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Inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ) is one of important kinases in inflammation to phosphorylate inhibitor of nuclear factor kappa-B (IκBα) and then activate nuclear factor kappa-B (NF-κB). Inhibition of IKKβ has been a therapeutic strategy for inflammatory and autoimmune diseases. Here we report that IKKβ is constitutively activated in healthy donors and healthy Ikkβ C46A (cysteine 46 mutated to alanine) knock-in mice although they possess intensive IKKβ-IκBα-NF-κB signaling activation. These indicate that IKKβ activation probably plays homeostatic role instead of causing inflammation. Compared to Ikkβ WT littermates, lipopolysaccharides (LPS) could induce high mortality rate in Ikkβ C46A mice which is correlated to breaking the homeostasis by intensively activating p-IκBα-NF-κB signaling and inhibiting phosphorylation of 5' adenosine monophosphate-activated protein kinase (p-AMPK) expression. We then demonstrated that IKKβ kinase domain (KD) phosphorylates AMPKα1 via interacting with residues Thr183, Ser184, and Thr388, while IKKβ helix-loop-helix motifs is essential to phosphorylate IκBα according to the previous reports. Kinase assay further demonstrated that IKKβ simultaneously catalyzes phosphorylation of AMPK and IκBα to mediate homeostasis. Accordingly, activation of AMPK rather than inhibition of IKKβ could substantially rescue LPS-induced mortality in Ikkβ C46A mice by rebuilding the homeostasis. We conclude that IKKβ activates AMPK to restrict inflammation and IKKβ mediates homeostatic function in inflammation via competitively phosphorylating AMPK and IκBα.
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Acidosis, regardless of hypoxia involvement, is recognized as a chronic and harsh tumor microenvironment (TME) that educates malignant cells to thrive and metastasize. Although overwhelming evidence supports an acidic environment as a driver or ubiquitous hallmark of cancer progression, the unrevealed core mechanisms underlying the direct effect of acidification on tumorigenesis have hindered the discovery of novel therapeutic targets and clinical therapy. Here, chemical-induced and transgenic mouse models for colon, liver and lung cancer were established, respectively. miR-7 and TGF-β2 expressions were examined in clinical tissues (n = 184). RNA-seq, miRNA-seq, proteomics, biosynthesis analyses and functional studies were performed to validate the mechanisms involved in the acidic TME-induced lung cancer metastasis. Our data show that lung cancer is sensitive to the increased acidification of TME, and acidic TME-induced lung cancer metastasis via inhibition of miR-7-5p. TGF-β2 is a direct target of miR-7-5p. The reduced expression of miR-7-5p subsequently increases the expression of TGF-β2 which enhances the metastatic potential of the lung cancer. Indeed, overexpression of miR-7-5p reduces the acidic pH-enhanced lung cancer metastasis. Furthermore, the human lung tumor samples also show a reduced miR-7-5p expression but an elevated level of activated TGF-β2; the expressions of both miR-7-5p and TGF-β2 are correlated with patients' survival. We are the first to identify the role of the miR-7/TGF-β2 axis in acidic pH-enhanced lung cancer metastasis. Our study not only delineates how acidification directly affects tumorigenesis, but also suggests miR-7 is a novel reliable biomarker for acidic TME and a novel therapeutic target for non-small cell lung cancer (NSCLC) treatment. Our study opens an avenue to explore the pH-sensitive subcellular components as novel therapeutic targets for cancer treatment.
