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Background Cancer-associated fibroblasts (CAFs) are an essential component of tumor microenvironment. They are attracting increasing attentions due to their crucial role in tumor growth, drug-resistance and metastasis. Cisplatin is a first-line chemotherapy drug applying in various types of cancer. There are intensive studies on cisplatin's effect on tumor cells, however, its effect on CAFs remains poorly understood. In the present study, we investigated the effect of cisplatin on CAFs. Methods Cell migration was detected by wound healing assay. Cell invasion was performed by the transwell assay. mRNA expression was detected by quantitative PCR, and protein expression was detected by Western blotting. Tumor growth was measured using BALB/c nude mice tumor models. Results Cisplatin attenuated the promoting capacity of CAFs on lung cancer cell migration and invasion, via suppressing CAFs' effect on metastasis-related genes including Twist1, vascular endothelial growth factor receptor (VEGFR), MMP2, and AKT signaling pathway. Keratin 8 (KRT8) was identified as a target of cisplatin. KRT8 upregulation in CAFs is responsible for the inhibitory effect of cisplatin on lung cancer cells metastasis potential through AKT pathway suppression. The stimulation of AKT by AKT activator SC79 reversed KRT8's effect on cell migration. Importantly, in vivo study also showed that CAFs enhanced tumor growth significantly, and cisplatin effectively abrogated the promoting effect of CAFs on tumor growth. Conclusion Our results revealed a novel mechanism that cisplatin attenuated the metastasis promoting effect of CAFs via KRT8/AKT signaling pathway. This finding highlights KRT8 in CAFs as a potential therapeutic candidate for metastasis treatment.

Tumor progression requires the communication between tumor cells and tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are major components of stromal cells. CAFs contribute to metastasis process through direct or indirect interaction with tumor cells; however, the underlying mechanism is largely unknown. Here, we reported that autophagy was upregulated in lung cancer-associated CAFs compared to normal fibroblasts (NFs), and autophagy was responsible for the promoting effect of CAFs on non-small cell lung cancer (NSCLC) cell migration and invasion. Inhibition of CAFs autophagy attenuated their regulation on epithelial–mesenchymal transition (EMT) and metastasis-related genes of NSCLC cells. High mobility group box 1 (HMGB1) secreted by CAFs mediated CAFs’ effect on lung cancer cell invasion, demonstrated by using recombinant HMGB1, HMGB1 neutralizing antibody, and HMGB1 inhibitor glycyrrhizin (GA). Importantly, the autophagy blockade of CAFs revealed that HMGB1 release was dependent on autophagy. We also found HMGB1 was responsible, at least in part, for autophagy activation of CAFs, suggesting CAFs remain active through an autocrine HMGB1 loop. Further study demonstrated that HMGB1 facilitated lung cancer cell invasion by activating the NFκB pathway. In a mouse xenograft model, the autophagy specific inhibitor chloroquine abolished the stimulating effect of CAFs on tumor growth. These results elucidated an oncogenic function for secretory autophagy in lung cancer-associated CAFs that promotes metastasis potential, and suggested HMGB1 as a novel therapeutic target.

Based on in vitro and in silico assays as well as proteome analysis, this study explored the nongenomic mechanism for butyl benzyl phthalate (BBP)-induced thyroid disruption. Molecular docking simulations showed that BBP could dock into the Arg-Gly-Asp (RGD) domain of integrin α

