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Cancer stem-like cells (CSCs), which play an important role in tumor initiation and progression, have been identified in many cancers. Diallyl trisulfide (DATS) is an organosulfur compound extracted from garlic with anticancer activities. Nanog is a transcription factor responsible for maintaining the stemness of CSCs, but its role in the DATS-induced attenuation of renal CSC properties is unknown. In this study, renal CSCs were enriched from human renal cancer cell lines 786-O and ACHN cultured in a serum-free medium (SFM). The properties of CSCs were analyzed by evaluating the ability of the cells in sphere formation and measuring the expression of stem cell markers. We found that downregulation of Nanog inhibited renal CSC properties. DATS suppressed renal CSC activities by reducing tumorsphere formation, decreasing stem cell markers including Nanog, CD44, ALDH1A1, and Oct4, inhibiting cell proliferation and promoting apoptosis. We further revealed that overexpression of Nanog reversed the suppressive effects of DATS on renal CSCs. Taken together, our results demonstrated that DATS inhibited renal CSCs by suppressing Nanog. These novel findings suggested that, through Nanog targeting, DATS can potentially be used as an anti-tumor agent for renal cancer.

Cancer stem cells (CSCs) function as the driving force of cancer initiation and progression. Wnt/β-catenin is the core pluripotency pathway in CSCs, while its crucial regulator has not been fully elucidated yet. Here, we evaluated the role of ZO-1, a component of the tight junction protein complex, in colorectal CSCs, and found ZO-1 downregulation in both colorectal cancer cells and spheres. Over-expression of ZO-1 can inhibit the sphere-forming capacity and CSC marker expression in spheres. Immunofluorescence staining and co-immunoprecipitation analysis further revealed the interaction between ZO-1 and β-catenin and the repressed role of ZO-1 in β-catenin nuclear accumulation. Using

Sulforaphane (SFN), a major isothiocyanate found in cruciferous vegetables, reportedly exerts extensive antitumor effects. Butyl benzyl phthalate (BBP), a widely used plasticizer, plays a crucial role in the promotion of breast cancer. In the present study, we demonstrated that SFN inhibited proliferation, induced apoptosis, and suppressed the stemness of MCF-7 cells, whereas BBP exerted the opposite effects; microRNA-19 (

Panax ginseng is a perennial plant in the Araliaceae family. In this study, we investigated the protective effects of ginseng stem-leaf saponins (GSLS) isolated from P. ginseng against D-galactose-induced reproductive function decline, oxidative stress, and inflammatory response. Reproductive injuries were induced in mice via the subcutaneous injection of D-galactose (300 mg/kg) for six weeks. The mice were then treated with GSLS by intragastric administration. GSLS inhibited markers of oxidative stress and inflammatory cytokines induced by D-galactose in serum, liver and kidney, whereas GSLS increased the activities of antioxidant enzymes. Compared to the mice treated only with D-galactose, GSLS treatment significantly increased the average path velocity, straight line velocity, curvilinear velocity, and amplitude of the lateral head displacement of mouse sperm. Meanwhile, GSLS significantly increased the testosterone level and reduced the cortisol, FSH, and LH levels. Histopathological examination revealed alterations in the number and the arrangement of spermatogenic cells in the seminiferous tubules of the mice in the GSLS group. GSLS treatment suppressed MAPKs pathway activation in testes. These results suggest that GSLS can attenuate D-galactose-induced oxidative stress and inflammatory response in serum, liver and kidney, and ameliorate reproductive damage by inhibiting MAPKs signaling pathway.

Gut microbiota are the candidate biomarkers for neurogenic bowel dysfunction (NBD) in patients with spinal cord injury (SCI). We aimed to identify the common features between patients with varying degree of thoracic SCI and healthy individuals and subpopulations of microbiota correlated with the serum biomarkers. Twenty-one patients with complete thoracic SCI (CTSCI), 24 with incomplete thoracic SCI (ITSCI), and 24 healthy individuals (HC) were enrolled in this study. Fresh stool samples and clinical data were collected from all participants, and their bowel functions with SCI were assessed. Microbial diversity and composition were analyzed by sequencing the 16S rRNA gene. The features of gut microbiota correlated with the serum biomarkers and their functions were investigated. The mean NBD score of patients with CTSCI was higher than that of patients with ITSCI. Diversity of the gut microbiota in SCI group was reduced, and with an increase in the degree of damage, alpha diversity had decreased gradually. The composition of gut microbiota in patients with SCI was distinct from that in healthy individuals, and CTSCI group exhibited further deviation than ITSCI group compared to healthy individuals. Four serum biomarkers were found to be correlated with most differential genera. Patients with thoracic SCI present gut dysbiosis, which is more pronounced in patients with CTSCI than in those with ITSCI. Therefore, the gut microbiota profile may serve as the signatures for bowel and motor functions in patients with thoracic SCI., GRAPHICAL ABSTRACT

Iron deficiency anemia (IDA) is a common micronutrient deficiency among pregnant women with severe consequences including impaired immuno-inflammatory system, premature birth, fetal death etc. The present study aimed to investigate the effects of three iron supplements on IDA female rats and their offspring. The IDA female rat model was established with low iron diet and the rats were then mated. After pregnancy, rats were fed diets containing different iron supplements (iron polysaccharide complex, iron protein succinylate and ferrous sulfate) until their offspring were 42 days old. Pregnancy outcomes, haematological, iron metabolism, physical and neurological development indexes were determined. The results showed that all three iron supplements improved the levels of hematological parameters of both mother and offspring rats. After iron supplementation, serum iron, transferrin saturation and serum ferritin levels were increased compared with the IDA group. The level of ferritin light chain in the liver and spleen of both mother and offspring rats in iron supplemented groups was significantly higher than that of the IDA group. The average number of born alive per litter in the iron treatment groups was significantly higher than that in the IDA group. Iron supplements also improved the physical growth and neurobehavioral development of offspring rats. It was also found that iron supplementation improved the expression of ferritin light chain and the synaptic growth associated proteins in the brain and hippocampus. No significant difference was found in the efficacy of three iron supplements. These results suggest that pregnant and postpartum IDA affects pregnancy outcomes, offspring physical development and causes neural impairment. Sufficient iron supplementation can significantly improve IDA and its adverse effects on both mother and offspring.

