LPS-induced Epithelial-mesenchymal Transition Research Articles

Citral-Enriched Fraction of Lemon Essential Oil Mitigates LPS-Induced Hepatocyte Injuries.

Lemon essential oil (LEO) is known for its aromatic and healthy properties; however, less consideration is given to the biological properties of the fractions obtained from LEO. This study aims to evaluate the ability of a citral-enriched fraction obtained from LEO (Cfr-LEO) to counteract lipopolysaccharide (LPS)-mediated inflammation, oxidative stress, and epithelial-mesenchymal transition (EMT) in healthy human hepatocytes. Human immortalized hepatocytes (THLE-2 cell line) were pretreated with Cfr-LEO and subsequently exposed to LPS at various time points. We report that the pretreatment with Cfr-LEO counteracts LPS-mediated effects by inhibiting inflammation, oxidative stress, and epithelial-mesenchymal transition in THLE-2. In particular, we found that pretreatment with Cfr-LEO reduced NF-κB activation and the subsequent proinflammatory cytokines release, ROS production, and NRF2 and p53 expression. Furthermore, the pretreatment with Cfr-LEO showed its beneficial effect in counteracting LPS-induced EMT. Taken together, these results support Cfr-LEO application in the nutraceutical research field not only for its organoleptic properties, conferred by citral enrichment, but also for its biological activity. Our study could lay the basis for the development of foods/drinks enriched with Cfr-LEO, aimed at preventing or alleviating chronic conditions associated with liver dysfunction.

Ginsenoside Rg1 Alleviates Lipopolysaccharide-Induced Fibrosis of Endometrial Epithelial Cells in Dairy Cows by Inhibiting Reactive Oxygen Species-Activated NLRP3

Abnormal function and the fibrosis of endometrium caused by endometritis in cows may lead to difficult embryo implantation and uterine cavity adhesions. Emerging evidence indicates that ginsenoside Rg1 can effectively resist inflammation and pathological fibrosis in different organs. It is hypothesized that ginsenoside Rg1 may possess the potential to mitigate endometrial fibrosis induced by lipopolysaccharides (LPS) in dairy cows. Herein, a model of LPS-stimulated fibrosis was constructed using bovine endometrial epithelial cell line (BEND) cells and ICR mice. Western blotting was used to detect the protein level, and reactive oxygen species (ROS) content was measured by means of DCFH-DA. The uterine tissue structure was stained with H&E and Masson staining. The murine endometrium was assessed for oxidative stress by detecting the concentration of MDA together with the activity of enzymatic antioxidants SOD and CAT. Ginsenoside Rg1 interfered with NLRP3 activation by reducing ROS generation. After the application of ROS inhibitor NAC and NLRP3 inhibitor MCC950, ginsenoside Rg1 could interfere in the ROS/NLRP3 inflammasome signaling pathway by suppressing the epithelial–mesenchymal transition (EMT) of BEND cells. Our in vivo data showed that ginsenoside Rg1 relieved endometrial fibrosis of the mouse model of LPS-induced endometritis by restraining the ROS/NLRP3 inflammasome signaling pathway. Ginsenoside Rg1 inhibits LPS-induced EMT progression in BEND cells probably by inhibiting the activation of ROS-NLRP3 inflammasome.

Angiotensin-Converting Enzyme 2 Inhibits Lipopolysaccharide-Caused Lung Fibrosis via Downregulating the Transforming Growth Factor β-1/Smad2/Smad3 Pathway.

