Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) wild-type is intrinsic resistance to EGFR-tyrosine kinase inhibitors (TKIs). In this study, we assessed whether the combination of bisdemethoxycurcumin (BDMC) and icotinib could surmount primary EGFR-TKI resistance in NSCLC cells and investigated its molecular mechanism. Results showed that the combination of BDMC and icotinib produced potently synergistic growth inhibitory effect on primary EGFR-TKI-resistant NSCLC cell lines H460 (EGFR wild-type and K-ras mutation) and H1781 (EGFR wild-type and Her2 mutation). Compared with BDMC or icotinib alone, the two drug combination induced more significant apoptosis and autophagy via suppressing EGFR activity and interaction of Sp1 and HDCA1/HDCA2, which was accompanied by accumulation of reactive oxygen species (ROS), induction of DNA damage, and inhibition of cell migration and invasion. ROS inhibitor (NAC) and autophagy inhibitors (CQ or 3-MA) partially reversed BDMC plus icotinib-induced growth inhibitory effect on the NSCLC cells. Meanwhile, co-treatment with NAC attenuated the two drug combination-induced autophagy, apoptosis, DNA damage and decrease of cell migration and invasion ability. Also, 3-MA or CQ can abate the combination treatment-induced apoptosis and DNA damage, suggesting that there is crosstalk between different signaling pathways in the effect produced by the combination treatment. Our data indicate that BMDC has the potential to improve the treatment of primary EGFR-TKI resistant NISCLC that cannot be controlled with single-target agent, such as icotinib.
Transforming growth factor β (TGF-β) is a polypeptide growth factor with various biological activities, and is widely distributed in various tissues. In mammals, TGF-β has three isoforms: TGF-β1, 2, and 3, of which TGF-β1 is most abundant in the TGF-β family. TGF-β1 is closely related to the occurrence and development of tumors. A large number of previous studies have shown that melatonin can inhibit a variety of malignancies. Thus, the aim of the present study was to investigate the role of TGF-β1 in the melatonin-mediated inhibition of the proliferation of gastric cancer cells in vitro and in vivo. TGF-β1 cytokine stimulation, anti-TGF-β1 neutralizing antibody blocking, siRNA TGF-β1 and other means were utilized to explore the role of TGF-β1 during the course of anti-gastric cancer by melatonin. The results showed that melatonin upregulated the expression of TGF-β1 in tumor tissues during the process of inhibiting gastric cancer tumor growth in vivo. Melatonin inhibited the proliferation of gastric cancer cells in vitro, accompanied by increased expression of TGF-β1 in a time-dependent manner. siRNA-mediated silencing of TGF-β1 and anti-TGF-β1 neutralizing antibody completely blocked the TGF-β1 pathway, which significantly antagonized the melatonin-mediated inhibition of the growth and proliferation of gastric cancer cells, and promoted G1 phase to S phase transformation of MFC cells. Our findings suggest that TGF-β1 is involved in the regulation of the proliferation of tumor cells. One of the ways in which melatonin inhibits the proliferation of gastric cancer cells is dependent on the TGF-β1 signaling pathway.
Abstract. The present study was performed to investigate the role of p38 mitogen-activated protein kinase (MAPK) in the resorption of herniated intervertebral discs in 30 rats. In the non-contained and p38 MAPK inhibition (p38i) groups, two coccygeal intervertebral discs (IVDs) were removed and wounded prior to relocation into the subcutaneous space of the skin of the back. In the contained group, the cartilage endplates maintained their integrity. Furthermore, SB203580 was injected intraperitoneally into the p38i group, whereas saline was injected into the other two groups. In the non-contained group, the weight of the relocated IVDs decreased to a greater extent over time when compared with the contained and p38i groups. Phosphorylated p38, tumor necrosis factor-α, and interleukin-1β were observed to exhibit higher expression levels in the non-contained group compared with the contained and p38i groups, at weeks 1 and 4 post-surgery. The expression level of caspase-3 and the densities of apoptotic disc cells were significantly higher in the non-contained group compared with the contained and p38i groups at 4 weeks post-surgery. In conclusion, p38 MAPK induces apoptosis in IVDs, while also accelerating the resorption of the relocated IVDs. Thus, p38 MAPK may be important in spontaneous resorption of IVDs.