Nanog plays an important role in the regulation of cancer stem cells (CSCs) which participate in tumorgenesis and progression. In renal cancer, tobacco smoke (TS) is considered a major risk factor. However, the molecular mechanism by which TS induces the development of renal CSC properties remains largely unknown. In this study, we showed that the level of Nanog was elevated in renal cell carcinoma (RCC) patients with a smoking history, and that Nanog overexpression promoted the traits of CSCs in renal cancer. We further demonstrated that a 8-week exposure of TS enhanced the formation of renal tumorspheres, increased the population of CD133-positive cells, and stimulated the expression of Nanog and CSC markers. In addition, TS was found to play a role in accelerating the cell growth transition from G1 to S phase in renal CSCs. Finally, we demonstrated that the TS-induced effects in renal CSCs could be reversed through the downregulation of Nanog. Our results suggested that Nanog plays a role in mediating TS-induced renal CSC properties. This study may provide new insights into the molecular mechanism of TS-related renal tumorigenesis, which can contribute to the future development of therapeutics for renal cancer.

The PD-1/PD-L1 immune checkpoint blockade therapy has shown revolutionary efficacy in the treatment of multiple cancers including gastric cancer. Isothiocyanates play important roles in cancer cell suppression and immunomodulation. However, the effects of isothiocyanates on immune checkpoint inhibitors are poorly understood in gastric cancer. The influence of three major isothiocyanates (sulforaphane, phenylethyl isothiocyanate, and benzhydryl isothiocyanate) on gastric cancer cell growth and PD-L1 expression was investigated. Syngeneic mouse models were administered by isothiocyanates and anti-PD-L1 monoclonal antibody, and the anti-tumor effects were assessed. The expression of PD-L1, proportion of lymphocytes and serum cytokine levels were detected to explore the underlying mechanisms. We found that PD-L1 expression was significantly induced by isothiocyanates which was associated with TAp63α up-regulation. We further revealed that TAp63α promoted PD-L1 through transcriptional activation. Combination treatment of isothiocyanates and anti-PD-L1 therapy weakened the sensitivity of gastric cancer cells to anti-PD-L1 drug. Moreover, in vivo studies illustrated that the interference effects of isothiocyanates on anti-PD-L1 antibody were related to PD-L1 expression and decreased infiltrating T lymphocytes in tumor bearing mouse hosts. Our findings provide novel insights as isothiocyanates could interfere with the successful application of immunotherapy in gastric cancer.

Liver disease has become a major cause of premature mortality worldwide. It is well known that dysregulated inflammation response plays a crucial role in most liver diseases. As a Chinese medicinal herb, Magnesium isoglycyrrhizinate (MgIG) has been proven to have good hepatoprotective activity and has been used in clinic to treat liver disease. However, the mechanisms by which MgIG regulates LPS-induced liver injury and inflammation in vivo remain elusive. In our study, MgIG pretreatment mitigated LPS-induced liver damage by suppressing apoptosis and inflammation via regulating macrophage/neutrophil infiltration. MgIG ameliorated the effects of LPS on pro-oxidant enzymes (NOX1/2/4) and anti-oxidant enzymes (SOD1/2). Interestingly, we found that the level of the hepatoprotective cytokine interleukin (IL)-22 was significantly upregulated in MgIG-treated liver tissues, which might be a potential mechanism of MgIG against liver injury. Moreover, we found that MgIG treatment not only inhibited TLR4/MyD88/NF-κB signaling pathway, but also activated autophagy. Furthermore, IL-22 treatment activated autophagy and inhibited TLR4/NF-κB signaling pathway in vitro, suggesting that IL-22-activated autophagy and -inhibited inflammation also participated in the protective effects of MgIG. Altogether, our results uncovered the potential mechanisms of the hepatoprotective effects of MgIG, which provided critical evidence to support the use of MgIG to prevent and treat liver diseases.

Increasing evidence indicate that cancer stem cells (CSCs) are the key driver of tumor initiation and recurrence. The cellular and soluble components of the tumor microenvironment (TME) impact on cancer initiation and progression, such as cytokines and chemokines. Thus, targeting CSCs and TME is a novel anti-cancer approach. Resveratrol (RES), a bioactive phytochemical extracted from various plants, exhibits tumor-suppressing activities in lung cancer, yet the mechanism remains poorly understood. Our data showed that the expression level of IL-6 was positively correlated with the presence of lung cancer stem-like cells (LCSCs) in human lung cancer tissues. In vitro results showed that IL-6 was highly elevated in lung cancer sphere-forming cells and could enhance the stemness of LCSCs, including tumor sphere formation ability, the percentage of CD133 positive cells, and the expression of LCSC specific markers (CD133, ALDH1A1 and Nanog). Simultaneously, our results confirmed that RES effectively inhibited LCSC properties, downregulated Wnt/β-catenin signaling and reduced IL-6 level in vitro and in vivo. Furthermore, we found RES treatment attenuated the activation of Wnt/β-catenin signaling by LiCl (GSK3β agonist). IL-6-promoted LCSC properties and Wnt/β-catenin signaling was also reversed by RES. Taken together, these data illustrated that RES inhibited lung cancer by targeting LCSCs and IL-6 in TME. The novel findings from this study provided evidence that RES exhibited multi-target effects on suppression of lung cancer and could be a novel potent cancer-preventive compound.