In our previous studies, angiotensin-converting enzyme 2 (ACE2) was shown to alleviate the severity of acute lung injury, but its effects on the development of lung injury-caused lung fibrosis have not been studied. In the present study, the effects of ACE2 on lipopolysaccharide (LPS)-induced fibrosis in the lung were studied. The role of epithelial-mesenchymal transition (EMT) and that of the transforming growth factor β-1 (TGF-β1)/Smad2/Smad3 pathway in LPS-induced fibrosis in the lung were investigated. ACE2 expression in the mouse model of LPS-induced lung fibrosis was significantly increased. ACE2 activator diminazene aceturate (DIZE) significantly reduced pulmonary fibrosis, decreased alpha-smooth muscle actin expression, collagen I, hydroxyproline, and TGF-β1 in the lung. DIZE significantly decreased TGF-β1 expression and the activation of Smad2 and Smad3. ACE2 overexpression inhibited the LPS-induced EMT in MLE-12 cells (lung epithelial cells) and small interfering RNA treatment of ACE2 stimulated EMT. ACE2 overexpression also inhibited TGF-β1 expression and activation of Smad2 and Smad3 in MLE-12 cells. Finally, after MLE-12 cells were treated with both ACE2 and TGF-β1 plasmid, TGF-β1 plasmid significantly abolished the effect of ACE2 plasmid on the EMT in MLE-12 cells. Combined with the in vivo study, it was revealed that ACE2 can suppress the TGF-β1/Smad2/Smad3 pathway in lung type II epithelial cells, thus reversing their EMT and lung fibrosis. The present study provides basic research data for the application of ACE2 in lung injury-caused lung fibrosis treatment and clarifies the intervention mechanism of ACE2 in pulmonary fibrosis, which has potential value for clinical application. Angiotensin-converting enzyme 2 (ACE2) can inhibit the epithelial-mesenchymal transition (EMT) in lung type II epithelial cells and lung fibrosis. ACE2 can regulate the transforming growth factor β-1/Smad2/Smad3 pathway in lung type II epithelial cells, which may be the underlying mechanism of ACE2's effect on EMT and lung fibrosis.

NF-κB-Dependent Snail Expression Promotes Epithelial-Mesenchymal Transition in Mastitis.

Mastitis is a common and important clinical disease in ruminants. This may be associated with inflammatory fibrosis if not treated promptly. Inflammation-derived fibrosis is usually accompanied by epithelial-mesenchymal transition (EMT) in epithelial cells. However, the precise molecular mechanism underlying mastitis-induced fibrosis remains unclear. Nuclear factor kappa-B (NF-κB) and Snail are key regulators of EMT. In this study, primary goat mammary epithelial cells (GMECs) were treated with 10 μg/mL lipopolysaccharide (LPS) for 14 d to mimic the in vivo mastitis environment. After LPS treatment, the GMECs underwent mesenchymal morphological transformation and expressed mesenchymal cell markers. Snail expression was induced by LPS and was inhibited by suppression of the TLR4/NF-κB signaling pathway. Snail knockdown alleviated LPS-induced EMT and altered the expression of inflammatory cytokines. Finally, we found that the expression of key molecules of the TLR4/NF-κB/Snail signaling pathway was increased in mastitis tissues. These results suggest that Snail plays a vital role in LPS-induced EMT in GMECs and that the mechanism is dependent on the activation of the TLR4/NF-κB signaling pathway.

Tanshinone ⅡA inhibits the lipopolysaccharide-induced epithelial-mesenchymal transition and protects bovine endometrial epithelial cells from pyolysin-induced damage by modulating the NF-κB/Snail2 signaling pathway

Mixed infection with Escherichia coli and Trueperella pyogenes (T. pyogenes) leads to purulent endometritis, but the underlying molecular mechanisms remain unclear. The aim of this study was to investigate the effect of tanshinone ⅡA (Tan ⅡA) on E. coli and T. pyogenes -induced purulent endometritis and explore the underlying mechanism. First, lipopolysaccharide (LPS) isolated from E. coli and bacteria-free filtrates (BFFs) isolated from T. pyogenes were used to induce a model of bovine endometrial epithelial cell (bEEC) damage in vitro. bEECs were pretreated with or without Tan ⅡA for 2 h, before LPS and BFFs were introduced to induce damage to investigate the protective effect of Tan IIA. Then, the cytolytic activity and inflammatory response in bEECs were examined using CCK-8, LDH and RT-qPCR assays. Furthermore, we confirmed the molecular mechanism by which Tan ⅡA reversed the damaged phenotypes in LPS- and BFFs-induced bEECs via the NF-κB/Snail2 pathway using qPCR and Western blotting. Tan ⅡA significantly decreased the cytolytic activity and inflammatory response in LPS- and BFFs-induced bEECs. In addition, Tan ⅡA reversed the dysregulation of E-cadherin, N-cadherin and vimentin. Moreover, Tan ⅡA significantly inhibited the activation of the NF-κB signaling pathway and decreased the expression level of Snail2, which is the main regulator of the epithelial-mesenchymal transition (EMT). In summary, Tan ⅡA inhibits the LPS-induced EMT and protects bEECs from pyolysin-induced damage by modulating the NF-κB/Snail2 signaling pathway.

