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1.
Heliyon ; 9(9): e20185, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37809806

ABSTRACT

The tumor microenvironment, especially the extracellular matrix (ECM), is strongly associated with tumor cell proliferation and metastasis. Numerous studies have provided evidence suggesting that fibronectin (FN) in ECM supports cancer cell escape and contributes to cell migration, resulting in distant cancer metastasis and poor outcomes in patients. In our study, it was demonstrated that FN expression was elevated in tumor tissues from highly malignant NSCLC patients, compared to those with low malignancy (p = 0.0076). Importantly, FN promoted proliferative phenotypes and strengthened tumorigenesis capabilities in NSCLC cells, including A549 and Lewis cells, leading to sustained tumor growth in vivo. Mechanistically, it was identified that FN facilitated the activation of the integrin αvß3/PI3K/AKT signaling pathway, which subsequently upregulated tumor stemness through the downstream transcription factor SOX2. Blockade of integrin αvß3 signal efficiently suppressed NSCLC proliferation and tumorigenesis both in vitro and in vivo. In conclusion, our study demonstrated that extracellular FN could facilitate NSCLC development through the integrin αvß3/PI3K/AKT/SOX2 signaling pathway. Blockade of integrin αvß3 could efficiently enhance the anticancer effects of chemotherapy, offering an innovative approach for clinical NSCLC therapy.

2.
Cell Physiol Biochem ; 51(1): 452-469, 2018.
Article in English | MEDLINE | ID: mdl-30453300

ABSTRACT

BACKGROUND/AIMS: Immunosuppression frequently occurs during the development of sepsis and is closely associated with poor outcome. Characteristics of immunosuppressive CD4+ T lymphocytes in sepsis have been reported to include dramatic cell loss and inactivation. p53 acts as a pivotal transcription factor in regulating cell proliferation and apoptosis, which control tumorigenesis. However, few studies have investigated the universal role of p53 in immune cells, especially in the development of sepsis. METHODS: A mouse model of sepsis was produced by cecal ligation and puncture (CLP), and isolated splenic CD4+ T cells or Jurkat cells were exposed to lipopolysaccharide (LPS) stimulation in vitro. We used genetic knockout (p53-/-) mice or the specific inhibitor pifithrin-α (PFT) to investigate the regulatory mechanisms of p53. Cell proliferation ability was assessed using a Cell Counting Kit-8 assay, and apoptotic cells were stained with annexin V/propidium iodide and then analyzed using a FACScan flow cytometer. Protein and mRNA expression levels were measured by western blotting and real-time PCR, and cytokine levels in culture supernatants were determined by enzyme-linked immunosorbent assay. RESULTS: Splenic CD4+ T lymphocytes from CLP mice expressed gradually elevated p53 mRNA and protein levels, which resulted in extracellular regulated protein kinase 1/2 inactivation and expression of apoptotic molecules. Specific inhibition of p53 by PFT or genetic knockout (p53-/-) maintained CD4+ T lymphocyte homeostasis, as indicated by protection from cell loss and restoration of immune function. A medium dose of PFT improved the survival rate of mice, while mortality rate showed only a slight improvement in p53-/- mice compared with wild-type mice. The in vitro responses to LPS were consistent with these results, and upregulation of p53 clearly affected the proliferation, apoptosis, and immune dysfunction of CD4+ T lymphocytes. In addition, we confirmed the regulatory effect of p53 in Jurkat cells, and inhibition of p53 by either inhibition or short hairpin RNA transduction markedly protected cells from LPS stimulation. CONCLUSION: Elevation of p53 in T lymphocytes during sepsis or endotoxin challenge might be responsible for inhibiting cell proliferation and enhancing both apoptosis and immune dysfunction of T cells.


Subject(s)
CD4-Positive T-Lymphocytes/metabolism , Sepsis/pathology , Tumor Suppressor Protein p53/metabolism , Animals , Apoptosis/drug effects , Benzothiazoles/pharmacology , Benzothiazoles/therapeutic use , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/drug effects , Disease Models, Animal , Humans , Jurkat Cells , Lipopolysaccharides/pharmacology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , RNA Interference , RNA, Small Interfering/metabolism , Sepsis/drug therapy , Sepsis/mortality , Survival Rate , Toluene/analogs & derivatives , Toluene/pharmacology , Toluene/therapeutic use , Tumor Suppressor Protein p53/antagonists & inhibitors , Tumor Suppressor Protein p53/genetics , Up-Regulation/drug effects
3.
Chin Med J (Engl) ; 129(11): 1285-90, 2016 Jun 05.
Article in English | MEDLINE | ID: mdl-27231164