In the process of enlarging of tumors, the dissolving tissue structures and remodeling endothelial cells for restoring gas exchange and nutritional support, further facilitate tumor cell invasion and metastasis. Activation of Ras plays a critical role in the development of esophageal squamous cell carcinoma (ESCC), but the underlying mechanisms remain poorly understood. We therefore investigated whether Ras guanyl-releasing protein 3 (RasGRP3), a Ras activator, could promote metastasis by inducing vascular regeneration and further epithelial-mesenchymal transition under nutrient stress (NS). In the present study, we explored that the accumulation of RasGRP3 regulated vascular endothelial growth factor-A production, co-stimulated Notch pathway with high expression of Notch intracellular domain (NICD) and Hes1. Moreover, ESCC cells under NS increased the expression of vimentin, Snail, Slug and MMP9 proteins; while inhibition of Notch activation by DAPT (a γ-secretase inhibitor) or RasGRP3-targeted RNA interference prevented from the effect. In conclusion, these findings provide a new insight into the upregulation of RasGRP3 involved in Notch pathway activation in the development of ESCC, especially under nutrient deprivation.
No abstract
Objective of current research was to investigate the effect of sevoflurane inhalation anesthesia on hemodynamics and inflammatory response in elderly patients with lung cancer lobectomy. Methods: A total of 168 patients with lung cancer who underwent lobectomy in our hospital from January 2019 to December 2019 were selected as the study subjects. The patients were divided into an observation group and control group according to the anesthesia program. In the control group, 1 mg/kg propofol intravenous pump induced anesthesia was maintained at 6mg/kg/h. In the observation group, 8% sevoflurane was used to induce anesthesia and 2% sevoflurane was used to maintain anesthesia. Mean artery pressure (MAP), heart rate (HR) and blood oxygen saturation (SpO 2 ) were monitored at the beginning of single-lung ventilation (t 1 ), when single-lung ventilation was changed to double-lung ventilation (t 2 ), and at 30 minutes after double-lung ventilation (t 3 ), respectively. Serum levels of interleukin-6 (IL-6), tumor necrosis factor (TNF-α), and matrix metalloproteinases (MMP-9) were measured using an enzymelinked immunosorbent assay (ELISA) kit. Assess the patient's adverse reactions. Results: At time t 1 and time t 2 , there was no significant difference in the three hemodynamic indicators between the two groups (P>0.05). However, at t 3 , both MAP and HR in the observation group were significantly lower than those in the control group, while SpO 2 was significantly higher than those in the control group (P<0.05). At t 1 and t 2 , there was no significant difference in IL-6 and TNF-levels between the two groups, but at t 3 , IL-6 and TNF-α levels in the observation group were significantly lower than those in the control group (P<0.05). Compared with the control group, serum MMP-9 level was significantly decreased in the whole t 1 to t 3 stage (P<0.05). The incidence of complications in the observation group was significantly higher than that in the control group. It was calculated that Sevoflurane can significantly improve hemodynamics and inflammatory response in elderly patients with lung cancer lobectomy, but the incidence of complications is high.
G kinase‐anchoring protein 1 (GKAP1) is a G kinase‐associated protein that is conserved in many eutherians and is mainly expressed in the testis, especially in spermatocytes and round spermatids. The function of GKAP1 in the testis is largely unknown. Here, we revealed that deletion of GKAP1 led to an increase in sperm production with swollen epididymis, and germ cell apoptosis was found to decrease in GKAP1 knock‐out mice. Further investigations showed that a deficiency of GKAP1 could partly change the cellular location of cGK‐Iα and increase the amount of active cAMP response element‐binding protein (CREB) in the nucleus. Therefore, the expression of a particular inhibitor of apoptosis proteins (IAPs) was upregulated because of the activation of CREB, and this increase in IAPs was associated with a decrease in the level of activated caspase‐3. These results suggest that a deficiency of GKAP1 in mouse testis could increase sperm production through a reduction of the spontaneous apoptosis of germ cells in the testis, possibly because of a change in the activity of the cGK‐Iα pathway.
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