Melatonin prevents LPS-induced epithelial-mesenchymal transition in human alveolar epithelial cells via the GSK-3β/Nrf2 pathway

BackgroundOxidative stress plays a critical role in pulmonary fibrosis after acute lung injury (ALI), and epithelial-mesenchymal transition (EMT) events are involved in this process. The purpose of this study was to investigate the protective effects of melatonin, a natural antioxidant, on lipopolysaccharide (LPS)-induced EMT in human alveolar epithelial cells. MethodsHuman type II alveolar epithelial cell-derived A549 cells were incubated with LPS and melatonin alone or in combination for up to 24 h. The morphological changes of the treated cells were evaluated as well as indexes of oxidative stress. EMT-related proteins and the Nrf2 signaling pathway were detected by western blot analysis and immunofluorescence staining, respectively. To further investigate the underlying mechanisms, the effects of melatonin on cells transfected Nrf2 short hairpin RNA (shRNA) and the PI3K / GSK-3β signaling pathway were evaluated. ResultsTreatment with melatonin upregulated Nrf2 expression, inhibited LPS-induced cell morphological change, reversed the expressions of EMT-related proteins, and reduced reactive oxygen species (ROS) production in A549 cells, as well as the levels of malondialdehyde (MDA) and anti-oxidative enzymes. Yet, the effects of melatonin were almost completely abolished in cells transfected Nrf2 shRNA. Furthermore, the data demonstrated that melatonin could activate the PI3K/AKT signaling pathway, resulting in phosphorylation of GSK-3β (Ser9) and upregulation of the Nrf2 protein in A549 cells, which ultimately attenuated LPS-induced EMT. ConclusionThe present study is the first to demonstrate that melatonin can protect human alveolar epithelial cells against oxidative stress by effectively inhibiting LPS-induced EMT, which was mostly dependent on upregulation of the Nrf2 pathway via the PI3K/GSK-3β axis. Further studies are warranted to investigate the role of melatonin for the treatment of oxidative stress-associated diseases, as well as pulmonary fibrosis after ALI.

Sodium Propionate Attenuates the Lipopolysaccharide-Induced Epithelial-Mesenchymal Transition via the PI3K/Akt/mTOR Signaling Pathway.

Short-chain fatty acids (SCFAs), especially propionate, originate from the fermentation of dietary fiber in the gut and play a key role in inhibiting pulmonary inflammation. Chronic inflammation may induce an epithelial-mesenchymal transition (EMT) in alveolar epithelial cells and result in fibrotic disorders. This study was designed to investigate the beneficial effect of sodium propionate (SP) on lipopolysaccharide (LPS)-induced EMT. In cultured BEAS-2B cells, the protein expression levels of E-cadherin, α-smooth muscle actin (SMA), and vimentin were 0.66 ± 0.20, 1.44 ± 0.23, and 1.32 ± 0.21 in the LPS group vs 1.11 ± 0.36 (P < 0.05), 1.04 ± 0.30 (P < 0.05), and 0.96 ± 0.13 (P < 0.01) in the LPS + SP group (mean ± standard deviation), respectively. Meanwhile, LPS-triggered inflammatory cytokines and extracellular proteins were also reduced by SP administration in BEAS-2B cells. Moreover, SP treatment attenuated inflammation, EMT, extracellular matrix (ECM) deposition, and even fibrosis in a mouse EMT model. In terms of mechanism, LPS-treated BEAS-2B cells exhibited a higher level of phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) phosphorylation, which was interrupted by SP treatment. It is worth noting that the blockade of the PI3K/Akt/mTOR signaling cascade reduced the LPS-evoked EMT process in BEAS-2B cells. These results suggest that SP can block LPS-induced EMT via inhibition of the PI3K/Akt/mTOR signaling cascade, which provides a basis for possible clinical use of SP in airway and lung diseases.