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OBJECTI VE To explore the effects of total flavonoids of Bidens polisa L.（TFB）on insulin resistance （IR）of HepG2 cells. METHODS B. polisa L. was refluxed and extracted with 80％ ethanol to obtain TFB. Palmitic acid was used to induce IR mode of HepG 2 cells in vitro . The effects of low-concentration ，medium-concentration and high-concentration （20，40， 80 mg/L） of TFB on the consumption of glucose were investigated. Using metformin as positive control ，the effects of low-concentration，medium-concentration and high-concentration （20，40，80 mg/L）of TFB on the protein expression of insulin receptor substrate- 1（IRS-1），c-Jun N-terminal kinase （JNK）and protein kinase C （PKC）were investigated. Molecular docking technology was used to explore the interaction between eight main active components of TFB such as quercetin ，quercitrin and IRS-1，JNK and PKC proteins. RESULTS The glucose consumption of TFB low-concentration ，medium-concentration and high-concentration groups were increased significantly （P＜0.05 or P＜0.01）. Compared with normal group ，the expression of IRS-1 and JNK protein in the model group decreased significantly ，and the expression of PKC protein increased significantly （P＜ 0.01）. Compared with model group ，the protein expression of IRS- 1 and JNK could up-regulated while the protein expression of PKC down-regulated in TFB low-concentration ，medium-concentration and high-concentration groups and metformin positive control group （P＜0.05 or P＜0.01）. The score of molecular docking energy between maritimetin in TFB and IRS- 1 protein was －7.9 kcal/mol（1 kcal＝4.816 kJ）. The scores of molecular docking energy of maritimetin ，rutin and JNK protein were －9.3 kcal/mol. The score of molecular docking energy between quercitrin and PKC protein was －4.9 kcal/mol. Interactions between components and proteins included forming hydrogen bonds ，hydrophobic bonds and so on. CONCLUSIONS TFB can significantly improve IR of HepG 2 cells，the mechanism of which may be related to the regulation of protein expression of IRS ，JNK and PKC. Maritimetin，rutin and quercitrin may be potential active ingredients for improving IR.
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Objective:To investigate the expression levels of matrix metalloproteinase-9 (MMP-9), procalcitonin (PCT), soluble triggering receptor expressed on myeloid cells (sTREM-1) and soluble cell differentiation 14 (sCD14) in pregnant women with premature rupture of membranes (PROM) and their predictive value for chorioamnionitis.Methods:A total of 132 pregnant women with PROM who received treatment in Tengzhou Central People's Hospital from January 2016 to June 2017 were included in the study group. These women were assigned to pre-term PROM group (gestational age < 37 weeks, n = 58) and full-term PROM group (gestational age > 37 weeks, n = 74). A total of 106 concurrent full-term healthy pregnant women were included in the control group. Pregnant women in the PROM group were also assigned into an infection group ( n = 51) and a non-infection group ( n = 81). Serum levels of MMP-9, PCT, sTREM-1 and sCD14 were compared between study and control groups, and their value in the diagnosis of PROM complicated with chorioamnionitis was analyzed. Results:The expression levels of MMP-9 [(271.42 ± 34.16) ng/L], PCT [(54.57 ± 8.16) pg/mL], sTREM-1 [(0.51 ± 0.11) ng/mL] and sCD14 [(60.23 ± 9.49) ng/mL] in the study group were significantly higher than those in the control group [(54.97 ± 10.08) ng/L, (26.04 ± 1.98) pg/mL, (0.19 ± 0.04) ng/mL, (42.04 ± 10.33) ng/mL, t = 27.064, 13.767, 14.831, -13.342, all P < 0.01). The expression levels of MMP-9 [(314.05 ± 45.37) ng/L], PCT [(0.61 ± 0.18) ng/mL], sTREM-1 [(63.12 ± 10.12) pg/mL] and sCD14 [(68.07 ± 11.05) ng/mL] in the pre-term PROM group were significantly higher than those in the full-term PROM group [(238.01 ± 40.45) ng/L, (47.87 ± 8.90) pg/mL, (0.43 ± 0.14) ng/mL, (54.09 ± 10.33) ng/mL, t = 9.103, 8.862, -10.538, 6.494, all P < 0.05). The expression levels of MMP-9 [(343.74 ± 43.74) ng/L], PCT [(69.88 ± 8.83) pg/mL], sTREM-1 [(0.67 ± 0.16) ng/mL], sCD14 [(70.41 ± 8.89) ng/mL] in the infection group were significantly higher than those in the non-infection group [(230.09 ± 49.82) ng/L, (45.82 ± 11.04) pg/mL, (0.42 ± 0.19) ng/mL and (54.41 ± 12.42) ng/mL, t = 23.655, 12.014, 9.382, 11.306, all P < 0.01]. The sensitivity (94.23%), specificity (93.75%), positive predictive value (92.45%) and negative predictive value (96.20%) of combined detection of these indexes in the diagnosis of PROM complicated by chorioamnionitis were significantly higher than those of other indexes detected alone (all P < 0.05). Conclusion:Combined detection of serum levels of MMP-9, PCT, sTREM-1 and sCD14 can be used as an effective auxiliary index for the diagnosis of early premature rupture of membranes complicated with chorioamnionitis.