An amendment to this paper has been published and can be accessed via the original article.

Background Recently, a variety of clinical trials have shown that apatinib, a small-molecule anti-angiogenic drug, exerts promising inhibitory effects on multiple solid tumors, including non-small cell lung cancer (NSCLC). However, the underlying molecular mechanism of apatinib on NSCLC remains unclear. Methods MTT, EdU, AO/EB staining, TUNEL staining, flow cytometry, colony formation assays were performed to investigate the effects of apatinib on cell proliferation, cell cycle distribution, apoptosis and cancer stem like properties. Wound healing and transwell assays were conducted to explore the role of apatinib on migration and invasion. The regulation of apatinib on VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling were detected. Furthermore, we collected conditioned medium (CM) from A549 and H1299 cells to stimulate phorbol myristate acetate (PMA)-activated THP-1 cells, and examined the effect of apatinib on PD-L1 expression in macrophages. The Jurkat T cells and NSCLC cells co-culture model was used to assess the effect of apatinib on T cells activation. Subcutaneous tumor formation models were established to evaluate the effects of apatinib in vivo. Histochemical, immunohistochemical staining and ELISA assay were used to examine the levels of signaling molecules in tumors. Results We showed that apatinib inhibited cell proliferation and promoted apoptosis in NSCLC cells in vitro. Apatinib induced cell cycle arrest at G1 phase and suppressed the expression of Cyclin D1 and CDK4. Moreover, apatinib upregulated Cleaved Caspase 3, Cleaved Caspase 9 and Bax, and downregulated Bcl-2 in NSCLC cells. The colony formation ability and the number of CD133 positive cells were significantly decreased by apatinib, suggesting that apatinib inhibited the malignant and stem-like features of NSCLC cells. Mechanistically, apatinib inhibited PD-L1 and c-Myc expression by targeting VEGFR2/STAT3 signaling. Apatinib also inhibited PD-L1 expression in THP-1 derived macrophages stimulated by CM from NSCLC cells. Furthermore, apatinib pretreatment increased CD69 expression and IFN-γ secretion in stimulated Jurkat T cells co-cultured with NSCLC cells. Apatinib also promoted ROS production and inhibited Nrf2 and p62 expression, leading to the autophagic and apoptotic cell death in NSCLC. Moreover, apatinib significantly inhibited tumor growth in vivo. Conclusion Our data indicated that apatinib induced autophagy and apoptosis in NSCLC via regulating VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-02069-4., Highlights Apatinib suppressed proliferation, induced cell cycle arrest and apoptosis, and inhibited malignancy in NSCLC in vitro and in vivo.Apatinib downregulated PD-L1 and c-Myc in NSCLC through VEGFR2/STAT3 pathway.Apatinib inhibited PD-L1 expression in THP-1 derived macrophages stimulated by the conditioned medium from NSCLC cells and partially restored the activation of Jurkat T cells co-cultured with NSCLC cells.Apatinib induced ROS generation and inhibited Nrf2 and p62 expression, leading to the autophagic and apoptotic cell death in NSCLC. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-02069-4.

Cancer stem cells (CSCs) have been implicated in the genesis, progression and recurrence of renal cancer. The sonic hedgehog (Shh) pathway serves a critical role in maintaining the stemness of CSCs. Genistein, a major isoflavone component extracted from soybeans and soy products, has been demonstrated to possess anticancer activity. However, the effects of genistein on renal CSCs and its underlying mechanisms remain to be fully elucidated. The aim of the present study was to investigate the role of the Shh pathway in genistein inhibition of renal CSCs. The results of the present study demonstrated that expression levels of renal CSC markers were markedly upregulated in the sphere-forming cells, which were isolated and enriched from 786-O and ACHN cells in a tumor sphere formation assay, and more cells were arrested at the G0/G1 phase instead of the S1 phase compared with the adherent cells. Furthermore, the present study demonstrated that genistein could effectively diminish the activity of renal CSCs by suppressing tumor sphere formation, decreasing renal CSCs markers, inhibiting proliferation and inducing apoptosis. Additionally, the downregulation of Shh pathway activity could inhibit renal CSCs. Genistein exhibited an inhibitory effect on renal CSCs by attenuating the activation of the Shh pathway. In conclusion, the results illustrated the role of the Shh pathway in regulating renal CSC traits and the intervention of renal CSCs by genistein, which could provide novel insights into the molecular mechanisms of renal CSC intervention.

Phenolic compounds are mainly derived from coal tar and coal liquefaction oil. The traditional acid-base separation method, also called caustic washing can result in serious environmental problems. In this work, we used ethanolamine (C2H7NO) to separate phenolic compounds from coal tar rather than caustic washing. Although a slightly lower efficacy of separation was obtained with C2H7NO, extracting phenolic compounds with C2H7NO provided better economic benefits than with caustic washing. The factors influencing the separation effect were studied in detail. In addition, the extraction mechanism of ethanolamine method was investigated by analyzing the chemical interaction of C2H7NO and phenolic compounds using Fourier transform infrared and nuclear magnetic resonance spectroscopy. Results showed that the phenolic compounds and C2H7NO formed complexes through hydrogen bonding, (coordination), leading to the formation of C2H7NO complexes, which resulted in the effective separation of phenolic compounds from other components in coal tar. The results are further supported by quantum chemical calculations. Most importantly, the experiment confirmed that the C2H7NO in the complex can be recovered via distillation and a complete phenol extraction process was conceptually designed and proposed by simulation. Considering the environmental and economic advantages, the ethanolamine method can be used to reduce the alkali residue and phenol-containing wastewater in the industrial production process, which is beneficial for environmental protection. By calculating the total cost of the two methods, the profit from using the ethanolamine method can reach $173,000 or more than the caustic washing method. Thus, the proposed ethanolamine method can be used as an environment-friendly substitute for industrial phenol separation.