Integrin \u03b1v\u03b26 mediates epithelial-mesenchymal transition in human bronchial epithelial cells induced by lipopolysaccharides of Pseudomonas aeruginosa via TGF-\u03b21-Smad2/3 signaling pathway

Lower respiratory tract infection due to Pseudomonas aeruginosa has become increasingly challenging, resulting in a worse morbidity and mortality. Airway remodeling is a common phenomenon in this process, to which epithelial-mesenchymal transition (EMT) may contribute as an important promoter. Previous studies showed that epithelium-specific integrin αvβ6–mediated EMT was involved in pulmonary fibrosis via transforming growth factor-β1 (TGF-β1) signaling, but whether integrin αvβ6 plays a role in the P. aeruginosa–associated airway remodeling remains unknown. BEAS-2B cells were incubated with lipopolysaccharide (LPS) from P. aeruginosa in the presence or the absence of integrin αvβ6–blocking antibodies. Morphologic changes were observed by an inverted microscopy. The EMT markers were detected using Western blotting and immunofluorescence. The activation of TGF-β1-Smad2/3 signaling pathway was assessed. Furthermore, matrix metalloproteinase (MMP)-2 and -9 in the medium were measured using ELISA. P. aeruginosa’s LPS decreased the expression of the epithelial marker E-cadherin and promoted the mesenchymal markers, vimentin and α-smooth muscle actin in BEAS-2B cells. The expression of integrin αvβ6 was significantly increased during EMT process. Blocking integrin αvβ6 could attenuate P. aeruginosa’s LPS-induced EMT markers’ expression via TGF-β1-Smad2/3 signaling pathway. Furthermore, blocking integrin αvβ6 could prevent morphologic changes and oversecretion of MMP-2 and -9. Integrin αvβ6 mediates epithelial-mesenchymal transition in human bronchial epithelial cells induced by lipopolysaccharides of P. aeruginosa via TGF-β1-Smad2/3 signaling pathway and might be a promising therapeutic target for P. aeruginosa–associated airway remodeling.

Matrine suppresses lipopolysaccharide-induced fibrosis in human peritoneal mesothelial cells by inhibiting the epithelial-mesenchymal transition.

Background:Peritoneal fibrosis is the primary reason that patients with end-stage renal disease (ESRD) have to cease peritoneal dialysis. Peritonitis caused by Gram-negative bacteria such as Escherichia coli (E. coli) were on the rise. We had previously shown that matrine inhibited the formation of biofilm by E. coli. However, the role of matrine on the epithelial-mesenchymal transition (EMT) in peritoneal mesothelial cells under chronic inflammatory conditions is still unknown.Methods:We cultured human peritoneal mesothelial cells (HPMCs) with lipopolysaccharide (LPS) to induce an environment that mimicked peritonitis and investigated whether matrine could inhibit LPS-induced EMT in these cells. In addition, we investigated the change in expression levels of the miR-29b and miR-129-5p.Results:We found that 10 μg/ml of LPS induced EMT in HPMCs. Matrine inhibited LPS-induced EMT in HPMCs in a dose-dependent manner. We observed that treatment with matrine increased the expression of E-cadherin (F = 50.993, P < 0.01), and decreased the expression of alpha-smooth muscle actin (F = 32.913, P < 0.01). Furthermore, we found that LPS reduced the expression levels of miR-29b and miR-129-5P in HPMCs, while matrine promoted the expression levels of miR-29b and miR-129-5P.Conclusions:Matrine could inhibit LPS-induced EMT in HPMCs and reverse LPS inhibited expressions of miR-29 b and miR-129-5P in HPMCs, ultimately reduce peritoneal fibrosis. These findings provide a potential theoretical basis for using matrine in the prevention and treatment of peritoneal fibrosis.

Toll-like receptor 4 shRNA attenuates lipopolysaccharide-induced epithelial-mesenchymal transition of intrahepatic biliary epithelial cells in rats

Background and aimIntrahepatic biliary epithelial cells (IBECs) of the bile duct in liver tissue of patients with hepatolithiasis promoted the development of diseases through epithelial–mesenchymal transition (EMT). This study investigated whether lipopolysaccharide (LPS), a cell-wall constituent of gram-negative bacteria, could induce EMT of IBECs and toll-like receptor 4 (TLR4) had a regulatory role via activating the nuclear factor-κB (NF-κB)/Snail signaling pathway during this process in vivo. MethodsTLR4 short hairpin RNA (shRNA) adenovirus or negative control shRNA (NC shRNA) adenovirus (1 × 109 plaque-forming unit (PFU), respectively) was injected into the caudal vein of rats. After 96 h, 1 mg/kg LPS was infused retrogradely into the common bile duct for 48 h per rat. The effects of TLR4 shRNA on LPS-induced EMT were determined by evaluating the histopathological changes in IBECs using hematoxylin and eosin staining and the changes in the levels of EMT markers, TLR4, NF-κB p65, pNF-κB p65, and Snail using real-time polymerase chain reaction and Western blot analysis. ResultsCompared with normal saline treatment, a loss of epithelial cell markers (E-cadherin and cytokeratin 7) and a gain of mesenchymal cell markers (N-cadherin and matrix metalloproteinase 2) were revealed. The levels of TLR4, NF-κB phosphorylation, and Snail significantly increased after LPS treatment, whereas pretreatment with TLR4 shRNA inhibited the LPS-induced EMT by downregulating the NF-κB/Snail signaling pathway. ConclusionsLPS induced the EMT of IBECs by activating TLR4. The RNAi-mediated knockdown of TLR4 suppressed EMT occurrence via downregulating the NF-κB/Snail signaling pathway, implicating TLR4 as a new target for human hepatolithiasis.