In order to elucidate the importance of biogeochemical interactions between NH4+ and aquifer media in groundwater runoff paths, a dynamic monitoring section in the riverbank zone, which is most sensitive to environmental characteristics and perpendicular to the flow direction of the Songhua River in northeastern China, was selected for field experiments in this study. The results indicated that the NH4+ concentration decreased gradually along the groundwater runoff path under exploitation conditions. The NH4+ concentrations of J1, J2, and J3 decreased by 8%, 18%, and 22%, respectively, as compared to the starting concentration of 1.3 mg/L. Adsorption of NH4+ by aquifer media at different depths is a monolayer adsorption process in accordance with pseudo-second-order kinetic equation. The maximum reduction of NH4+ from the aquifer media from top to bottom was 76%, 67%, 56%, and 42%, respectively. The function and activity of dominant functional bacteria have characteristics of coevolution with the NH4+ transformation process. The main genera in the fluctuation zone are Pseudomonas (8.83%) and Acinetobacter (4.37%), which mainly transform NH4+ by heterotrophic nitrification–aerobic denitrification (HN–AD). The main genera in the saturated zone are Flavobacterium (32.60%) and Sphingobium (3.54%), which mainly transform NH4+ by anaerobic denitrification. The spatial variations of species and abundance for NH4+ transformation functional bacteria decrease by 2.74% and 3.47%, respectively, along groundwater runoff paths. In the vertical and horizontal directions of groundwater runoff, the percentage of adsorption in NH4+ transformation gradually decreased and the percentage of biotransformation gradually increased. The adsorption processes in the O2/NO3− reduction, Fe/Mn reduction, and SO42− reduction zones were 20.7%, 3.6%, and 1.0%, respectively. The corresponding proportions of the biotransformation process were 79.3%, 96.4%, and 99.0%. This research is critical for elucidating the bio-geochemical interaction between NH4+ and aquifer media along the course of groundwater runoff in order to offer a scientific basis for the prevention and management of groundwater nitrogen pollution.

Groundwater pollution is controlled by many anthropogenic processes, and source apportionment is particularly difficult in cases with multiple superimposed anthropogenic influences. Forty-three shallow groundwater samples in the Hun River alluvial fan were collected and 15 parameters comprising Ca2+, Mg2+, Fe2+, Mn2+, NH4+, NO3−, NO2−, F−, SO42−, PO43−, Cl−, COD, TDS, CN− and HCO3− were studied using principal component analysis (PCA) and factor analysis (FA), coupled with the absolute principal-component-score multiple-linear-regression (APCS-MLR) receptor model. The relationship among land-use types, hydrochemical composition and change of the groundwater quality from natural and anthropogenic sources was demonstrated. The results show that the four major potential pollution sources were water–rock interaction, agricultural fertilizer pollution, geological background and domestic and industrial wastewater; the contribution was 36.4%, 24.1%, 14.7% and 11.8%, respectively. The high-concentration areas were mainly located in the western and northwestern areas, especially in the downstream portion of the Hun River. Rapid economic development and the acceleration of urbanization led to an increase in industrial sewage effluent with complex and changeable composition. The variation of land-use type and evolution of the spatial distribution of the pollution sources in the groundwater show good consistency, which demonstrate that PCA/FA coupled with APCS-MLR is a versatile tool for comprehensive source apportionment of groundwater.

Pollution risk assessment of a groundwater resource area is instrumental in contributing to groundwater protection. This study considered the evaluation results of source apportionment by combining...

The South-to-North water diversion Middle Route Project (MRP) is expected to alleviate the long-term groundwater storage (GWS) depletion in North China Plain (NCP) after the beginning of its operation in December 2014. This study aims to investigate the effect of MRP on GWS by comparing GWS changes before (2003–2014) and after (2015–2018) the MRP operation. The analysis was conducted by using groundwater level data from 617 wells in NCP, and then evaluated against satellite-based water storage data from Gravity Recovery and Climate Experiment (GRACE) and its Follow-On missions. On average in NCP, a decreasing trend of −19.1 ± 5.1 mm/yr was seen in GWS based on well observations during 2003–2014, but a recovery trend of +1.8 ± 0.7 mm/yr was found during 2015–2018. The GWS recovery was most prominent in subregions where groundwater over-utilization had occurred in NCP. GRACE exhibited the capacity to detect the regional GWS depletion during 2003–2014, but difficult to distinguish the sub-regional GWS recovery during 2015–2018. The potential causes for GWS recovery were found to be complicated, not only caused by the reduction of groundwater pumping as accelerated by MRP-diverted water, but also the increasing precipitation recharge of aquifers and the enhanced management of groundwater system. The findings highlight that GWS in NCP has started a gradual transition from unsustainable depletion to sub-regional recovery as benefit from the MRP water diversion.

