonstrated that Cornus officinalis extracts could alleviate the cadmium chloride-induced renal fibrosis by targeting MMP9, and might provide new insights into the mechanism of treating renal fibrosis by Cornus officinalis.

Tim-3 deficiency aggravates cadmium nephrotoxicity via regulation of NF-κB signaling and mitochondrial damage.

Kidney is the target organ of serious cadmium injury. Kidney damage caused by cadmium exposure is greatly influenced by the inflammatory response and mitochondrial damage. T cell immunoglobulin domain and mucin domain 3 (Tim-3) is an essential protein that functions as a negative immunological checkpoint to regulate inflammatory responses. Mice were given cadmium treatments at various dosages (0, 1.5, 3, 4.5 mg/kg) and times (0, 3, 5, 7 days) to assess the effects of cadmium on kidney damage. We found that the optimal way to induce kidney injury in mice was to inject 4.5 mg/kg of cadmium intraperitoneally for five days. It is interesting that giving mice 4.5 mg/kg of cadmium intravenously for seven days drastically lowered their survival rate. After cadmium exposure, Tim-3 knockout mice exhibited higher blood concentrations of urea nitrogen and creatinine compared to control mice. Tim-3 impacted the expression of oxidative stress-associated genes such as UDP glucuronosyltransferase family 1 member A9 (Ugt1a9), oxidative stress-induced growth inhibitor 2 (Osgin2), and S100 calcium binding protein A8 (S100a8), according to RNA-seq and real-time RT-PCR data. Tim-3 deficiency also resulted in activated nuclear factor-kappa B (NF-κB) signaling pathway. The NF-κB inhibitor 2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1) significantly alleviated cell apoptosis, oxidative stress response, and renal tubule inflammation in Tim-3 knockout mice exposed to cadmium. Furthermore, cadmium caused obvious B-cell lymphoma protein 2 (Bcl-2)-associated X (Bax) translocation from cytoplasm to mitochondria, which can be inhibited by TPCA-1. In conclusion, Tim-3 prevented mitochondrial damage and NF-κB signaling activation, hence providing protection against cadmium nephrotoxicity.

Tim-3 protects against cisplatin nephrotoxicity by inhibiting NF-κB-mediated inflammation.

The impact of Tim-3 (T cell immunoglobulin and mucin domain-containing protein 3) on cisplatin-induced acute kidney injury was investigated in this study. Cisplatin-induced Tim-3 expression in mice kidney tissues and proximal tubule-derived BUMPT cells in a time-dependent manner. Compared with wild-type mice, Tim-3 knockout mice have higher levels of serum creatinine and urea nitrogen, enhanced TUNEL staining signals, more severe 8-OHdG (8-hydroxy-2' -deoxyguanosine) accumulation, and increased cleavage of caspase 3. The purified soluble Tim-3 (sTim-3) protein was used to intervene in cisplatin-stimulated BUMPT cells by competitively binding to the Tim-3 ligand. sTim-3 obviously increased the cisplatin-induced cell apoptosis. Under cisplatin treatment conditions, Tim-3 knockout or sTim-3 promoted the expression of TNF-α (tumor necrosis factor-alpha) and IL-1ß (Interleukin-1 beta) and inhibited the expression of IL-10 (interleukin-10). NF-κB (nuclear factor kappa light chain enhancer of activated B cells) P65 inhibitor PDTC or TPCA1 lowed the increased levels of creatinine and BUN (blood urea nitrogen) in cisplatin-treated Tim-3 knockout mice serum and the increased cleavage of caspase 3 in sTim-3 and cisplatin-treated BUMPT cells. Moreover, sTim-3 enhanced mitochondrial oxidative stress in cisplatin-induced BUMPT cells, which can be mitigated by PDTC. These data indicate that Tim-3 may protect against renal injury by inhibiting NF-κB-mediated inflammation and oxidative stress.

Dilemma and solution of land scarcity, agro-production, and environmental risk for typical grain-producing areas in rapid urbanizing process in China.