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PURPOSE: Cancer-associated fibroblasts (CAFs) activated by cancer cells has a central role in development and malignant biological behavior in colorectal cancer (CRC). Adult fibroblasts do not express Snail, but Snail-positive fibroblasts are discovered in the stroma of malignant CRC and reported to be the key role to chemoresistance. However, the reciprocal effect of CAFs expressed Snail to chemoresistance on CRC cells and the underlying molecular mechanisms are not fully characterized. MATERIALS AND METHODS: Snail-overexpressed 3T3 stable cell lines were generated by lipidosome and CT26 mixed with 3T3-Snail subcutaneous transplanted CRC models were established by subcutaneous injection. Cell Counting Kit-8, flow cytometry and western blotting assays were performed, and immunohistochemistry staining was studied. The cytokines participated in chemoresistance was validated with reverse transcriptase-polymerase chain reaction and heatmap. RESULTS: Snail-expression fibroblasts are discovered in human and mouse spontaneous CRCs. Overexpression of Snail induces 3T3 fibroblasts transdifferentiation to CAFs. CT26 co-cultured with 3T3-Snail resisted the impairment from 5-fluorouracil and paclitaxel in vitro. The subcutaneous transplanted tumor models included 3T3-Snail cells develop without restrictions even after treating with 5-fluorouracil or paclitaxel. Moreover, these chemoresistant processes may be mediated by CCL1 secreted by Snail-expression fibroblasts via transforming growth factor β/nuclear factor-κB signaling pathways. CONCLUSION: Taken together, Snail-expressing 3T3 fibroblasts display CAFs properties that support 5-fluorouracil and paclitaxel chemoresistance in CRC via participation of CCL1 and suggest that inhibition of the Snail-expression fibroblasts in tumor may be a useful strategy to limit chemoresistance.
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Adult , Animals , Humans , Mice , Blotting, Western , Cell Count , Cell Line , Colorectal Neoplasms , Cytokines , Drug Resistance, Multiple , Fibroblasts , Flow Cytometry , Fluorouracil , Immunohistochemistry , In Vitro Techniques , Injections, Subcutaneous , Paclitaxel , Snails , Transforming Growth FactorsABSTRACT
Objective To investigate the high sensitive C reactive protein(hs-CRP),homocysteine(Hcy), interleukin 2(IL-2)and lipoprotein associated phospholipase A 2(Lp-PLA2)analysis and correlation test for coronary heart disease.Methods 147 cases were selected from our hospital in December 2015 to December 2016 in patients with coronary heart disease(observation group).At the same time,we selected 51 healthy persons in our hospital during December 2015 to December 2016 as control group.The content of hs-CRP was determined by immune transmission turbidimetry.The content of Hcy was determined by cyclic enzymatic method.The content of IL-2 was determined by enzyme linked immunosorbent assay(ELISA).The content of Lp-PLA2 was determined by immune transmission turbidimetry.Results The observation group serum levels of hs-CRP,Hcy,IL-2 and Lp-PLA2 were significantly higher than those in the control group,and the differ-ence were statistically significant(P<0.05).The coronary heart disease each group serum levels of hs-CRP, Hcy,IL-2 and Lp-PLA2 were significantly higher than those in the control group,and the differences were sta-tistically significant(P<0.05).The serum levels of hs-CRP,Hcy,IL-2 and Lp-PLA2 of AMI group were sig-nificantly higher than those in UAP group and SAP group,and the differences were statistically significant (P<0.05).The UAP group serum levels of hs-CRP,Hcy,IL-2 and Lp-PLA2 were significantly higher than those in SAP group,and the difference was statistically significant(P<0.05).Conclusion Hs-CRP,Hcy,IL-2,Lp-PLA2 have significant correlation with coronary heart disease.