By means of factor analysis (FA) and positive matrix factorization (PMF) methods, groundwater pollution sources were identified in the Jinji groundwater source area, which is beside the Yellow River and is the only urban water supply source for the city of Wuzhong in Northwestern China. The sources of groundwater were quantified based on 16 samples of shallow groundwater from the source area. The source apportionment with the PMF model identified three dominant groundwater pollution sources. These were anthropogenic activities of agricultural and industrial pollution with a pollution contribution of 53.0%, water–rock interaction of 24.6%, and evaporation and concentration of 22.4%. The source apportionment with the FA model identified four sources which were evaporation and concentration, with the largest contribution (42.6%), followed by anthropogenic activities (29.2%), mineral dissolution and industrial pollution (22.4%), and natural effects (5.8%). Specific attention should be paid to these na...

Isothiocyanates (ITCs) are natural compounds abundant in cruciferous vegetables. Numerous studies have shown that ITCs exhibit anticancer activity by affecting multiple pathways including apoptosis and oxidative stress, and are expected to be developed into novel anticancer drugs. In our previous studies, we demonstrated that ITCs effectively inhibit the proliferation of non-small cell lung cancer (NSCLC) cells, also induce apoptosis and autophagy. In the present study, we found that phenethyl isothiocyanate (PEITC) had significant synergistic effects with epidermal growth factor receptor tyrosine kinase inhibitor Gefitinib in NSCLC cell lines NCI-H1299 and SK-MES-1; and the degradation of antiapoptotic factor myeloid cell leukemia 1 (Mcl-1) caused by PEITC treatment played key roles in the sensitivity of NSCLC cells to Gefitinib. We further illustrated that PEITC regulated the expression of Mcl-1 through protein kinase RNA-like endoplasmic reticulum kinase (PERK)-eukaryotic translation initiation factor 2α-CHOP-Noxa pathway by a posttranscriptional modulation. Pretreatment with endoplasmic reticulum stress (ER stress) inhibitor tauroursodeoxycholic acid and knockdown of PERK expression attenuated the degradation of Mcl-1 caused by PEITC. In in vivo study, nude mice bearing NCI-H1299 xenograft were administrated with PEITC (50 mg/kg, ip) and Gefitinib (50 mg/kg, ig) for 15 days, the PEITC-Gefitinib combination treatment resulted in a significant synergistic reduction in tumor growth, and significantly induced both ER stress and Mcl-1 degradation in tumor tissues. In conclusion, we explored the prospect of PEITC in improving the efficacy of targeted drug therapy and demonstrated the synergistic effects and underlined mechanisms of PEITC combined with Gefitinib in NSCLC cells treatment. This study provided useful information for developing novel therapy strategies by combination treatment of PEITC with targeted drugs.

[Su(var)3‑9, enhancer of zeste, Trithorax] domain‑​containing protein 7 (SETD7) is a protein lysine methyltransferase that methylates both histone H3K4 and non‑histone proteins, such as transcription factors. The methylation on proteins alters their activity and affects a series of biological processes. Recent studies have demonstrated that SETD7 contributes to tumor progression and may play different roles in tumor development. However, the effect of SETD7 on lung cancer cell migration and invasion has not been fully elucidated. The present study demonstrated that the expression of SETD7 was significantly downregulated in lung cancer tissues in comparison with that in matched non‑cancer tissues, and lung cancer cell lines also exhibited lower SETD7 levels compared with normal human bronchial epithelial cells. Overexpression of SETD7 inhibited the migration and invasion of lung cancer cells, whereas decreased SETD7 expression promoted cell migration and invasion. Further study revealed that SETD7 regulated the expression of the metastasis‑related genes metalloproteinase 2, Twist1 and vascular endothelial growth factor. Furthermore, SETD7 knockdown activated the Janus kinase 2/signal transducer and activator of transcription 3 (STAT3) signaling pathway and enhanced lung cancer cell migration, whereas the STAT3‑specific inhibitor Stattic abrogated the effect of SETD7 on cell migration. Taken together, these data indicated that SETD7 acts as a tumor suppressor, and the reduced expression of SETD7 may contribute to lung cancer progression. The findings of the present study suggest that SETD7 may be a novel candidate for the treatment of metastatic lung cancer.