ABSTRACT

BACKGROUND: Epilepsy is one of the most common serious neurological disorders. The present study aimed to investigate the influence of occupational status on the quality of life of Chinese adult patients with epilepsy. METHODS: This study surveyed 819 subjects clinically diagnosed with epilepsy for more than 1 year in 11 hospitals in Beijing; 586 were employed (71.55%). All subjects completed the case report form with inquiries on demographic data, social factors, and illness. The patients' quality of life was assessed using the quality of life in patients with epilepsy-31 items (QOLIE-31) questionnaire. RESULTS: The QOLIE-31 score in the employed group was significantly higher than that in the unemployed group. Furthermore, the scores in all the sections (overall quality of life, energy/fatigue, emotional well-being, seizure worry, cognition, social function, and medication effects) of the employed group were higher than those of the unemployed group. Both the employed and unemployed groups achieved the highest difference in social function. The QOLIE-31 score of students was higher than those of farmers and workers. Both the students and workers scored higher in the quality of life compared with the adult peasants living with epilepsy. The students and farmers showed significant differences in QOLIE-31 score, cognition, emotional well-being, overall quality of life, energy/fatigue, and social function. In contrast, no significant difference was noted in seizure worry and medication effects across the three different kinds of occupation. CONCLUSION: Occupational status might affect the quality of life of Chinese adult patients with epilepsy, and social function is the most important contributing factor.


Subject(s)
Employment , Epilepsy/epidemiology , Quality of Life , Adolescent , Adult , Aged , Asian People , Female , Humans , Male , Middle Aged , Surveys and Questionnaires , Young Adult
4.
Mol Med Rep ; 10(4): 2165-71, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25050982

ABSTRACT

There is evidence that astroglial connexin43 (Cx43) in the supraoptic nucleus (SON) is required for the hyperosmolarity­induced increase in Fos protein expression in magnocellular neurosecretory cells (MNCs). In the present study, the role of astroglial Cx43 in the synthesis and release of vasopressin (VP) by MNCs in the SON subjected to hyperosmotic stimulus was examined. The results revealed that the VP levels in the SON and plasma were increased following acute hyperosmotic stimulus. Treatment of MNCs with Cx43­specific antisense oligodeoxynucleotides (ASODN), which temporarily reduced Cx43 protein production, limited the VP synthesis and release induced by a hyperosmotic stimulus. Similarly, the addition of gap junction and Cx43 hemichannel blockers also attenuated the VP synthesis and release induced by an acute hyperosmotic stimulus. A high extracellular [Ca2+]([Ca2+]o) has been demonstrated to reduce the gap junction activity or opening probability of Cx54 hemichannels. Notably, it was identified that high [Ca2+]o attenuated the VP synthesis and release induced by acute hyperosmotic stimulus, while low [Ca2+]o had a weak or no effect. These results suggested that Cx43 participates in the VP synthesis and release induced by hyperosmotic stimulation in the SON.


Subject(s)
Connexin 43/metabolism , Osmotic Pressure , Supraoptic Nucleus/metabolism , Vasopressins/metabolism , Animals , Calcium/metabolism , Carbenoxolone/pharmacology , Connexin 43/antagonists & inhibitors , Connexin 43/genetics , Gap Junctions/metabolism , Male , Oligodeoxyribonucleotides, Antisense/metabolism , Peptides/pharmacology , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Up-Regulation/drug effects , Vasopressins/genetics
5.
Neurochem Res ; 39(5): 833-42, 2014 May.
Article in English | MEDLINE | ID: mdl-24634254

ABSTRACT

Infrasonic noise/infrasound is a type of environmental noise that threatens public health as a nonspecific biological stressor. Glutamate-related excitotoxicity is thought to be responsible for infrasound-induced impairment of learning and memory. In addition to neurons, astrocytes are also capable of releasing glutamate. In the present study, to identify the effect of infrasound on astroglial glutamate release, cultured astrocytes were exposed to infrasound at 16 Hz, 130 dB for different times. We found that infrasound exposure caused a significant increase in glutamate levels in the extracellular fluid. Moreover, blocking the connexin43 (Cx43) hemichannel or gap junction, decreasing the probability of Cx43 being open or inhibiting of Cx43 expression blocked this increase. The results suggest that glutamate release by Cx43 hemichannels/gap junctions is involved in the response of cultured astrocytes to infrasound.


Subject(s)
Acoustic Stimulation/adverse effects , Connexin 43/physiology , Glutamic Acid/metabolism , Noise/adverse effects , Animals , Astrocytes/metabolism , Cells, Cultured , Connexin 43/antagonists & inhibitors , Rats, Sprague-Dawley , Stress, Physiological
6.
J Burn Care Res ; 32(3): e51-8, 2011.
Article in English | MEDLINE | ID: mdl-21436719

