Carboplatin-induced hematotoxicity among patients with non-small cell lung cancer: Analysis on clinical adverse events and drug-gene interactions.

In order to clarify the risk of hematotoxicity of carboplatin, we inspected 19901 case reports of non-small cell lung cancer patients that were submitted to the FDA Adverse Event Reporting System (FAERS) between January 2004 and December 2015. These comprised 3907 cases which were treated with carboplatin and 15994 cases which were treated with other therapies in the absence of carboplatin. By comparison, carboplatin cases were significantly more likely to report anemia (OR = 2.27, 95% CI 1.85-2.78, P = 5.04×10-15), neutropenia (OR = 2.27, 95% CI 1.76-2.92, P = 2.39×10-10), and thrombocytopenia (OR = 2.38, 95% CI 1.84-3.08, P = 5.60×10-11). We further explored published evidences and found 205 human genes interacting with carboplatin. Functional analysis corroborated that these genes were significantly enriched in the biochemical pathway of hematopoietic cell lineage (adjusted P = 6.02×10-11). This indicated that carboplatin could profoundly affect the development of blood cells. Given the early awareness of the hematologic risks, great caution should be exercised in prescribing carboplatin to non-small cell lung cancer patients. And functional enrichment analysis on carboplatin-related genes warranted subsequent research with regard to the underlying toxicological mechanisms.

A long-acting ß2-adrenergic agonist increases the expression of muscarine cholinergic subtype­3 receptors by activating the ß2-adrenoceptor cyclic adenosine monophosphate signaling pathway in airway smooth muscle cells.

The persistent administration of ß2­adrenergic (ß2AR) agonists has been demonstrated to increase the risk of severe asthma, partly due to the induction of tolerance to bronchoprotection via undefined mechanisms. The present study investigated the potential effect of the long­acting ß2­adrenergic agonist, formoterol, on the expression of muscarinic M3 receptor (M3R) in rat airway smooth muscle cells (ASMCs). Primary rat ASMCs were isolated and characterized following immunostaining with anti­α­smooth muscle actin antibodies. The protein expression levels of M3R and phospholipase C­ß1 (PLCß1) were characterized by western blot analysis and the production of inositol 1,4,5­trisphosphate (IP3) was determined using an enzyme­linked immunosorbent assay. Formoterol increased the protein expression of M3R in rat ASMCs in a time­ and dose­dependent manner, which was significantly inhibited by the ß2AR antagonist, ICI118,551 and the cyclic adenosine monophosphate (cAMP) inhibitor, SQ22,536. The increased protein expression of M3R was positively correlated with increased production of PLCß1 and IP3. Furthermore, treatment with the glucocorticoid, budesonide, and the PLC inhibitor, U73,122, significantly suppressed the formoterol­induced upregulated protein expression levels of M3R and PLCß1 and production of IP3. The present study demonstrated that formoterol mediated the upregulation of M3R in the rat ASMCs by activating the ß2AR­cAMP signaling pathway, resulting in increased expression levels of PLCß1 and IP3, which are key to inducing bronchoprotection tolerance. Administration of glucocorticoids or a PLC antagonist prevented formoterol­induced bronchoprotection tolerance by suppressing the protein expression of M3R.

Andrographolide protects against LPS-induced acute lung injury by inactivation of NF-κB.

BACKGROUND: Nuclear factor-κB (NF-κB) is a central transcriptional factor and a pleiotropic regulator of many genes involved in acute lung injury. Andrographolide is found in the plant of Andrographis paniculata and widely used in Traditional Chinese Medicine, exhibiting potently anti-inflammatory property by inhibiting NF-κB activity. The purpose of our investigation was designed to reveal the effect of andrographolide on various aspects of LPS induced inflammation in vivo and in vitro. METHODS AND RESULTS: In vivo, BALB/C mice were subjected to LPS injection with or without andrographolide treatments to induce ALI model. In vitro, MLE-12 cells were stimulated with LPS in the presence and absence of andrographolide. In vivo, pulmonary inflammation, pulmonary edema, ultrastructure changes of type II alveolar epithelial cells, MPO activity, total cells, neutrophils, macrophages, TNF-α, IL-6 and IL-1ß in BALF, along with the expression of VCAM-1 and VEGF were dose-dependently attenuated by andrographolide. Meanwhile, in vitro, the expression of VCAM-1 and VEGF was also reduced by andrographolide. Moreover, our data showed that andrographolide significantly inhibited the ratios of phospho-IKKß/total IKKß, phospho-IκBα/total IκBα and phospho-NF-κB p65/total NF-κB p65, and NF-κB p65 DNA binding activities, both in vivo and in vitro. CONCLUSIONS: These results indicate that andrographolide dose-dependently suppressed the severity of LPS-induced ALI, more likely by virtue of andrographolide-mediated NF-κB inhibition at the level of IKKß activation. These results suggest andrographolide may be considered as an effective and safe drug for the potential treatment of ALI.