The presence of gastric cancer stem cells (GCSCs) marks the onset of gastric carcinoma. The sonic hedgehog (SHH) pathway plays a vital role in the maintenance of GCSC characteristics. Apatinib has been approved in China for advanced gastric cancer (GC) treatment. However, whether apatinib can target GCSCs and affect the SHH pathway remains unclear. The present study aimed to investigate the underlying mechanism of apatinib’s antitumor effects on GC. The expression levels of GCSC markers and number of CD133+ cells were significantly elevated in the sphere-forming cells. Apatinib effectively suppressed GCSC traits by inhibiting tumorsphere formation and cell proliferation, suppressing GCSC markers expression and CD133+ cell number, and inducing apoptosis. Apatinib downregulated the activation of the SHH pathway; while upregulation of the SHH pathway attenuated the inhibitory effects of apatinib on GCSCs. Moreover, apatinib treatment significantly delayed tumor growth and inhibited GCSC characteristics in the xenograft model. Our data suggested that apatinib exhibited inhibitory effects on GCSCs by suppressing SHH pathway both in vitro and in vivo, thus providing new insights into the therapeutic application of apatinib in GCSC suppression and advanced gastric cancer treatment.

Interleukin-17A (IL-17A) is an essential inflammatory cytokine in the progress of carcinogenesis. Tobacco smoke (TS) is a major risk factor of lung cancer that influences epithelial-mesenchymal transition (EMT) process. However, the potential mechanism by which IL-17A mediates the progression of lung cancer in TS-induced EMT remains elusive. In the present study, it was revealed that the IL-17A level was elevated in lung cancer tissues, especially in tumor tissues of cases with experience of smoking, and a higher IL-17A level was correlated with induction of EMT in those specimens. Moreover, the expression of ΔNp63α was increased in IL-17A-stimulated lung cancer cells. ΔNp63α functioned as a key oncogene that bound to the miR-17-92 cluster promoter and transcriptionally increased the expression of miR-19 in lung cancer cells. Overexpression of miR-19 promoted EMT in lung cancer with downregulation of E-cadherin and upregulation of N-cadherin, while its inhibition suppressed EMT. Finally, the upregulated levels of IL-17A, ΔNp63α, and miR-19 along with the alteration of EMT-associated biomarkers were found in lung tissues of TS-exposed mice. Taken together, the abovementioned results suggest that IL-17A increases ΔNp63α expression, transcriptionally elevates miR-19 expression, and promotes TS-induced EMT in lung cancer. These findings may provide a new insight for the identification of therapeutic targets for lung cancer.

Background Gastric cancer stem cells (GCSCs) are considered as the basis of gastric carcinoma onset. Sonic Hedgehog (SHH) pathway plays a crucial role in maintaining GCSCs characteristics. Apatinib, a highly selective vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor, has been approved in China for the treatment of advanced gastric cancer after the failure of second-line therapy. To data, the effects of apatinib on GCSCs and the underlying mechanisms have not been elucidated yet.Methods Tumorsphere formation assay was used to enrich GCSCs from BGC-823 and SGC-7901 cells and the number of CD133-positive cells was examined by flow cytometry. Western blotting, immunofluorescence and immunohistochemistry assays were used to determine protein expression. Cell proliferation and apoptosis of GCSCs after apatinib treatment were evaluated by CCK8, colony formation, flow cytometry and Hoechst 33258 assays. Transient transfection assay was used to upregulate Gli1 expression in GCSCs. Nude mouse xenograft was used to investigate the suppressive effects of apatinib in vivo. Results We revealed that the levels of GCSCs markers and the number of CD133-positive cells were significantly elevated in the sphere-forming cells. We further illustrated that apatinib efficiently abolished GCSCs traits, as manifested by inhibition of tumorsphere formation, decreased expression of GCSCs markers, reduced number of CD133-positive cells, drug resistance protein suppression as well as proliferation inhibition and apoptosis induction. Furthermore, we found that apatinib downregulated the activation of SHH pathway, while upregulation of SHH pathway attenuated the inhibitory effects of apatinib on GCSCs. Furthermore, apatinib treatment significantly delayed tumor growth and inhibited GCSCs characteristics in xenograft model. Conclusions Taken together, our data suggested that apatinib exhibited its inhibitory effects on GCSCs via suppression of SHH pathway. These findings could provide new insights into the therapeutic application of apatinib in GCSCs suppression and advanced gastric cancer treatment.

Substantial evidence suggests that cancer stem cells (CSCs) are the main cause of the initiation, progression and recurrence of tumors. Benzidine has been identified as a risk factor for bladder cancer. The aim of the present study was to investigate the effects of benzidine on bladder CSCs (BCSCs) and the possible mechanism underlying its action. The bladder cancer cell lines UM-UC-3 and EJ were maintained in serum-free medium and cells forming three-dimensional spheres were characterized as BCSCs. The sphere-forming cells were exposed to different concentrations of benzidine and vismodegib, and western blotting was performed to evaluate the expression of markers associated with CSCs and the Sonic hedgehog (SHH) signaling pathway. Flow cytometry was used to detect the distribution of cells in different phases of the cell cycle, and immunofluorescence staining was used to detect the protein expression of CD44. The results revealed that the levels of BCSC markers, namely CD133, CD44, aldehyde dehydrogenase 1-A1, Nanog and octamer-binding transcription factor-4, in the cell spheres were markedly elevated compared with those in cells cultured in serum-supplemented medium. Furthermore, benzidine increased the expression of BCSC markers and promoted the sphere-forming ability of the cells. In addition, it was observed that benzidine activated the SHH pathway, while inhibition of the Shh pathway using vismodegib diminished the promoting effects of benzidine on BCSCs. The findings of the present study indicate that benzidine promoted the stemness of BCSCs via activation of the SHH pathway, which may support further exploration of the molecular basis of the association between benzidine exposure and bladder oncogenesis.