ABSTRACT

Nonmetabolic effects of intensive insulin therapy in critically ill patients have been reported, but the underlying mechanisms are unclear. This study was designed to test the hypothesis that intensive insulin treatment would attenuate burn-induced acute lung injury by protecting the pulmonary microvascular endothelium. The rat model of burn injury was achieved by exposure to 92°C water for 18 seconds. The rats were randomly allocated into the sham, burn/normal saline (NS), and burn/intensive insulin treatment groups. Blood glucose level was maintained between 5 and 7 mmol/L in rats in the burn/intensive insulin treatment group. Pulmonary injury was assessed by hematoxylin and eosin staining, scanning electron microscopy, bronchoalveolar lavage fluid protein concentrations, the lung wet:dry weight ratio, and lung myeloperoxidase activity. Pulmonary microvascular endothelial cells were examined by transmission electron microscopy. Western blotting was used to determine the protein expression of caspase-3. Intensive insulin treatment markedly attenuated the acute lung injury, revealed by improvements in histological features and significant decreases in bronchoalveolar lavage fluid protein concentrations, pulmonary wet:dry weight ratio, and myeloperoxidase activity at 12 hours after injury (P < .05 or P < .01 vs burn/NS). Moreover, the injured pulmonary microvascular endothelial cells showed significant improvements, whereas caspase-3 was markedly downregulated in the burn/intensive insulin treatment group when compared with the burn/NS group. Overall, intensive insulin treatment efficiently attenuated pulmonary microvascular endothelial cell dysfunction, decreased cell apoptosis, and inhibited acute lung injury after a burn. These findings may be useful in preventing organ failure after burn injury.


Subject(s)
Acute Lung Injury/prevention & control , Burns/complications , Insulin/pharmacology , Lung/drug effects , Acute Lung Injury/etiology , Acute Lung Injury/pathology , Analysis of Variance , Animals , Blood Glucose/analysis , Blotting, Western , Caspase 3/metabolism , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Administration Schedule , Endothelium/drug effects , Endothelium/pathology , Immunohistochemistry , Injections, Subcutaneous , Lung/pathology , Male , Peroxidase/metabolism , Random Allocation , Rats , Rats, Sprague-Dawley , Reference Values
7.
Zhonghua Shao Shang Za Zhi ; 26(3): 175-9, 2010 Jun.
Article in Chinese | MEDLINE | ID: mdl-20723418

ABSTRACT

OBJECTIVE: To study the inhibitory effects of insulin on nuclear factor-kappa B (NF-kappaB) nuclear translocation of vascular endothelial cells induced by burn serum and its correlative mechanism. METHODS: Human umbilical vein endothelial cells (HUVECs) were cultured in vitro and divided into 5 groups: blank control group (BC, ordinary culture without any stimulation), normal serum control group (NS, cultured with nutrient solution containing 20% healthy human serum), burn serum stimulation group (BS, cultured with nutrient solution containing 20% burn human serum), burn serum+insulin treatment group (BI, cultured with nutrient solution containing 20% burn human serum and 1x10(-7) mol/L insulin), inhibitor pretreatment group [IP, pretreated with 50 micromol/L protein kinase B (Akt) specific inhibitor LY-294002, then cultured with the same medium as used in BI group 30 minutes later] according to the random number table. Six hours later, the injury and apoptosis of HUVECs was respectively observed by the scanning electron microscope and determined by the flow cytometry. Meanwhile, the phosphorylation of inhibitor kappa B-alpha (p-IkappaB-alpha) and Akt (p-Akt) in cytoplasm, and the content of NF-kappaB-p65 in nucleus were determined with Western blot. RESULTS: (1) Compared with those in BC group, HUVECs in BS group shrank obviously with irregular nuclear structure, and intercellular links jagged or vanished. Slight change was observed in HUVECs structure in NS and BI groups, with the cell ductility and nuclear structure much better than those in BS group. (2) The apoptosis rates of HUVECs in BS group [(28.5+/-2.3)%], BI group [(22.3+/-1.8)%], and IP group [(29.7+/-2.4)%] were all obviously higher than that in BC group [(15.7+/-2.2)%, F=14.288, P<0.05 or P<0.01]. There was no significant statistical difference between NS group [(17.0+/-2.5)%] and BC group in apoptosis rate (F=14.288, P>0.05). The apoptosis rate of HUVECs in BI group was obviously lower than that in BS group (F=14.288, P<0.05). (3) Compared with those in BC group, the protein expressions of p-IkappaB-alpha in cytoplasm and NF-kappaB-p65 in nucleus were up-regulated, and the protein expression of p-Akt in cytoplasm was down-regulated in BS and IP groups. The expression levels of the three proteins in NS and BI groups were close to those in BC group. CONCLUSIONS: Insulin could inhibit the IkappaB phosphorylation, and then restrict NF-kappaB nuclear translocation and improve the vascular endothelial cells function accordingly through regulating phosphatidylinositol 3 kinase/Akt pathway.


Subject(s)
Burns/blood , Endothelial Cells/metabolism , Insulin/pharmacology , NF-kappa B/metabolism , Apoptosis , Cells, Cultured , Endothelium, Vascular/cytology , Endothelium, Vascular/metabolism , Humans , I-kappa B Proteins/metabolism , Phosphorylation , Serum/metabolism , Umbilical Veins/cytology
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