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AIM:To explore the effect of dasatinib on the viability, migration, cell cycle and apoptosis of human bone marrow mesenchymal stem cells (hBMSCs), as well as the underlying signal pathway to evaluate the influence of dasatinib on hematopoietic microenvironment clinically.METHODS:The cell viability was measured by CCK-8 assay.The migration ability was detected by wound healing assay.The cell cycle and apoptosis were analyzed by flow cytometry.Acridine orange/ethidium bromide staining was also used to detected apoptosis.The secretion of transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α (TNF-α) were measured by ELISA.The protein levels of cleaved caspase-3, protein kinase B (Akt) and phosphorylated Akt were determined by Western blot.RESULTS:Compared with control group, dasatinib at 1~10 nmol/L suppressed the viability and migration ability of hBMSCs, and dasatinib at concentration of 7 nmol/L was adopted in the following assays.Dasatinib promoted apoptosis, and blocked the cell cycle in G1 phase.In addition, the secretion of TGF-β1 and TNF-α was increased markedly.The protein levels of cleaved caspase-3 was increased, but the protein levels of Akt and phosphorylated Akt were decreased.CONCLUSION:Dasatinib inhibits the viability and migration ability of hBMSCs in a dose-dependent manner, promotes the secretion TGF-β1 and TNF-α, and induces cell cycle arrest and apoptosis.Dasatinib might regulate the biological behaviors of hBMSCs observed above by modulating the expression and phosphorylation of Akt.
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ObjectiveTo investigate the mechanism of action of PNPLA3 I148M mutation in the development and progression of non-alcoholic fatty liver fibrosis. MethodsThe lentiviral vectors carrying the mutant or wild-type PNPLA3 I148M gene were constructed and transfected into rat hepatic stellate (HSC-T6) cells. Quantitative real-time PCR was applied to measure the mRNA expression of transforming growth factor β1 (TGF β1). The t-test was applied for statistical analysis. ResultsThe lentiviral vectors carrying the mutant or wild-type PNPLA3 I148M gene were successfully constructed and transfected into HSC-T6 cells, and a HSC-T6 cell line with stable expression of the mutant or wild-type PNPLA3 gene was established. Compared with the cell line carrying the wild-type gene, the cell line carrying the mutant gene showed significantly higher mRNA expression of TGF β1 (1.25±0.15 vs 0.48±0.07; t=11.826, P＜0001). ConclusionPNPLA3 I148M mutation can increase the expression of TGF β1 in HSC-T6 cells, which provides a new cell model and new research ideas for investigating the role of PNPLA3 I148M mutation in non-alcoholic fatty liver fibrosis.
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Currently the incidence of nonalcoholic fatty liver disease (NAFLD) is increasing, and the age of onset is getting younger worldwide, resulting in a heavy economic burden for both individuals and the society. Since NAFLD is closely related to heredity, metabolism, and the environment, genetic factors play an important role in the development and progression of NAFLD. With the development and wide application of the techniques from the genome-wide association studies, new research advances have been achieved in the susceptibility genes of NAFLD. This review summarizes the related research findings at home and abroad, and investigates the pathogenic factors for NAFLD and related mechanisms with a focus on the polymorphisms of susceptibility genes.
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In recent years, with an increasing number of drug types and unreasonable drug use, the incidence and mortality of drug-induced liver injury (DILI) have been increasing. The pathogenesis of DILI is complex, and may involve liver injury caused by the direct effect of drugs, immune-mediated liver injury, mitochondrial injury, and bile duct injury, etc. This article investigates the pathogenesis and its important role in the prevention and treatment of DILI, and reviews the research advances in the pathogenesis of DILI.
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Objective:This study has two objectives. One is to detect the methylation status of reversion-inducing cysteine-rich protein with Kazal motifs (RECK, a new tumor suppressor gene) gene promoter in primary laryngeal squamous cell carcinoma and nor-mal laryngeal mucosa. The other is to analyze the correlation between RECK gene methylation status and radiosensitivity in laryngeal squamous cell carcinoma. Methods:Methylation-specific polymerase chain reaction was used to detect the RECK gene methylation of 70 specimens of laryngeal squamous cell carcinoma and 15 normal tissues of laryngeal mucosa. The patients underwent six cycles of ra-diotherapy and were followed-up for 5 years. The correlation between RECK gene methylation status and radiosensitivity in laryngeal squamous cell carcinoma was analyzed. Results: After six cycles of radiotherapy, 47 patients (67.14%) showed sensitivity and 23 (32.86%) showed tolerance to radiotherapy. The methylation level of the RECK gene was lower in the radiation-sensitive group than in the nonradiation-sensitive group (P<0.05). The methylation level of the RECK gene was lower in the remission group than in the non-remission group. RECK gene methylation could increase the risk of cancer by approximately 5.010 times (OR=5.010, 95%CI:1.616-15.533). Conclusion:RECK gene promoter methylation in human laryngeal squamous cell carcinoma is an early event that is correlated with the patient's sensitivity to radiotherapy. Thus, the patient's sensitivity to radiation can be predicted by detecting the meth-ylation status of the RECK gene promoter.
