Upregulation of GOLPH3 mediated by Bisphenol a promotes colorectal cancer proliferation and migration: evidence based on integrated analysis.

Background: The interaction between environmental endocrine-disrupting chemicals, such as Bisphenol A (BPA), and their influence on cancer progression, particularly regarding the GOLPH3 gene in colorectal cancer, remains unclear. Methods: We performed an integrated analysis of transcriptional profiling, clinical data, and bioinformatics analyses utilizing data from the Comparative Toxicogenomics Database and The Cancer Genome Atlas. The study employed ClueGO, Gene Set Enrichment Analysis, and Gene Set Variation Analysis for functional enrichment analysis, alongside experimental assays to examine the effects of BPA exposure on colorectal cancer cell lines, focusing on GOLPH3 expression and its implications for cancer progression. Results: Our findings demonstrated that BPA exposure significantly promoted the progression of colorectal cancer by upregulating GOLPH3, which in turn enhanced the malignant phenotype of colorectal cancer cells. Comparative analysis revealed elevated GOLPH3 protein levels in cancerous tissues versus normal tissues, with single-cell analysis indicating widespread GOLPH3 presence across various cell types in the cancer microenvironment. GOLPH3 was also associated with multiple carcinogenic pathways, including the G2M checkpoint. Furthermore, our investigation into the colorectal cancer microenvironment and genomic mutation signature underscored the oncogenic potential of GOLPH3, exacerbated by BPA exposure. Conclusion: This study provides novel insights into the complex interactions between BPA exposure and GOLPH3 in the context of colorectal cancer, emphasizing the need for heightened awareness and measures to mitigate BPA exposure risks. Our findings advocate for further research to validate these observations in clinical and epidemiological settings and explore potential therapeutic targets within these pathways.

USP6 and circCYFIP2 target oncoprotein GOLPH3 for deubiquitination and induce platinum resistance in colon cancer.

GOLPH3 has been identified as an oncoprotein, playing a crucial role on progression and chemoresistancein of colon adenocarcinoma (COAD). However, it is still unclear the regulation of GOLPH3 expression at protein level. We discovered ubiquitin-specific proteases 6 (USP6) directly regulated the deubiquitination of the GOLPH3 protein and enhanced its stability in COAD. Overexpression of USP6 promoted COAD cell viability, inhibited apoptosis, and accelerated the growth of transplanted tumors growth in vitro and in vivo by deubiquitinating GOLPH3. Additionally, circCYFIP2 showed high expression levels in DDP-resistant colon cancer cells, promoting the cell proliferation. Mechanically, circCYFIP2 binds to both GOLPH3 protein and USP6, strengthening the interaction between GOLPH3 and USP6, and consequently induced DDP resistance in vitro and in vivo. In conclusion, USP6 operates as a deubiquitinase, targeting the GOLPH3 protein in COAD and enhancing its stability. Meanwhile, circCYFIP2 is crucial for the deubiquitination of GOLPH3 protein mediated by USP6 and acts as a scaffold to confer platinum resistance. The discovery of circCYFIP2/USP6/GOLPH3 pathway offers a potential target for overcoming chemoresistance in COAD.

Can e-commerce alleviate agricultural non-point source pollution? - A quasi-natural experiment based on a China's E-Commerce Demonstration City.

Agricultural non-point source pollution is an important driving factor that causes systemic pollution of the ecological environment and directly threatens the sustainable development of agriculture, human health, and safety. As a new engine to reshape the agricultural development model, e-commerce is of great significance to the mitigation of agricultural non-point source pollution. This study regards China's National E-commerce Demonstration Cities (NEDCs) as a quasi-natural experiment and uses the Multi-period difference in difference (DID) method to investigate the impact of urban e-commerce development on agricultural non-point source pollution and its mechanism. The results show that compared with the control group, the NEDC policy reduced the total fertilizer consumption in the pilot cities by 7.5 percentage points, and at the same time had a reduction effect on the consumption of nitrogen fertilizers, pesticides, and agricultural films. According to the analysis of the underlying mechanism, this abatement effect is achieved by increasing the economic performance of the NEDC pilot cities represented by GDP and GDP per capita, and promoting technological innovation represented by green patents and green utility patents. The analysis of heterogeneity finds that the reduction effect of e-commerce on agricultural non-point source pollution is stronger in areas such as main grain production areas and high-value agrochemical input areas. Accordingly, this study proposes that the government should pay attention to regional heterogeneity and formulate support policies for agricultural e-commerce based on local conditions. Moreover, we should actively advance the development of the new business model of "e-commerce + agriculture" and promote the organic integration of agricultural development and ecological civilization.