Renal cell cancers typically exhibit high metastasis and recurrence, and this is thought to be due to renal cancer stem cells (CSCs). Meanwhile, aberrant activation of Sonic hedgehog (Shh) signaling is linked with CSCs. Resveratrol has direct or indirect impacts on the pathological activities of CSCs. However, the effects of resveratrol on renal CSCs remain to be elucidated.We cultured renal CSCs in serum-free medium. Western blotting was used to analyze the expression levels of related proteins. The mRNA changes were detected by qRT-PCR after resveratrol treatment. The CD133Renal CSCs were enriched by tumorsphere formation assays of ACHN and 786-O cells. Resveratrol treatments markedly decreased the size and number of cell spheres and downregulated the expression of the Shh pathway-related proteins and CSCs markers. Moreover, we observed that resveratrol inhibited cell proliferation and induced cell apoptosis, while purmorphamine upregulated the Shh pathway and weakened the effects of resveratrol on renal CSCs.These results suggested that resveratrol is a potential novel therapeutic agent that targets inactivation of renal CSCs by affecting the function of the Shh pathway.

Background: Tobacco smoke (TS) critically contributes to the development of lung cancer; however, the underlying molecular mechanisms remain unclear. The induction of cancer stem cells (CSCs) by TS represents an early event in tumor initiation. The lung cancer-related gene ΔNp63α is highly expressed in epithelial tissues and drives tumor formation and cancer stem cell properties. This study investigated the role of ΔNp63α in the long-term acquisition of TS-induced lung CSC-like properties. Methods: The expression levels of ΔNp63α, lung CSC markers, and interleukin (IL)-6 in lung carcinoma specimens were determined by western blotting and enzyme linked immunosorbent assays. Human bronchial epithelial (HBE) cells were chronically exposed to 2 % cigarette smoke extract for 55 passages, following which colony formation capacity, expression of proteins associated with malignant transformation, lung CSC markers, and tumor incidence were investigated. The effects of ΔNp63α on long-term TS exposure-induced lung CSC-like properties and Notch activation were analyzed using tumorsphere formation ability, immunofluorescence assays, luciferase reporter assays, and western blotting. The roles of IL-6 on chronic TS exposure-induced lung CSC-like properties and ΔNp63α expression were also examined. Moreover, the effects of sulforaphane (SFN) on TS-transformed lung CSC-like properties, IL-6 and ΔNp63α expression, and Notch signaling were investigated in vitro and in vivo. Results: Higher levels of ΔNp63α were observed in the lung cancer tissues of smokers than in those of non-smokers, whereas ΔNp63α was positively correlated with CD133 and Oct4 expression in lung cancer tissues. Data from the in vivo and in vitro experiments demonstrated that long-term TS exposure-transformed HBE (THBE) cells acquired lung CSC-like properties. Furthermore, ΔNp63α transcriptionally activated the Notch signaling pathway to promote the acquisition of CSC-like properties by the THBE cells. TS upregulated IL-6, which increased ΔNp63α expression in THBE sphere-forming cells. Finally, SFN inhibited the TS-induced CSC-like properties of THBE cells via the IL-6/ΔNp63α/Notch axis. Conclusion: Our data suggest that the IL-6/ΔNp63α/Notch axis plays an important role in the long-term TS exposure-induced acquisition of lung CSC-like properties and SFN intervention.

OBJECTIVE The aim of the study was to examine the effectiveness of noninvasive brain stimulation on neuropathic pain in individuals with spinal cord injury. METHODS A meta-analysis on pain intensity, depression, and anxiety levels was conducted to evaluate the effect of noninvasive brain stimulation on neuropathic pain in individuals with spinal cord injury. The authors searched Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (PubMed), Embase (OvidSP), PsycINFO (OvidSP), and Physiotherapy Evidence Database (PEDro). Randomized controlled trials comparing noninvasive brain stimulation with sham stimulation were included. RESULTS Eleven studies were selected. The pooled analysis demonstrated no significant effect of repetitive transcranial magnetic stimulation, transcranial direct current stimulation, or cranial electrotherapy stimulation on neuropathic pain reduction after spinal cord injury. In addition, noninvasive brain stimulation showed no beneficial effect over sham stimulation on the improvement of depression, while it yielded a significant reduction of anxiety levels immediately after treatment. Subgroup analysis showed that only cranial electrotherapy stimulation had a significant effect on the reduction of anxiety levels among the three types of noninvasive brain stimulation. CONCLUSIONS In individuals with spinal cord injury, no significant effects of noninvasive brain stimulation on neuropathic pain and depression were observed. Cranial electrotherapy stimulation may be beneficial for the management of anxiety. These findings do not support the routine use of noninvasive brain stimulation for neuropathic pain in individuals with spinal cord injury.