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<p><b>OBJECTIVE</b>This study aimed to investigate the expression function of substance P and the formation of osteoclasts in the periodontal tissues after the inferior alveolar nerve sectioned in rats.</p><p><b>METHODS</b>Thirty Wistar male rats were used in the experiment and were divided into six groups (n = 5) randomly: 0 d (normal), 3 d, 7 d, 14 d, 21 d, and 28 d. The periodontal tissues were removed from the denervation of the inferior alveolar nerve in rats. The periodontal tissues were checked by paraffin sections through immunohistochemical staining to trace the expression of substance P and through tratrate resistant acid phosphatase (TRAP) staining to detect the osteoclasts. The average optical density and osteoclast were measured, and the obtained data was statistically analyzed.</p><p><b>RESULTS</b>The expression level of substance P in the first three days decreased significantly after the inferior alveolar nerve was cut. In addition, the lowest expression level was measured after 7 d. Normal levels in the periodontal tissue were measured after 21 d. In addition, we found that osteoclasts vary proportionally with the changes in substance P.</p><p><b>CONCLUSION</b>The changes in substance P is positively correlated with the quantity of osteoclasts after the inferior alveolar nerve section. Therefore, we deduce that substance P may regulate the differentiation of osteoclasts formation, and thereby participate in the balancing of aveular bone metabolism.</p>
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Animals , Male , Rats , Cell Differentiation , Mandibular Nerve , Osteoclasts , Rats, Wistar , Substance PABSTRACT
<p><b>OBJECTIVE</b>To investigate whether fenvalerate can induce mouse hippocampal nerve cell damage by interfering with estrogen (E2) effect.</p><p><b>METHODS</b>Hippocampus were dissected and cultured from Embryo 18 d ICR mice, the cells were cultured for 7 days. Fenvalerate (FEN, 0, 1, 10, 50 µg/ml), FEN (10, 50 µg/ml) and estrogen receptor antagonist ICI 182, 780 (1 µmol/L), FEN (0, 10, 50 µg/ml) and E2 (10 nmol/L) were applied to the cultured cells for 48h. Immunocytochemically stained with neurons and astrocytes to evaluate the levels respectively, and the growth of neurite. Result 1µg/ml FEN have no effect on neurons, neurites and protoplasmic astrocytes, 10 and 50 µg/ml FEN can significantly decrease the neuron viability and the length of neurite as well as increase the level of protoplasmic astrocytes (P < 0.05 vs. control group). ICI 182, 780 alone have no effect on neurons, neurites and protoplasmic astrocytes; ICI+10 µg/ml FEN significantly increase the cell viability and extend neurite length as well as decrease protoplasmic astrocytes (P < 0.05 vs. 10 µg/ml FEN alone group); ICI+50 µg/ml FEN significantly increase the cell viability and decrease protoplasmic astrocytes (P < 0.05 vs. 50 µg/ml FEN alone group). E2 alone have no effect on protoplasmic astrocytes, while can promote neuronal survival and neurite growth; E2+10 µg/ml FEN and E2+50 µg/ml FEN significantly decrease neuronal survival and neurite growth, as well as increase protoplasmic astrocytes (P < 0.05 vs. E2 alone group).</p><p><b>CONCLUSION</b>Fenvalerate can induce the loss of hippocampal neurons through disrupting estrogen nuclear receptor signaling, and inhibit the length of neurite through disrupting estrogen nuclear receptor and membrane receptor signaling. The effect of estrogen disruption play an important role in developmental neurotoxicity by fenvalerate.</p>
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Animals , Mice , Astrocytes , Cells, Cultured , Estrogens , Pharmacology , Hippocampus , Pathology , Mice, Inbred ICR , Neurons , Pathology , Nitriles , Toxicity , Pyrethrins , ToxicityABSTRACT
Metastasis is the main cause of death in cancer patients. To improve the outcomes of patients undergoing a surgery, new adjuvant therapies that can effectively inhibit metastases have to be developed. Studies have shown that flavonoid naringenin, a natural product that is mainly present in grapes and citrus, may contribute to cancer prevention. It has many advantages compared to traditional chemotherapeutic drugs, such as low toxicity. To determine whether naringenin can also inhibit metastases, a breast cancer resection model that mimics clinical situations was established. We found that orally administered naringenin significantly decreased the number of metastatic tumor cells in the lung and extended the life span of tumor resected mice. Flow cytometry analysis revealed that T cells displayed enhanced antitumor activity in naringenin treated mice, with an increased proportion of IFN-γ and IL-2 expressing T cells. In vitro studies further demonstrated that relief of immunosuppression caused by regulatory T cells might be the fundamental mechanism of metastasis inhibition by naringenin. These results indicate that orally administered naringenin can inhibit the outgrowth of metastases after surgery via regulating host immunity. Thus, naringenin can be an ideal surgical adjuvant therapy for breast cancer patients.