Plantamajoside inhibits lipopolysaccharide-induced epithelial-mesenchymal transition through suppressing the NF-κB/IL-6 signaling in esophageal squamous cell carcinoma cells

Plantamajoside (PMS) is a major compound of Plantago asiatica and possesses anti-tumor activity. However, the effect of PMS on esophageal squamous cell carcinoma (ESCC) and the underlying mechanism of action are unclear. The present study aimed to evaluate the effect of PMS on lipopolysaccharide (LPS)-induced epithelial-mesenchymal transition (EMT) in ESCC. The results showed that PMS inhibited viability of ESCC cell lines (Eca-109 and TE-1) in a concentration-dependent manner. PMS also inhibited LPS-induced EMT in ESCC cells. PMS inhibited LPS-induced activation of the NF-κB pathway and IL-6 expression. PMS also suppressed IL-6-induced EMT in ESCC cells. Treatment of BAY11-7082 (an inhibitor of NF-κB) or antibody against IL-6 alleviated the effect of LPS-induced EMT in ESCC cells. Besides, inhibition of NF-κB decreased IL-6 expression. In conclusion, the results indicated that PMS inhibited LPS-induced EMT through suppressing the NF-κB/IL-6 signaling in ESCC cell lines, suggesting that PMS might be a useful agent for the treatment of ESCC.

LPS-induced CXCR4-dependent migratory properties and a mesenchymal-like phenotype of colorectal cancer cells

ABSTRACTColorectal cancer (CRC) is the most commonly diagnosed cancer worldwide, and over 50% of patients will develop hepatic metastasis during the course of their disease. CXCR4 and its ligand, stromal cell-derived factor 1α (SDF-1α)/chemokine (C-X-C motif) ligand 12 (CXCL12) have been revealed as regulatory molecules involved in the spreading and progression of a variety of tumors. Here we have shown that lipopolysaccharides (LPS) promoted the migratory capacity of colon cancer cells in vivo and in vitro, which correlated with the activation of SDF-1α/CXCR4 axis and epithelial-mesenchymal transition (EMT) occurrence. Additionally, we found that LPS-induced CXCR4 expression and EMT through NF-κB signaling pathway activation. And inhibition of NF-κB pathway, which recovered the epithelial phenotype and attenuated CXCR4 expression, inhibited cell migratory capacity. Clinically, high levels of CXCR4 always correlated with metastasis and poor prognosis of CRC patients. In conclusion, LPS participate in the whole process of hepatic metastasis of CRC, not only causing liver damage resulting in the production of SDF-1α, but also enhancing the invasive potential of CRC cells by promoting CXCR4 expression and EMT occurrence, which would contribute to the enhancement of cell migration and invasion.

Statin pretreatment inhibits the lipopolysaccharide-induced epithelial-mesenchymal transition via the downregulation of toll-like receptor 4 and nuclear factor-κB in human biliary epithelial cells.