Cancer stem cells (CSCs) are essential in every step of tumorigenesis and progression. As an important process in cancer development, epithelial-mesenchymal transition (EMT) has been reported to promote stem-like cells. Bladder cancer is one of the most common cancers in the urinary tract, and cigarette smoke (CS) is a preventable risk factor. In the present study, we tested the hypothesis that CS could promote stemness and EMT in bladder cancer. Bladder cancer UM-UC-3 and EJ cell lines were maintained in serum-free medium to grow as tumor spheres, characteristic of CSCs. Results demonstrated that CS enhanced tumor sphere formation capacity, upregulated expression of CSC markers, increased the proportion of the CD44(+) cell population, and promoted EMT. Mechanistically, the Sonic Hedgehog (SHH) pathway regulated CS-triggered EMT and stemness. More importantly, among bladder cancer patients, smokers harbored higher levels of CSC markers and proteins for SHH signaling than non-smokers. Collectively, findings in this study highlight the critical role of CS in the stemness and EMT of bladder cancer. Smoking cessation and intervening in the SHH pathway may both be strategies to prevent bladder cancer.

Wastewater containing 1-amino-2-naphthol-4-sulfonic acid (ANS) is mainly derived from the dye production process, causing serious environmental problems. In this work, extraction of ANS from wastewater was carried out using trioctylamine (TOA) under condition of methyl isobutyl ketone (MIBK) as a diluent. The effects of diluent type, concentration of TOA, temperature and pH on the distribution coefficient (D) were discussed in detail. The results showed that the value of D = 76 was obtained with TOA (1.41 mol kg−1) + MIBK at 25 °C and pH = 1.1. After that, the extraction mechanism was determined by analyzing the chemical bonds of the complex compound using UV–vis, FT-IR and 1H NMR. The experimental results showed that the extractant could be regenerated by back extraction. Specially the distillation process was simulated using Aspen Plus and the results verified its feasibility in the process of extractant regeneration. The proposed extraction system is conductive to both environment and technology.

Prostate cancer is one of the most commonly diagnosed cancers in man. Studies have shown that phthalates may act as promoters in various types of cancer; however, the role of phthalates in prostate cancer has been rarely reported. The MAPK/AP-1 pathway is a vital regulator of cell proliferation in cancer. In this report we found that three typical phthalates, diethylhexyl phthalate (DEHP), Butyl benzyl phthalate (BBP) and Dibutyl phthalate (DBP), up-regulated cyclinD1 and PCNA, down-regulated P21, inducing proliferation of prostate cancer cells. Furthermore, we found that phthalates increased the expression of p-ERK5 and p-p38, along with upregulation of AP-1 (p-c-fos and p-c-jun). In studies with ERK5 and a p38 inhibitor, our data showed that downregulation of p-ERK5 or p38 inhibited phthalate-triggered cell proliferation. Taken together, findings from this study suggest that phthalates activate MAPK/AP-1 pathway and may potentially promote cell proliferation in prostate cancer, thus providing new insight into the effects and the underlying mechanism of phthalates on prostate cancer.

Ambient fine particulate matter (PM2.5) is capable of inducing pulmonary oxidative injury. Autophagy maintains basal cellular homeostasis and plays a critical role in the pathogenesis of lung diseases. Resveratrol, a natural polyphenol, is an effective antioxidant agent against particulate matter (PM)-induced injuries. The current study was designed to investigate whether resveratrol can regulate autophagy in the process of PM2.5-mediated pulmonary oxidative injury. In the mice model of PM2.5 exposure, we found that PM2.5 increased the contents of malondialdehyde (MDA) and nitric oxide (NO) while decreased the expression of nuclear factor erythroid-2-related factor 2 in the lungs. The levels of 8-hydroxydeoxyguanosine and inflammatory cytokines were increased following PM2.5 exposure. Histological analysis of the lungs revealed inflammatory change in PM2.5 group. Meanwhile, PM2.5 triggered autophagy, as evidenced by the elevated expression of microtubule-associated proteins light chain 3II, Beclin1 and p62. Transmission electron microscopy images showed that autophagosomes accumulated in the lungs after PM2.5 exposure. Furthermore, resveratrol intervention suppressed autophagy and attenuated the oxidative injury resulting from PM2.5 exposure. Our findings provided a valuable insight into the underlying mechanism for the protective effects of resveratrol against PM2.5-induced lung injury, which involves suppression of the autophagic process.

Cancer stem cells (CSCs) are considered to play essential roles in the process of origination, proliferation, migration, and invasion of cancer, and their properties are regulated by Wnt/β-catenin pathway. Phenethyl isothiocyanate (PEITC) is a natural product obtained from cruciferous vegetables with anticancer activities. The present study aimed to investigate the inhibitory effect and the underlying mechanisms of PEITC on colorectal CSCs. In this study, we found that PEITC can significantly reduce the size and number of colorectal cancer cell spheroids in serum-free medium. With increasing PEITC concentrations (10-40 μM), the number of spheroids was reduced to about 10% of the control group, and the percentage of CD133+ cells was decreased by about 3-16 folds. PEITC also decreased the expression of CSC markers. Meanwhile, inhibition of proliferation as well as induction of apoptosis of colorectal CSCs was observed after PEITC treatment. Furthermore, through activating Wnt/β-catenin pathway with LiCl, the inhibitory effects of PEITC on colorectal CSCs were diminished. Our data suggested that PEITC can be an effective inhibitor of colorectal CSCs by targeting Wnt/β-catenin pathway.