Subject(s)
Animals , Female , Humans , Mice , Anticarcinogenic Agents , Therapeutic Uses , Antigens, CD , Breast Neoplasms , Drug Therapy , Allergy and Immunology , Pathology , General Surgery , Cell Line, Tumor , Cell Proliferation , Chemotherapy, Adjuvant , Flavanones , Therapeutic Uses , Immunosuppressive Agents , Therapeutic Uses , Interferon-gamma , Allergy and Immunology , Interleukin-2 , Allergy and Immunology , Lung Neoplasms , Drug Therapy , Allergy and Immunology , Mice, Inbred BALB C , Mice, Inbred C57BL , T-Lymphocytes, Regulatory , Allergy and Immunology , MetabolismABSTRACT
Objective:To evaluate the effect of Helicobacter pylori infection on hyperdynamic circulatory state and portal hypertensive gastrropathy in liver cirrhotic patients.Methods:Helicobacter pylori infection,IL-1,IL-8,TNF-?,Endotoxin,NO,ET,anti-VacA and anti-CagA levels were determined in cirrhotic patients by using rapid urease test,()~(14)C-urea expiratory test,immunoimpression test,nitrite colorimetric test and ELISA.The parameters of portal venous system flow were determined by doppler ultrasonography.Results:HP prevalence in patients with liver cirrhosis was 77.1%,anti-VacA and antiCagA positive rate was 60.4% in common.IL-1,IL-8,TNF-?,Endotoxin,NO and ET levels in anti-VacA and anti-CagA positive group were significantly higher than in anti-VacA and anti-CagA negtive group.The amount of splenic venous flow(SVF) and superior mesenteric venous flow(SMVF)in anti-VacA and anti-CagA positive group was greater and the amount of portal venous flow(PVF) was smaller than those in negtive group.Conclusion:There was the effect of Helicobacter pylori infection on hyperdynamic circulatory state and portal hypertensive gastrropathy in liver cirrhotic patients.
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Objective:To evaluate p53,c erbB 2,p21 and nm23 oncoprotein expression in diagnosis and treatment of gastric cancer.Methods:The expression of p53,c erbB 2,p21 and nm23 oncoproteins was detected with immunohistochemical method in 63 surgically resected specimens and its endoscopic biopsy specimens of gastric cancer.Results:The positive rates of p53,c erbB 2,p21 and nm23 oncoprotein expression were 37 6%～46 2%,34 6%～56 8%,37 8%～61 5%,70 3%～30 8% respectively.Oncoprotein expression was not observed in non tumor endoscopic biopsy specimens.The expression of c erbB 2,p21 was correlated with grade of tumor differentiation and the expression of p21,nm23 oncoproteins was correlated with the depth of tumor invasion and clinical different stage,namely tumor metastasis.Positive rates of p53,c erbB 2,p21 and nm23 oncoproteins between biopsy and resected specimens was of coincidence.Conclusion:Determination of p53,c erbB 2,p21 and nm23 oncoprotein expression was might be useful in diagnosis and treatment of gastric cancer,differentiating benign and malignant tumor and clinical stages,of gastric cancer. [