Alleviating water scarcity and poverty through water rights trading pilot policy: A quasi-natural experiment based approach.

Water poverty is among the most significant global challenges and severely restricts the sustainable development of societies and economies, especially in the world's arid regions. Many countries have attempted to address this challenge. Market-based trading mechanisms represent an essential method of resolving the problem of water shortages and alleviating water poverty. Based on a quasi-natural experiment of water rights trading pilots in China, this study uses panel data from 31 provinces (municipalities) from 2009 to 2019 to explore the impact of water rights trading pilot policy on water poverty through a difference-in-differences (DID) model. The research results show that such policies can effectively alleviate water poverty by improving water-saving irrigation technology, promoting industrial and agricultural water trading, and optimizing the industrial structure. Additionally, dynamic effect and spatial heterogeneity analyses show that the water rights trading pilot policy have long-term effects and have a stronger mitigation effect on the western region of China compared with the central and eastern regions. Therefore, the Chinese government should not only further expand the implementation scope of these policies but also adjust measures according to local conditions to accurately and effectively implement such policies in different regions. Our study provides insights into water policies in China that can better manage natural resources and reduce water poverty in the arid areas around the world.

Contract farming, social trust, and cleaner production behavior: field evidence from broiler farmers in China.

Pollution from livestock and poultry is the main source of rural pollution, which directly affects the rural ecological environment as well as the quality and safety of agricultural products. Based on field experiment data on broiler farmers in China, this paper analyzes farmers' cleaner production behavior from the perspective of incomplete contracts and social trust. We find that social trust can promote farmers' cleaner production behavior. Moreover, our evidence suggests that contract farming (CF) has a significant positive effect on farmers' social trust and cleaner production behaviors. Further analysis indicates that CF not only directly promotes farmers' cleaner production, but can also indirectly promote farmers' cleaner production by improving their interpersonal trust and institutional trust. Overall, this paper offers a new point of view for improving the rural environment and sheds light upon how the government can formulate relevant policies to promote farmers' cleaner production behavior.

Hsa_circ_0044235 regulates the pyroptosis of rheumatoid arthritis via MiR-135b-5p-SIRT1 axis.

Studies have found that cell pyroptosis is involved in the occurrence and development of rheumatoid arthritis (RA). Hsa_circ_0044235 has been found to be significantly low-expressed in RA patients. The purpose of this research was to reveal the regulatory mechanism of hsa_circ_0044235 in the pyroptosis pathway of RA. Serum expressions of hsa_circ_0044235 and SIRT were detected by RT-qPCR, and the relationship of the two genes was analyzed by Pearson. Next, a collagen-induced arthritis (CIA) mouse model was constructed to examine the effect of hsa_circ_0044235 on knee joint injury. The number of apoptotic cells and the level of inflammatory cytokines in synovial tissue were detected by TUNEL and ELISA. Fibroblast-like synoviocytes (FLSs) were extracted as in vitro study subject. Functional assays including flow cytometry and immunofluorescence staining, molecular experiments including RT-qPCR, Western blot and dual luciferase assay, and bioinformatics analysis were performed to analyze the mechanism of hsa_circ_0044235 in pyroptosis in FLSs. Hsa_circ_0044235 and SIRT1 expressions were suppressed in RA patients and the two were positively correlated. Overexpressed hsa_circ_0044235 attenuated joint inflammation, cell apoptosis, and joint damage, reduced foot pad thickness, clinical case scores, inhibited the NLRP3-mediated pyroptosis pathway but promoted SIRT1 expression in CIA mice. Overexpressed hsa_circ_0044235 inhibited caspase-1 content and the NLRP3-mediated pyroptosis pathway. Moreover, hsa_circ_0044235 promoted SIRT1 expression by sponging miR-135b-5p in FLSs. Additionally, the effect of overexpressed hsa_circ_0044235 on FLSs was reversed by miR-135b-5p mimic and siSIRT1, while the effect of siSIRT1 was reversed by miR-135b-5p inhibitor. Hsa_circ_0044235 regulated NLRP3-mediated pyroptosis through miR-135b-5p-SIRT1 axis to regulate the development of RA.