Lung cancer is the leading cause of cancer-related death worldwide; tobacco smoke (TS) constitutes the main causes of lung cancer. Acquisition of cancer stem cells (CSCs)-like properties is the essential progression for the initiation of lung cancer. However, the mechanisms for tobacco smoke-induced lung carcinogenesis remain elusive. In the present study, we demonstrated that long-term exposure of human bronchial epithelial (HBE) cells to TS resulted in malignant transformation and acquisition of CSC-like properties. Moreover, Wnt/β-catenin pathway was involved in acquisition of the CSC-like phenotype during neoplastic transformation of HBE cells induced by TS. Downregulation of β-catenin reduced the tumorsphere and decreased the protein expression of lung CSCs markers in TS-transformated HBE sphere-forming cells. Furthermore, Diallyl trisulfide (DATS) inhibited the CSCs activity of TS-transformed HBE cells, as well as Wnt/β-catenin suppression. Activation of Wnt/β-catenin diminished the inhibitory effects of DATS on TS-induced stemness of HBE cells. Together, the present investigation elucidates the modulation of Wnt/β-catenin in chronic TS exposure-triggered pulmonary acquisition of CSCs properties and DATS intervention, which may provide new insights into the interventional strategies against lung CSCs.

Although separation of phenolic compounds from coal tar has a good practical application value in industry, the traditional separation method can result in serious environmental problems. In the present work, three ionic liquids (ILs) with dual Lewis basic sites were designed and synthesized by neutralizating 1,1,3,3-tetramethylguanidine (TMG) and corresponding acids (L-proline, acetate acid, and tetrafluoroboric acid), which were employed to separate phenolic compounds from the model oil and coal tar. The basicity of TMG-based ILs were characterized by a probe molecule through 1H NMR and quantum chemical calculations. Moreover, the influence of factors on the separation efficiency, such as stirring time, extraction temperature, and the ratio of ILs to model oil, was investigated in detail. The results showed that [TMG][BF4] showed the best extraction efficiency of 98.2%, at a extraction temperature of 30 °C, stirring time of 35 min, and extraction ratio of 1.1 g/4 mL. After being separated, these ILs wer...

Oxidative stress and inflammation are critically implicated in ambient fine particulate matter (mean diameter < 2.5 μm; PM2.5 )-induced lung injury. Autophagy, playing a crucial role in various physiopathological conditions, modulates cellular homeostasis and stress adaptation. Resveratrol is a phytoalexin that exerts potent antioxidant effects on cardiopulmonary diseases. To date, the mechanisms by which resveratrol protects against PM2.5 remain to be elucidated. In the present study, we investigated the effect of resveratrol on PM2.5 -induced oxidative injury. The potential role of nuclear factor erythroid-2-related factor 2 and autophagy in this progress was explored. Human bronchial epithelial cells were treated with PM2.5 and the cytotoxicity and oxidative stress markers were determined. The results showed that PM2.5 decreased cell viability and elevated the level of lactate dehydrogenase. The levels of malondialdehyde and reactive oxygen species were increased by PM2.5 exposure. PM2.5 also induced a significant increase of the inflammatory cytokines including interleukin (IL)-6, IL-8, IL-1β and tumor necrosis factor α. Meanwhile, PM2.5 triggered autophagy formation and alteration of the nuclear factor erythroid-2-related factor 2 pathway. Furthermore, human bronchial epithelial cells were co-treated with PM2.5 and resveratrol in the presence or absence of 3-methylamphetamine, an inhibitor of autophagic formation. It was revealed that resveratrol intervention abolished PM2.5 -induced oxidative injury partially through the suppression of autophagy deregulation. Findings from this study could provide new insights into the molecular mechanisms of pulmonary intervention during PM2.5 exposure.

Cancer stem cells (CSCs) play a central role in the development of breast cancer. The canonical Wnt/β-catenin signal pathway is critical for maintaining CSCs characteristics. Diallyl trisulfide (DATS), a natural organosulfur compound from the garlic, exhibits effective antitumor properties. However, the role of DATS in regulating breast CSCs activity and the underlying molecular mechanisms remain obscure. In the present study, we reported that DATS efficiently inhibited the viability of breast CSCs as evidenced by reducing turmorspheres formation, decreasing the expression of breast CSCs markers (CD44, ALDH1A1, Nanog, and Oct4), as well as inhibiting proliferation and inducing apoptosis. Furthermore, we showed that DATS downregulated the activity of Wnt/β-catenin pathway, while LiCl-triggered Wnt/β-catenin activation diminished DATS inhibition on breast CSCs. Taken together, our results illustrated that DATS suppressed breast CSCs through inhibiting Wnt/β-catenin pathway activation. These novel findings could provide new insights into the molecular mechanisms of breast CSCs regulation as well as its target intervention and might provide new strategies for preventing and treating breast cancers.

Tobacco smoke is a major risk factor for hepatic cancer. Epithelial–mesenchymal transition (EMT) induced by tobacco smoke is crucially involved in the initiation and development of cancer. Mitogen-activated protein kinase (MAPK) pathways play important roles in tobacco smoke-associated carcinogenesis including EMT process. The chemopreventive effect of curcumin supplementation against cancers has been reported. In this study, we investigated the effects of tobacco smoke on MAPK pathway activation and EMT alterations, and then the preventive effect of curcumin was examined in the liver of BALB/c mice. Our results indicated that exposure of mice to tobacco smoke for 12 weeks led to activation of ERK1/2, JNK, p38 and ERK5 pathways as well as activator protein-1 (AP-1) proteins in liver tissue. Exposure of mice to tobacco smoke reduced the hepatic mRNA and protein expression of the epithelial markers, while the hepatic mRNA and protein levels of the mesenchymal markers were increased. Treatment of curcumin effectively attenuated tobacco smoke-induced activation of ERK1/2 and JNK MAPK pathways, AP-1 proteins and EMT alterations in the mice liver. Our data suggested the protective effect of curcumin in tobacco smoke-triggered MAPK pathway activation and EMT in the liver of BALB/c mice, thus providing new insights into the chemoprevention of tobacco smoke-associated hepatic cancer. Copyright © 2017 John Wiley & Sons, Ltd.

