- Dihydrodiosgenin protects against experimental acute pancreatitis and associated lung injury through mitochondrial protection and PI3Kγ/Akt inhibition. [Journal Article]
- BJBr J Pharmacol 2018 Feb 19
- CONCLUSIONS: These data provide in vitro and in vivo mechanistic evidence that diosgenin analog, Dydio could be potential treatment for AP. This study suggests that further medicinal optimization of diosgenin and its analog might serve as a useful strategy for identifying lead candidates for inflammatory diseases.
- Inhibition of KRAS-dependent lung cancer cell growth by deltarasin: blockage of autophagy increases its cytotoxicity. [Journal Article]
- CDCell Death Dis 2018 Feb 13; 9(2):216
- Deltarasin is a recently identified small molecule that can inhibit KRAS-PDEδ interactions by binding to a hydrophobic pocket on PDEδ, resulting in the impairment of cell growth, KRAS activity, and R...
Deltarasin is a recently identified small molecule that can inhibit KRAS-PDEδ interactions by binding to a hydrophobic pocket on PDEδ, resulting in the impairment of cell growth, KRAS activity, and RAS/RAF signaling in human pancreatic ductal adenocarcinoma cell lines. Since KRAS mutations are the most common oncogene mutations in lung adenocarcinomas, implicated in over 30% of all lung cancer cases, we examined the ability of deltarasin to inhibit KRAS-dependent lung cancer cell growth. Here, for the first time, we document that deltarasin produces both apoptosis and autophagy in KRAS-dependent lung cancer cells in vitro and inhibits lung tumor growth in vivo. Deltarasin induces apoptosis by inhibiting the interaction of with PDEδ and its downstream signaling pathways, while it induces autophagy through the AMPK-mTOR signaling pathway. Importantly, the autophagy inhibitor, 3-methyl adenine (3-MA) markedly enhances deltarasin-induced apoptosis via elevation of reactive oxygen species (ROS). In contrast, inhibition of ROS by N-acetylcysteine (NAC) significantly attenuated deltarasin-induced cell death. Collectively, these observations suggest that the anti-cancer cell activity of deltarasin can be enhanced by simultaneously blocking "tumor protective" autophagy, but inhibited if combined with an anti-oxidant.
- Mechanism of ECM-induced dormancy and chemoresistance in A549 human lung carcinoma cells. [Journal Article]
- OROncol Rep 2018 Feb 12
- It is now widely accepted that the tumor microenvironment influences the fate of cancer cells and plays crucial roles in regulating tumor dormancy and chemoresistance. The standard cell culture syste...
It is now widely accepted that the tumor microenvironment influences the fate of cancer cells and plays crucial roles in regulating tumor dormancy and chemoresistance. The standard cell culture system on plastic surfaces does not account for cell interactions with the extracellular matrix (ECM), and is thus a less reliable approach to analyze cellular activity ex vivo. In the present study, A549 lung cancer cells were cultured in a semi-solid growth substrate (Matrigel) to mimic the tumor microenvironment and to investigate the role played by ECM proteins, as well as to evaluate the mechanism of cell-ECM communication. A549 cells embedded in semi-solid Matrigel exhibited dormant cell characteristics, including decreased cell proliferation, migration and invasion rates, compared with the corresponding cells cultured on plastic plates. Exposure of A549 cells to Matrigel leads to resistance against conventional chemotherapeutic drugs (etoposide, paclitaxel, vinblastine, doxorubicin and 2-deoxy-D-glucose). Cell cycle distribution analysis indicated that a larger percentage of the cells embedded within semi-solid Matrigel was arrested in the G0/G1 phase. RT-qPCR analysis revealed that A549 cells cultured in semi-solid Matrigel exhibited a marked decrease in the expression levels of genes that are related to tumor progression and invasion (uPA, uPAR, MMP2, MMP7, MMP9 and CXCR4). The effects of altering various signaling pathways, such as p-ERK, p-Akt and p-STAT3, were evaluated, in order to assess whether these pathways could account for the observed responses of the cells. The inhibition of ERK1/2 and Akt activation using specific inhibitors induced G0/G1 arrest and drug resistance. These results demonstrated that Matrigel drove A549 cells into a drug-resistant dormancy state, most likely through inhibition of the ERK1/2 and PI3K/Akt pathways. Cell culture within semi-solid Matrigel offered a simple in vitro model for studying the mechanisms responsible for tumor dormancy and drug resistance. These studies may lead to therapeutic approaches that can eliminate dormant tumor cells and prevent disease recurrence.