CircMAPK9 promotes the progression of fibroblast-like synoviocytes in rheumatoid arthritis via the miR-140-3p/PPM1A axis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory joint disease, and fibroblast-like synoviocytes (FLSs) are key effector cells in RA development. Mounting evidence indicates that circular RNAs (circRNAs) participate in the occurrence and development of RA. However, the precise mechanism of circRNA mitogen-activated protein kinase (circMAPK9) in the cell processes of FLSs has not been reported. METHODS: The expression levels of circMAPK9, microRNA-140-3p (miR-140-3p), and protein phosphatase magnesium-dependent 1A (PPM1A) were determined by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot assay. Cell proliferation was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell apoptosis and cycle distribution were assessed by flow cytometry. Cell migration and invasion were tested by transwell assay. All the proteins were inspected by western blot assay. Inflammatory response was evaluated by enzyme-linked immunosorbent assay (ELISA). The interaction between miR-140-3p and circMAPK9 or PPM1A was verified by dual-luciferase reporter assay. RESULTS: CircMAPK9 and PPM1A were upregulated and miR-140-3p was downregulated in RA patients and FLSs from RA patients (RA-FLSs). CircMAPK9 silence suppressed cell proliferation, migration, invasion, inflammatory response, and promoted apoptosis in RA-FLSs. MiR-140-3p was a target of circMAPK9, and miR-140-3p downregulation attenuated the effects of circMAPK9 knockdown on cell progression and inflammatory response in RA-FLSs. PPM1A was targeted by miR-140-3p, and circMAPK9 could regulate PPM1A expression by sponging miR-140-3p. Furthermore, miR-140-3p could impede cell biological behaviors in RA-FLSs via targeting PPM1A. CONCLUSION: CircMAPK9 knockdown might inhibit cell proliferation, migration, invasion, inflammatory response, and facilitate apoptosis in RA-FLSs via regulating miR-140-3p/PPM1A axis, offering a new mechanism for the comprehension of RA development and a new insight into the potential application of circMAPK9 in RA treatment.

Land Tenure and Green Production Behavior: Empirical Analysis Based on Fertilizer Use by Cotton Farmers in China.

Stable land rights can increase farmers' expectations regarding the future and encourage their adoption of green production methods, which is an important guarantee for promoting the development of green agriculture development. This paper takes the fertilizer use as an example and systematically investigated the impact of land tenure stability on the green production behavior of heterogeneous farmers based on a field survey data of 349 cotton-planting farmers from Xinjiang, China. Furthermore, this research aims to assess the differential impact of land tenure stability on different risk preferences, organizational forms and ethnic groups. This study is a continuation of previous studies on factors influencing green production behavior. The results show that land transfers have an inhibiting effect on farmers' green production behavior and this effect is more significant among risk-averse farmers, local farmers and minority nationalities farmers. The land tenure period can promote the green production of farmers and alleviate the restraining effect of land transfers on farmers' green production behavior. Additionally, farmers of Xinjiang Production and Construction Corps (XPCC) and large-scale households are more inclined to green production. The Chinese Government needs to further promote land transfer to large-scale households, improve the stability of land rights and adopt differentiated policies for heterogeneous farmers to encourage their green production.