How to satisfy food production sustainably in the rapid urbanizing process is a vital problem for major grain-producing areas. Taking two national grain-producing regions in China, Shandong and Dongting Lake Region as examples, this study uses step-by-step prediction and a double-objective linear programming model to analyze the dilemma of land scarcity, food demand, and environmental load. It is found that food demand by 2030 will induce partial regional cropland deficiency and heterogeneous agro-environmental risk among cities. The double-objective linear programming model finds possible solutions in different scenarios: on the premise of keeping the current cropland area unchanged, the upper threshold of crop yield by 2030 will be 2539.06 × 104 t in Dongting and 7175.13 × 104 t in Shandong, respectively. On the condition of guaranteeing food self-sufficiency and minimizing the environmental load, the lower threshold of arable land area should be 99.47 × 104 ha in Dongting and 436.85 × 104 ha in Shandong. Pollutant reduction will be realized by reallocation of agro-production task and optimized practices. The food carbon impact can be reduced by up to 1.27 kg CO2 eq/kg. This study contributes to feasible pathways towards adequate agro-production, lessened land scarcity, and minimal environmental risk for rapid urbanizing cities in a sustainable way.

Discussing the regional-scale arable land use intensity and environmental risk triggered by the micro-scale rural households' differentiation based on step-by-step evaluation-a case study of Shandong Province, China.

Under the rapid social-economic development process, the income structure and arable land size among rural households are facing with increasing differentiation in China. How the regional-scale arable land use intensity and environmental risk triggered by the rural households' differentiation would be is a question that has not been widely discussed. To fill this research gap, this study established three step-by-step indexes, rural households' ER index, arable land use intensity (LUI), and environmental risk index (RI), to measure rural households' differentiation, regional arable land use intensity, and environmental risk, respectively. By gathering data from questionnaire investigation of 950 rural households in Shandong Province, China, the result showed a wide range of ER index (0.006-0.056), LUI (2748.90-6361.54), and RI (0.0966-0.5032). ER index based on farm income, nonfarm income, and arable land size among rural households showed different distributions among cities. Though huge differences of arable land use existed in different rural households, including land area, crop species, use of production materials (agro-machinery, fertilizer, pesticide), and attitude towards land transferring, the farmers' sense of belonging to farmland and their dependence on agriculture did not disappear in the process of rural households' differentiation. Moreover, as aggregated effects of rural households' behavior, differentiation of regional arable land use intensity and environmental risk appeared later and lower than the level of rural households' differentiation in the same city. Among this process, Laiwu, Weihai, and Yantai became "hotspots" with higher level of rural households' differentiation, arable land use intensity, and agro-environmental risk, respectively. This study pointed out a possibility of policy designation that prior controlling environmental risk of arable land use could be realized by identifying the rural households' differentiation on arable land use.

Effects of urbanization on Cd accumulation in agricultural soils: From the perspective of accessibility gradient.

Road accessibility clearly reflects the spatial heterogeneity of urbanization. This study therefore adopted accessibility gradient to analyze the effects of urbanization on Cadmium (Cd) accumulation in agricultural soils. In total, 212 soil samples were collected along the accessibility gradient from agricultural soils in the Guangzhou-Foshan metropolitan region. Cd concentration showed a clearly decreasing pattern in agricultural soils with a decrease in accessibility level. The decreasing patterns varied in different accessibility ranges. The urban-rural ecotone (accessibility range 10-15) was the region with the most drastic changes in Cd accumulation. The influencing factors of Cd accumulation in agricultural soils mainly include industrial pollutants, agriculture chemicals, mining activities, domestic wastes, and soil properties. The importance of these factors varies across different accessibility ranges. Our findings imply that the characteristic variation of Cd accumulation with the road accessibility gradient must be considered in the formulation of targeted policies for controlling Cd contamination in agricultural soils.

The sustainable arable land use pattern under the tradeoff of agricultural production, economic development, and ecological protection-an analysis of Dongting Lake basin, China.