- ARDS following oesophagectomy: a comparison of two trials. [Journal Article]
- BOBMJ Open Respir Res 2017; 4(1):e000207
- CONCLUSIONS: Smoking cessation trials should be promoted. Dihydropyridine effects perioperatively require further clinical and mechanistic evaluation. Patients undergoing oesophagectomy are a useful model for studying perioperative ARDS.
- Tubeimoside I attenuates inflammation and oxidative damage in a mice model of PM2.5-induced pulmonary injury. [Journal Article]
- ETExp Ther Med 2018; 15(2):1602-1607
- In the present study, the effects of tubeimoside I (TBMS1) on particulate matter <2.5 µm in diameter (PM2.5)-induced pulmonary injury and its mechanisms of action were investigated. Male BALB/c mice ...
In the present study, the effects of tubeimoside I (TBMS1) on particulate matter <2.5 µm in diameter (PM2.5)-induced pulmonary injury and its mechanisms of action were investigated. Male BALB/c mice were randomly assigned into five groups (n=10/group): Control, PM2.5, PM2.5 + TBMS1 45 mg/kg, PM2.5 + TBMS1 90 mg/kg and PM2.5 + TBMS1 180 mg/kg. The dose of the PM2.5 suspension administered to the mice was 40 mg/kg via nasal instillation. The PM2.5 + TBMS1 groups received TBMS1 daily orally for 21 consecutive days, while the mice in the control and PM2.5 groups received equivalent volumes of PBS. Subsequently, lactic dehydrogenase, acid phosphatase, alkaline phosphatase, albumin, tumor necrosis factor-α and interleukin-6 protein levels in bronchoalveolar lavage fluid were determined. Oxidative stress was evaluated by detecting the protein levels of malondialdehyde, superoxide dismutase and inducible nitric oxide synthase, and the level of nitric oxide in lung tissue. Lastly, histopathological images of lung sections were obtained to observe changes in the lung tissue with treatment. The results indicated that exposure to PM2.5 induced pathological pulmonary changes, and biofilm and parenchymal cell damage, and promoted inflammation and oxidative stress. Treatment with TBMS1 attenuated the development of PM2.5-induced pulmonary injury. Its mechanisms of action were associated with reducing cytotoxic effects, levels of inflammatory mediators and oxidative damage. In conclusion, the results of the present study indicate that TBMS1 is a potential therapeutic drug for treating PM2.5-induced pulmonary injury.
- A Combination of the Aerosolized PPAR-γ Agonist Pioglitazone and a Synthetic Surfactant Protein B Peptide Mimic Prevents Hyperoxia-Induced Neonatal Lung Injury in Rats. [Journal Article]
- NNeonatology 2018 Feb 09; 113(4):296-304
- CONCLUSIONS: Nebulized PPAR-γ agonist PGZ with a synthetic lung surfactant accelerates lung maturation and prevents neonatal hyperoxia-induced lung injury more than either modality alone, with the potential to provide more effective prevention of BPD.
- Novel Ligustrazine-Based Analogs of Piperlongumine Potently Suppress Proliferation and Metastasis of Colorectal Cancer Cells in Vitro and in Vivo. [Journal Article]
- JMJ Med Chem 2018 Feb 15
- Piperlongumine 1 increases reactive oxygen species (ROS) levels and preferably induces cancer cell apoptosis by triggering different pathways. However, the poor solubility of 1 limits its intensive i...
Piperlongumine 1 increases reactive oxygen species (ROS) levels and preferably induces cancer cell apoptosis by triggering different pathways. However, the poor solubility of 1 limits its intensive investigation and clinical application. Ligustrazine possesses a water-soluble pyrazine skeleton and can inhibit proliferation and metastasis of cancer cells. We synthesized compound 3 by replacement of the trimethoxyphenyl of 1 with ligustrazine moiety and further introduced 2-Cl, -Br, and -I to 3 for synthesis of 4-6, respectively. Compound 4 possessed 14-fold greater aqueous solubility than 1 and increased ROS levels in colorectal cancer HCT-116 cells. Additionally, 4 preferably inhibited proliferation, migration, invasion, and heteroadhesion of HCT-116 cells. Treatment with 4 suppressed tumor growth and lung metastasis in vivo and prolonged the survival of tumor-bearing mice. Furthermore, 4 mitigated TGF-β1-induced epithelial-mesenchymal transition and Wnt/β-catenin activation by inhibiting the Akt and GSK-3β phosphorylation in HCT-116 cells. Collectively, 4 displayed significant antiproliferation and antimetastasis activities, superior to 1.