Andrographolide mitigates cartilage damage via miR-27-3p-modulated matrix metalloproteinase13 repression.

BACKGROUND: As a potential anti-arthritic agent, Andrographolide (And) is capable of promoting chondrocyte proliferation and preventing apoptosis in pathologic condition. The present study aimed to explore the roles of And in in vivo and in vitro models of osteoarthritis (OA), as well as its underlying molecular mechanisms. METHODS: An OA mouse model was established using anterior cruciate ligament transection operation on the left knee joint. The pathological changes of articular cartilage were assessed using safranin O staining. Chondrocyte proliferation and apoptosis were measured using cell a counting kit-8 assay and flow cytometry. Bioinformatics algorithms and a luciferase reporter assay were used to evaluate matrix metalloproteinase13 (MMP13) as a direct target of miR-27-3p. RESULTS: And had the ability to prevent catabolism and facilitate anabolism of articular cartilage in an experimental OA model in mice. In addition, And alleviated chondrocyte apoptosis in in vitro and in vivo models of OA. We also found that both up-regulation of MMP13 and down-regulation of miR-27-3p in the proximal tibia of OA mice and interleukin (IL)-1ß-stimulated chondrocytes were reversed by And administration simultaneously. MMP13 was validated as direct target of miR-27-3p and could be suppressed by overexpression of miR-27-3p in mouse chondrocyte. Furthermore, overexpression of miR-27-3p or MMP13 loss-of-function in chondrocytes could alleviate IL-1ß-induced apoptosis. CONCLUSIONS: These results indicated that miR-27-3p/MMP13 signaling axis might be a potential therapeutic target of And for preventing the progression of OA.

Effect and molecular mechanism of Lin28 on 5-Fu sensitivity of hepatocellular carcinoma HepG2 cells / 中国肿瘤生物治疗杂志

@# Objective: To investigate the effect and mechanism of RNA binding protein Lin28 on the 5-fluorouracil (5-Fu) sensitivity of HepG2 cells. Methods: HepG2 cells were transfected with plasmid pcDNA3.1-Lin28 or si-Lin28 (small interfering RNA of Lin28). qPCR and Western blotting were used to detect the expression of Lin28 in HepG2 cells after transfection. Changes of cell proliferation in transfected cells after 5-Fu treatment was detected by CCK8 assay and the 50% inhibitory concentration (IC50) was calculated. Flow cytometry was used to detect apoptotic rate after 5-Fu treatment and the expression of apoptosis-related protein was assayed by Western blotting. The mRNA expressions of drug-resistant miRNAs (let-7a and let-7b), as well as cancer stem cell markers (Oct4, Nanog and Sox2) after transfection were detected by qPCR. Results: As compared to the HepG2/Vector cells, the mRNA and protein expressions of Lin28 were significantly up-regulated in HepG2/Lin28 cells (P<0.05 or P<0.01). Over-expression of Lin28 significantly suppressed the sensitivity of HepG2 cells to 5-Fu (IC50elevated obviously, P<0.05) and significantly increased cell proliferation while decreased apoptotic rate and expression of apoptotic-related protein caspase-3 (all P<0.01). As compared to si-control group, expression of Lin28 in HepG2/si-Lin28 cells was significantly down-regulated (P<0.01). Lin28 knockdown significantly reduced cell proliferation and IC50 of 5-Fu (all P<0.01) but increased apoptotic rate and expression of apoptosis-related protein (P<0.01). Compared with HepG2/Vector group, expressions of let-7a and let-7b, as well as cancer stem cell markers (Oct4, Nanog and Sox2) were significantly increased in HepG2/Lin28 cells (all P<0.01); while these molecules were significantly decreased in HepG2/si-Lin28 cells as comparing to si-control group (all P<0.01). Conclusion: Lin28 can modulate the chemosensitivity of HepG2 cells by regulating the expression of miRNAs and the formation of cancer stem cells. Targeting Lin28 might be a promising approach to improve the chemotherapy efficacy in HCC.