Cancer stem cells (CSCs) are highly implicated in the progression of human cancers. Thus, targeting CSCs may be a promising strategy for cancer therapy. Wnt/β-catenin and Sonic Hedgehog pathways play an important regulatory role in maintaining CSC characteristics. Natural compounds, such as curcumin, possess chemopreventive properties. However, the interventional effect of curcumin on lung CSCs has not been clarified. In the present study, tumorsphere formation assay was used to enrich lung CSCs from A549 and H1299 cells. We showed that the levels of lung CSC markers (CD133, CD44, ALDHA1, Nanog and Oct4) and the number of CD133-positive cells were significantly elevated in the sphere-forming cells. We further illustrated that curcumin efficiently abolished lung CSC traits, as evidenced by reduced tumorsphere formation, reduced number of CD133-positive cells, decreased expression levels of lung CSC markers, as well as proliferation inhibition and apoptosis induction. Moreover, we demonstrated that curcumin suppressed the activation of both Wnt/β-catenin and Sonic Hedgehog pathways. Taken together, our data suggested that curcumin exhibited its interventional effect on lung CSCs via inhibition of Wnt/β-catenin and Sonic Hedgehog pathways. These novel findings could provide new insights into the potential therapeutic application of curcumin in lung CSC elimination and cancer intervention. Copyright © 2017 John Wiley & Sons, Ltd.

Bisphenol S is considered as a safer alternative to bisphenol A. In the present study, we used murine macrophages to investigate the effects of BPS exposure on oxidative stress and inflammatory response as well as the underlying mechanism. Cells were exposed to BPS at various concentrations for short period of times. Results showed that 10-8 M BPS triggered oxidative stress by increasing ROS/RNS production, increased the levels of oxidant enzyme NOX1/2, and decreased the levels of antioxidant enzymes SOD1/2, CAT and GSH-Px. 10-8 M BPS exposure significantly induced the production of proinflammatory mediators. Activation of the NLRP3 inflammasome, TLR4, and MAPK pathways was involved in this process. Furthermore, we illustrated that NAC pretreatment diminished these effects triggered by BPS exposure. Collectively, our data suggested that BPS at a dose relevant to human serum concentration induced oxidative stress and inflammatory response in macrophages. These novel findings shed light on the concerns regarding the potential adverse effects of BPS exposure that requires further careful attention.

Introducing electron-rich nitrogen atoms to ordered mesoporous carbons (OMC) as supports for noble metal catalysts, not only improves the hydrophilic properties of a mesoporous carbon surface, but also enhances the coordination and binding abilities of metal ion. In the present work, nitrogen-doped ordered mesoporous carbons (NOMCs) were successfully fabricated via a facile hydrothermal self-assembly. The prepared NOMCs were characterized through powder X-ray diffraction (XRD), Raman spectroscopy, transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), and nitrogen adsorption-desorption isotherm. The analyses demonstrated that the NOMCs prepared at a pyrolysis temperature of 750°C possessed an ordered 2D hexagonal mesoporous structure, a high graphitization degree, large surface area, and a well-distributed pore size. In particular, NOMCs could anchor Pd nanoparticles uniformly because of the introducing N atoms with strong electronegativity, which were selected as efficient catalysts for the partial oxidation of benzyl alcohol to benzaldehyde. Approximately 24.63% conversion with 85.71% selectivity to benzaldehyde was obtained without using any solvent by molecular O2 oxidation. Most importantly, the TOF value of the catalyst in the reaction system was up to 8698 h−1. After five runs reaction, TOF and selectivity of the catalyst remained essentially same. Hence, the proposed catalyst has a potential engineering application value.

Background: Tobacco smoke (TS) critically contributes to the development of lung cancer; however, the underlying molecular mechanisms remain unclear. The induction of cancer stem cells (CSCs) by TS represents an early event in tumor initiation. The lung cancer-related gene ΔNp63α is highly expressed in epithelial tissues and drives tumor formation and cancer stem cell properties. This study investigated the role of ΔNp63α in the long-term acquisition of TS-induced lung CSC-like properties. Methods: The expression levels of ΔNp63α, lung CSC markers, and interleukin (IL)-6 in lung carcinoma specimens were determined by western blotting and enzyme linked immunosorbent assays. Human bronchial epithelial (HBE) cells were chronically exposed to 2 % cigarette smoke extract for 55 passages, following which colony formation capacity, expression of proteins associated with malignant transformation, lung CSC markers, and tumor incidence were investigated. The effects of ΔNp63α on long-term TS exposure-induced lung CSC-like properties and Notch activation were analyzed using tumorsphere formation ability, immunofluorescence assays, luciferase reporter assays, and western blotting. The roles of IL-6 on chronic TS exposure-induced lung CSC-like properties and ΔNp63α expression were also examined. Moreover, the effects of sulforaphane (SFN) on TS-transformed lung CSC-like properties, IL-6 and ΔNp63α expression, and Notch signaling were investigated in vitro and in vivo. Results: Higher levels of ΔNp63α were observed in the lung cancer tissues of smokers than in those of non-smokers, whereas ΔNp63α was positively correlated with CD133 and Oct4 expression in lung cancer tissues. Data from the in vivo and in vitro experiments demonstrated that long-term TS exposure-transformed HBE (THBE) cells acquired lung CSC-like properties. Furthermore, ΔNp63α transcriptionally activated the Notch signaling pathway to promote the acquisition of CSC-like properties by the THBE cells. TS upregulated IL-6, which increased ΔNp63α expression in THBE sphere-forming cells. Finally, SFN inhibited the TS-induced CSC-like properties of THBE cells via the IL-6/ΔNp63α/Notch axis. Conclusion: Our data suggest that the IL-6/ΔNp63α/Notch axis plays an important role in the long-term TS exposure-induced acquisition of lung CSC-like properties and SFN intervention.