Globally, groundwater resources are being deteriorated by rapid social development. Thus, there is an urgent need to assess the combined impacts of natural and enhanced anthropogenic sources on groundwater chemistry. The aim of this study was to identify seasonal characteristics and spatial variations in anthropogenic and natural effects, to improve the understanding of major hydrogeochemical processes based on source apportionment. 34 groundwater points located in a riverside groundwater resource area in northeast China were sampled during the wet and dry seasons in 2015. Using principal component analysis and factor analysis, 4 principal components (PCs) were extracted from 16 groundwater parameters. Three of the PCs were water-rock interaction (PC1), geogenic Fe and Mn (PC2), and agricultural pollution (PC3). A remarkable difference (PC4) was organic pollution originating from negative anthropogenic effects during the wet season, and geogenic F enrichment during the dry season. Groundwater exploitation resulted in dramatic depression cone with higher hydraulic gradient around the water source area. It not only intensified dissolution of calcite, dolomite, gypsum, Fe, Mn and fluorine minerals, but also induced more surface water recharge for the water source area. The spatial distribution of the PCs also suggested the center of the study area was extremely vulnerable to contamination by Fe, Mn, COD, and F−.

Hydrogeochemical evolution of interactions between surface water and groundwater is crucial for guaranteeing water supply quality in a riverside water source area. This study focuses on the seasonal and spatial characteristics of hydrogeochemical evolution affected by groundwater exploitation in the Hulan water source area using hydrochemical analyses and stable isotope tracers. Results show that the concentrations of major ions and total dissolved solids (TDS) increase considerably during the dry season. A bicarbonate water type is primarily produced by the dissolution of calcite, dolomite and gypsum, as well as the cation exchange and human activities. Along the typical infiltration path, the proportions of surface water increase with proximity to the river from 8%-63% during the wet season to 11%-84% during the dry season, which are attributed to an increased hydraulic gradient by exploitation. The typical path is classified into two zones. The first is the intensive mixing zone (within 1 km) with increasing concentrations of major ions and TDS due to mixing effect. The second is the exploitation influence zone (1-3.3 km) with increased concentrations of Ca2+ , Mg2+ , SO42- , and HCO3- during the dry season due to two reasons of seasonal variations in evaporation, stronger water-rock interactions and mixing effects with increased surface water by exploitation.

The objective of this study was to explore the controlling factors on the migration and transformation of nitrogenous wastes in groundwater using long-term observations from a contaminated site on the southwestern edge of the Tengger Desert in northwestern China. Contamination was caused by wastewater discharge rich in ammonia. Two long-term groundwater monitoring wells (Wells 1# and 2#) were constructed, and 24 water samples were collected. Five key indicators were tested: ammonia, nitrate, nitrite, dissolved oxygen, and manganese. A numerical method was used to simulate the migration process and to determine the migration stage of the main pollutant plume in groundwater. The results showed that at Well 1# the nitrogenous waste migration process had essentially been completed, while at Well 2# ammonia levels were still rising and gradually transitioning to a stable stage. The differences for Well 1# and Well 2# were primarily caused by differences in groundwater flow. The change in ammonia concentration was mainly controlled by the migration of the pollution plume under nitrification in groundwater. The nitrification rate was likely affected by changes in dissolved oxygen and potentially manganese.