Robust Single-Shot T2 Mapping via Multiple Overlapping-Echo Acquisition and Deep Neural Network.

Quantitative magnetic resonance imaging (MRI) is of great value to both clinical diagnosis and scientific research. However, most MRI experiments remain qualitative, especially dynamic MRI, because repeated sampling with variable weighting parameter makes quantitative imaging time-consuming and sensitive to motion artifacts. A single-shot quantitative T2 mapping method based on multiple overlapping-echo acquisition (dubbed MOLED-4) was proposed to obtain reliable T2 mapping in milliseconds. Different from traditional MRI acceleration methods, such as compressed sensing and parallel imaging, MOLED-4 accelerates quantitative T2 mapping via synchronized multisampling and then deep learning to map the complex nonlinear relationship that is difficult to solve by traditional optimization-based methods. The results of simulation, phantom, and in vivo human brain experiments show the great performance of the proposed method. The principle of MOLED-4 may be extended to other ultrafast quantitative parameter mappings and potentially lead to new dynamic MRI with high efficiency to catch quantitative variation of tissue properties.

[Predictive value of plasma cell-free DNA for prognosis of sepsis].

OBJECTIVE: To explore the predictive value of plasma cell-free DNA (cf-DNA) for prognosis in patients with sepsis. METHODS: 105 patients with sepsis admitted to department of emergency of the First Hospital of Quanzhou Affiliated to Fujian Medical University from June 2015 to June 2017 were enrolled. Patients were divided into sepsis group (n = 50) and severe sepsis group (n = 55). At the same time, 50 cases of physical examination center in our hospital were randomly selected as the healthy control group. The differences of cf-DNA, procalcitonin (PCT) and acute physiology and chronic health evaluation II (APACHE II) score among the three groups were compared. The correlation between cf-DNA and PCT or APACHE II were analyzed by Bivarite method. Logistic regression was used to analyze the independent predictors of sepsis. The receiver operating characteristic curve (ROC) was made to evaluate cf-DNA, PCT, APACHE II alone or combined ability to predict the prognosis of sepsis. RESULTS: The PCT, APACHE II and cf-DNA in the sepsis group and severe sepsis group were significantly higher than those in the healthy control group [PCT (µg/L): 5.80 (3.28, 8.85), 17.53 (8.40, 29.61) vs. 0.02 (0.01, 0.03); APACHE II: 13.04±3.03, 23.29±8.02 vs. 2.10±1.05; cf-DNA (µg/L): 1 438.0 (1 154.0, 1 576.0), 2 595.0 (2 162.0, 5 198.0) vs. 17.0 (13.0, 20.5); all P < 0.05], and the indicators in the severe sepsis group were further higher than the sepsis group (all P < 0.05). Correlation analysis showed that cf-DNA was significantly positive correlated with PCT [r = 0.675, 95% confidence interval (95%CI) = 0.575-0.766, P < 0.001] and APACHE II (r = 0.911, 95%CI = 0.874-0.939, P < 0.001). ROC curve analysis showed that the areas under ROC curve (AUC) of PCT, APACHE II, cf-DNA, PCT+APACHE II, cf-DNA+PCT, cf-DNA+APACHE II, cf-DNA+PCT+APACHE II to predict the prognosis of sepsis patients were 0.898, 0.905, 0.961, 0.941, 0.974, 0.976 and 0.982, respectively. It was shown that when predicted alone with PCT, APACHE II and cf-DNA, the AUC of cf-DNA was the largest (0.961), the sensitivity was 100%, and the specificity was 81.43%; the combined prediction of cf-DNA with PCT or APACHE II could further increase AUC, and the combined prediction of cf-DNA, PCT and APACHE II had the highest AUC (0.982), the sensitivity was 94.29%, the specificity was 98.57%. CONCLUSIONS: cf-DNA, PCT and APACHE II have certain predictive value for the prognosis of sepsis. The value of cf-DNA was the highest when predicted alone, but the predictive ability of cf-DNA combined with PCT and APACHE II was the best.