To find a solution regarding sustainable arable land use pattern in the important grain-producing area during the rapid urbanization process, this study combined agricultural production, locational condition, and ecological protection to determine optimal arable land use. Dongting Lake basin, one of the major grain producing areas in China, was chosen as the study area. The analysis of land use transition, the calculation of arable land barycenter, the landscape indices of arable land patches, and the comprehensive evaluation of arable land quality(productivity, economic location, and ecological condition) were adopted in this study. The results showed that (1) in 1990-2000, the arable land increased by 11.77%, and the transformation between arable land and other land use types actively occurred; in 2000-2010, the arable land decreased by 0.71%, and more ecological area (forestland, grassland, and water area) were disturbed and transferred into arable land; (2) urban expansion of the Changsha-Zhuzhou-Xiangtan city cluster (the major economy center of this area) induced the northward movement of the arable land barycenter; (3) the landscape fragmentation and decentralization degree of arable land patches increased during 1990-2010; (4) potential high-quality arable land is located in the zonal area around Dongting Lake, which contains the Li County, Linli County, Jinshi County, Taoyuan County, Taojiang County, Ningxiang County, Xiangxiang County, Shaoshan County, Miluo County, and Zhuzhou County. The inferior low-quality arable land is located in the northwestern Wuling mountainous area, the southeastern hilly area, and the densely populated big cities and their surrounding area. In the optimized arable land use pattern, the high-quality land should be intensively used, and the low-quality arable land should be reduced used or prohibitively used. What is more, it is necessary to quit the arable land away from the surrounding area of cities appropriately, in order to allow more space for urban expansion. This study could provide guidance for sustainable arable land use by both satisfying the future agricultural production and the local economic development, which can be used for the other major grain-producing areas in this rapid developing country.

A comprehensive assessment of agricultural intensification scenarios for the Dongting Lake basin in south-central China in 2030.

To explore the future of the material demand, pollutant emission, production, and arable land area surrounding the Dongting Lake basin, and to find a potential solution for agricultural development, this study assumes the following four agriculture intensification scenarios: the natural development scenario (ND), the production development scenario (PD), the moderate intensification scenario (MI), and the local resilience scenario (LR). The scenarios focus on different developmental patterns (natural development, short-term production growth, long-term sustainability, or self-sufficiency).The result shows to satisfy the food demand in 2030, and the production of crop and meat will be 26.96, 30.25, 28.05, and 16.27 × 10(6) t in ND, PD, MI, and LR, respectively; more than 1.78 × 10(6) ha of arable land is needed. Compared with the year 2012, the material input and pollutant output will increase by a maximum of 18.32 and 122.31 %, respectively. By classifying the environmental risk into four categories-greenhouse gas emission, air pollution, eutrophication, and ecotoxicity-the composite environmental risk index (CER) is calculated. The CER in PD was the highest, followed by that in ND, LR, and MI. Due to the production allocation within the 35 cities and counties, the spatial distribution of CER is more homogenous in PD and MI than in ND. The analysis of the scenarios reveals that through technological improvement and spatial allocation of agricultural production, scenario MI could be a potential direction for the government to design a sustainable agricultural-environmental system.

Assessing environmental risks for high intensity agriculture using the material flow analysis method--a case study of the Dongting Lake basin in South Central China.

This study primarily examined the assessment of environmental risk in high intensity agricultural areas. Dongting Lake basin was taken as a case study, which is one of the major grain producing areas in China. Using data obtained from 1989 to 2012, we applied Material Flow Analysis (MFA) to show the material consumption, pollutant output and production storage in the agricultural-environmental system and assessed the environmental risk index on the basis of the MFA results. The results predicted that the status of the environmental quality of the Dongting Lake area is unsatisfactory for the foreseeable future. The direct material input (DMI) declined by 13.9%, the domestic processed output (DPO) increased by 28.21%, the intensity of material consumption (IMC) decreased by 36.7%, the intensity of material discharge (IMD) increased by 10%, the material productivity (MP) increased by 27 times, the environmental efficiency (EE) increased by 15.31 times, and the material storage (PAS) increased by 0.23%. The DMI and DPO was higher at rural places on the edge of cities, whereas the risk of urban agriculture has arisen due to the higher increasing rate of DMI and DPO in cities compared with the counties. The composite environmental risk index increased from 0.33 to 0.96, indicating that the total environmental risk changed gradually but seriously during the 24 years assessed. The driving factors that affect environmental risk in high intensity agriculture can be divided into five classes: social, economic, human, natural and disruptive incidents. This study discussed a number of effective measures for protecting the environment while ensuring food production yields. Additional research in other areas and certain improvements of this method in future studies may be necessary to develop a more effective method of managing and controlling agricultural-environmental interactions.