Rosuvastatin attenuates mucus secretion in a murine model of chronic asthma by inhibiting the gamma-aminobutyric acid type A receptor.

BACKGROUND: Asthma is a chronic inflammatory disease characterized by reversible bronchial constriction, pulmonary inflammation and airway remodeling. Current standard therapies for asthma provide symptomatic control, but fail to target the underlying disease pathology. Furthermore, no therapeutic agent is effective in preventing airway remodeling. A substantial amount of evidence suggests that statins have anti-inflammatory properties and immunomodulatory activity. In this study, we investigated the effect of rosuvastatin on airway inflammation and its inhibitory mechanism in mucus hypersecretion in a murine model of chronic asthma. METHODS: BALB/c mice were sensitized and challenged by ovalbumin to induce asthma. The recruitment of inflammatory cells into bronchoalveolar lavage fluid (BALF) and the lung tissues were measured by Diff-Quik staining and hematoxylin and eosin (H&E) staining. ELISA was used for measuring the levels of IL-4, IL-5, IL-13 and TNF-α in BALF. Periodic acid-Schiff (PAS) staining was used for mucus secretion. Gamma-aminobutyric acid type A receptor (GABAAR) ß2 expression was measured by means of immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. RESULTS: Rosuvastatin reduced the number of total inflammatory cells, lymphocytes, macrophages, neutrophils, and eosinophils recruited into BALF, the levels of IL-4, IL-5, IL-13 and TNF-α in BALF, along with the histological mucus index (HMI) and GABAAR ß2 expression. Changes occurred in a dose-dependent manner. CONCLUSIONS: Based on its ability to reduce the inflammatory response and mucus hypersecretion by regulating GABAAR activity in a murine model of chronic asthma, rosuvastatin may be a useful therapeutic agent for treatment of asthma.

[Effect of RNA interference on CTGF expression and collagen synthesis induced by hypoxia in rat cardiac fibroblasts].

OBJECTIVE: To investigate the effect of the lentiviral vector pGCL-GFP transferred connective tissue growth factor (CTGF) short hairpin RNA (CTGF-ShRNA) on CTGF expression, cell proliferation and collagen synthesis induced by hypoxia in rat cardiac fibroblasts (CFs). METHODS: CTGF-ShRNA plasmids successfully constructed and screened. CFs of adult Sprague-Dawley (SD) rats isolated with the method of trypsin digestion and differential anchoring velocity which randomly divided into the control group, the hypoxia group, Hypo+pGCL-GFP group and Hypo+CTGF-ShRNA group. The mRNA and protein levels of CTGF were detected by means of semi-quantitative reverse transcriptional polymerase chain reaction (RT-PCR) and Western blot 24 h later. Proliferation of CFs was observed by WST-1 coloricmetric assay and synthesis of collagen was observed by the hydroxyproline. RESULTS: Successfully constructed and screened CTGF short hairpin RNA. Compared with control group, the expression of CTGF mRNA and protein levels induced by hypoxia in CFs were markedly up-regulated in Hypoxia, Hypo + pGCL-GFP and Hypo + CTGF-ShRNA group (P < 0.05). CFs proliferation and collagen synthesis in Hypoxia, Hypo+pGCL-GFP and Hypo+CTGF-ShRNA group were significantly higher than that of the control group (P < 0.05). In comparison to Hypoxia and Hypo+pGCL-GFP group, the CTGF mRNA and protein levels induced by hypoxia in CFs were markedly down-regulated in Hypo + CTGF-ShRNA group (P < 0.01). CFs proliferation and collagen synthesis in Hypo+CTGF-ShRNA group were significantly lower than that of the Hypoxia and Hypo+pGCL-GFP group (P < 0.01). CONCLUSION: CTGF mRNA and protein expression, CFs proliferation and collagen synthesis induced by hypoxia in CFs effectively inhibited by CTGF-ShRNA.