Epithelial-mesenchymal transition (EMT) of biliary epithelial cells (BECs) plays an important role in biliary fibrosis. This study investigated the effects of simvastatin on the lipopolysaccharide (LPS)-induced EMT and related signal pathways in BECs. Biliary epithelial cells were exposed to LPS (2 µg/mL) or transforming growth factor β1 (TGF-β1) (5 ng/mL) for 5 days. The EMT was assessed by a gain of mesenchymal cell markers (vimentin, N-cadherin, slug, and Twist-1) and a loss of epithelial cell markers (E-cadherin). The effects of simvastatin on the EMT induced by LPS or TGF-β1 were determined by the changes in the levels of EMT markers and TLR4 and in the c-Jun N-terminal kinase (JNK), p38, and nuclear factor-κB (NF-κB) signaling pathways. Compared with the BECs treated with LPS alone, co-treatment with simvastatin and LPS induced an increase in the expression of E-cadherin and decreases in the expression levels of mesenchymal cell markers. The LPS-induced TLR4 expression level was slightly decreased by co-treatment with simvastatin. LPS-induced BEC growth was markedly inhibited by co-treatment with simvastatin. Furthermore, pretreatment with simvastatin inhibited the LPS-induced EMT in BECs by downregulating NF-κB and JNK phosphorylation. The suppressive effects of simvastatin pretreatment on the induction of the EMT by TGF-β1 were also demonstrated in H69 cells. Our results demonstrate that LPS or TGF-β1 promote the EMT in BECs that that pretreatment with simvastatin inhibited the induced EMT by downregulating toll-like receptor 4 and NF-κB phosphorylation. This finding suggests that simvastatin can be considered a new agent for preventing biliary fibrosis associated with the EMT of BECs.

Shikonin as an inhibitor of the LPS-induced epithelial-to-mesenchymal transition in human breast cancer cells.

Shikonin (SK), a natural naphthoquinone isolated from the Chinese medicinal herb, has been known to suppress the proliferation of several cancer cells. However, its role in the epithelial mesenchymal transition (EMT) has yet to be demonstrated. The aim of the present study was to examine the effects of SK on EMT. Lipopolysaccharide (LPS) induced EMT-like phenotypic changes, enhancing cell migration and invasion. SK markedly reduced the expression of the LPS-induced EMT markers, including N-cadherin in MDA-MB‑231 cells, and increased the expression of E-cadherin in MCF-7 cells. SK also inhibited cell migration and invasion in vitro. The effects of SK on the LPS-induced EMT were mediated by the inactivation of the NF-κB-Snail signaling pathway. The results provided new evidence that SK suppresses breast cancer cell invasion and migration by inhibiting the EMT. Therefore, SK is a potentially effective anticancer agent for breast tumors, by inhibiting metastasis.

Suppression of LPS-induced epithelial-mesenchymal transition by aqueous extracts of Prunella vulgaris through inhibition of the NF-κB/Snail signaling pathway and regulation of EMT-related protein expression.

Epithelial-mesenchymal transition (EMT) is a pivotal event in the invasion and metastasis of cancer cells. Prunella vulgaris (PV) inhibits the proliferation of various cancer cells; however, its possible role in EMT has not been demonstrated. In the present study, we explored the effect of PV aqueous extract (PVAE), a typical medicine for decoction, on EMT. Lipopolysaccharide (LPS) induced EMT-like phenotype changes in cancer cell lines that enhanced cell migration and invasion. PVAE markedly inhibited these effects and produced accompanying changes in the expression of EMT markers, including decreased expression of N-cadherin and vimentin, and increased expression of β-catenin. We found that PVAE effects on LPS-induced EMT were mediated by inhibition of the NF-κB/Snail signaling pathway. Our findings provide new evidence that PVAE suppresses cancer invasion and migration by inhibiting EMT. Therefore, we suggest that PVAE is an effective dietary chemopreventive agent with antimetastatic activity against malignant tumors.

Aqueous extract of Psoralea corylifolia L. inhibits lipopolysaccharide-induced endothelial-mesenchymal transition via downregulation of the NF-κB-SNAIL signaling pathway.

The epithelial-mesenchymal transition (EMT) is a pivotal event in the invasion and metastasis of cancer cells. Psoraleacorylifolia L. (PC) inhibits the proliferation of various cancer cells. However, its possible role in EMT has not been identified. In the present study, we examined the effects of an aqueous extract of Psoraleacorylifolia L. (PCAE), a typical medicinal decoction, on the EMT. Lipopolysaccharide (LPS) induced EMT-like phenotypic changes, enhancing cell migration and invasion. However, PCAE markedly reduced the expression of the LPS-induced EMT markers, including N-cadherin and vimentin, and increased the expression of β-catenin. PCAE also inhibited cell migration and invasion invitro. The effects of PCAE on the LPS-induced EMT were mediated by the inactivation of the NF-κB-SNAIL signaling pathway. The results provide new evidence that PCAE suppresses cancer cell invasion and migration by inhibiting EMT. Therefore, PCAE is a potentially effective dietary chemopreventive agent for malignant tumors since it inhibits metastasis.