- DRUG INDUCED PULMONARY ARTERIAL HYPERTENSION: A PRIMER FOR CLINICIANS AND SCIENTISTS. [Journal Article]
- AJAm J Physiol Lung Cell Mol Physiol 2018 Feb 08
- Drug-induced pulmonary arterial hypertension (D-PAH) is a form of World Health Organization (WHO) Group 1 pulmonary hypertension (PH) defined by severe small vessel loss and obstructive vasculopathy,...
Drug-induced pulmonary arterial hypertension (D-PAH) is a form of World Health Organization (WHO) Group 1 pulmonary hypertension (PH) defined by severe small vessel loss and obstructive vasculopathy, which leads to progressive right heart failure and death. To date, 16 different compounds have been associated with D-PAH, including anorexigens, recreational stimulants, and more recently, several Food and Drug Administration (FDA)-approved medications. While the clinical manifestation, pathology, and hemodynamic profile of D-PAH are indistinguishable from other forms of PAH, its clinical course can be unpredictable and to some degree dependent on removal of the offending agent. Since only a subset of individuals develop D-PAH, it is probable that genetic susceptibilities play a role in the pathogenesis, but the characterization of the genetic factors responsible for these susceptibilities remains rudimentary. Besides aggressive treatment with PH-specific therapies, the major challenge in the management of D-PAH remains the early identification of compounds capable of injuring the pulmonary circulation in susceptible individuals. The implementation of pharmacovigilance, precision medicine strategies, and global warning systems will help facilitate the identification of high-risk drugs and incentivize regulatory strategies to prevent further outbreaks of D-PAH. The goal for this review is to inform clinicians and scientists of the prevalence of D-PAH and to highlight the growing number of common drugs that have been associated with the disease.
- The peroxisome proliferator-activated receptor agonist pioglitazone and 5-lipoxygenase inhibitor zileuton have no effect on lung inflammation in healthy volunteers by positron emission tomography in a single-blind placebo-controlled cohort study. [Journal Article]
- PlosPLoS One 2018; 13(2):e0191783
- CONCLUSIONS: Endotoxin-induced lung inflammation in humans is not responsive to pioglitazone or zileuton, highlighting the challenge in translating anti-inflammatory drug efficacy results from murine models to humans.
New Search Next
- Current perspective: Osimertinib-induced QT prolongation: new drugs with new side-effects need careful patient monitoring. [Journal Article]
- EJEur J Cancer 2018; 91:92-98
- An increasing number of tyrosine kinase inhibitors (TKIs) are available for the treatment of non-small cell lung cancer (NSCLC). QT prolongation is one of the known, but relatively rare, adverse even...
An increasing number of tyrosine kinase inhibitors (TKIs) are available for the treatment of non-small cell lung cancer (NSCLC). QT prolongation is one of the known, but relatively rare, adverse events of several TKIs (e.g. osimertinib, crizotinib, ceritinib). Screening for QT prolongation in (high risk) patients is advised for these TKIs. When a QT prolongation develops, the physician is challenged with the question whether to (permanently) discontinue the TKI. In this perspective, we report on a patient who developed a grade III QT prolongation during osimertinib (a third-generation epidermal growth factor receptor [EGFR]-TKI) treatment. On discontinuation of osimertinib, she developed a symptomatic disease flare, not responding to subsequent systemic treatment. The main aim of this perspective is to describe the management of QT prolongation in stage IV EGFR driver mutation NSCLC patients. We also discuss the ethical question of how to weigh the risk of a disease flare due to therapy cessation against the risk of sudden cardiac death. A family history of sudden death and a prolonged QT interval might indicate a familiar long QT syndrome. We have summarised the current monitoring advice for TKIs used in the treatment of lung cancer and the most common drug-TKI interactions to consider and to optimise TKI treatment in lung cancer patients.