Resveratrol ameliorates lipopolysaccharide-induced epithelial mesenchymal transition and pulmonary fibrosis through suppression of oxidative stress and transforming growth factor-β1 signaling

Fibrotic changes seem to be responsible for the high mortality rate observed in patients with acute respiratory distress syndrome (ARDS). The present study aimed to determine whether resveratrol, a natural antioxidant polyphenol, had anti-fibrotic effects in the murine model of lipopolysaccharide (LPS)-induced pulmonary fibrosis. Fibrosis was assessed by determination of collagen deposition, hydroxyproline and type I collagen levels in lung tissues. Development of epithelial-mesenchymal transition (EMT) was identified by the loss of E-cadherin accompanying by the acquisition of α-smooth muscle actin (α-SMA). Transforming growth factor (TGF)-β1 content, levels of phosphorylated Smad2/Smad3 and Smad4, malondialdehyde (MDA) content, total antioxidant capacity (T-AOC), superoxide dismutase (SOD) activity, and catalase (CAT) activity in lung tissues were determined. LPS increased collagen deposition, hydroxyproline and type I collagen contents, and meanwhile induced EMT process, stimulated TGF-β1 production and Smad activation in lung tissues on day 21 to day 28 after LPS administration. In addition, LPS treatment resulted in a rapid induction of oxidative stress as evidenced by increase of MDA and decreases of T-AOC, CAT and SOD activities as early as 7 days after LPS treatment, which was persistent for at least 4 weeks. In contrast, resveratrol treatment attenuated LPS-induced EMT and pulmonary fibrosis, meanwhile it suppressed LPS-induced oxidative stress, TGF-β1 production and activation of Smad signaling pathway. Resveratrol may ameliorate LPS-induced EMT and pulmonary fibrosis through suppression of oxidative stress and TGF-β1/Smad signaling pathway. Application of antioxidants may represent a useful adjuvant pharmacologic approach to reduce ARDS-associated pulmonary fibrosis.

LPS promotes epithelial-mesenchymal transition and activation of TLR4/JNK signaling.

The endotoxin level in the portal and peripheral veins of hepatocellular carcinoma (HCC) patients is higher and lipopolysaccharide (LPS), has been reported to inhibit tumor growth. However, in this study, we found that LPS-induced Toll-like receptor 4 (TLR4) signaling was involved in tumor invasion and the molecular mechanism was investigated. The HCC cells were used to study the invasion ability of LPS-induced HCC cells and the epithelial-mesenchymal transition (EMT) in vitro. The in vitro experiments demonstrated that LPS could significantly enhance the invasive potential and induce EMT in HCC cells with TLR4 dependent. Further studies showed that LPS could directly activate JNK/MAPK signaling through TLR4 in HCC cells. Interestingly, blocking JNK/MAPK signaling significantly inhibited EMT occurrence. Our results indicate that TLR4/JNK/MAPK signaling is required for LPS-induced EMT, tumor cell invasion and metastasis, which provide molecular insights for LPS-related pathogenesis and a basis for developing new strategies against metastasis in HCC.

Curcumin inhibits LPS-induced EMT through downregulation of NF-κB-Snail signaling in breast cancer cells

Epithelial-mesenchymal transition (EMT) is considered a critical event in cancer cell invasion and metastasis. Emerging evidence has shown that curcumin may prevent or delay the progression of cancer, an effect that may be partially due to its ability to disrupt EMT, yet this has not yet been demonstrated. In this study, we used lipopolysaccharide (LPS) to trigger EMT in MCF-7 and MDA-MB-231 breast cancer cell lines and showed that curcumin inhibited LPS-induced morphological changes, decreased the expression of LPS-induced markers of EMT such as vimentin, and increased the expression of E-cadherin, resulting in the inhibition of invitro cell motility and invasiveness. We discovered that these actions were mediated through the inactivation of NF-κB-Snail signaling pathways. Our results indicate that curcumin plays an important role in the inhibition of LPS-induced EMT in breast cancer cells through the downregulation of NF-κB-Snail activity. These data provide a new perspective of the anti-invasive mechanism of curcumin, indicating that the effect is partly due to its ability to attack the EMT process.