The Cholinergic Pathways in Inflammation: A Potential Pharmacotherapeutic Target for COPD

In COPD, the activity of the cholinergic system is increased, which is one of the reasons for the airflow limitation caused by the contraction of airway smooth muscles. Therefore, blocking the contractive actions with anticholinergics is a useful therapeutic intervention to reduce the airflow limitation. In addition to the effects of bronchoconstriction and mucus secretion, accumulating evidence from animal models of COPD suggest acetylcholine has a role in inflammation. Experiments using muscarinic M3-receptor deficient mice or M3 selective antagonists revealed that M3-receptors on parenchymal cells, but not on hematopoietic cells, are involved in the pro-inflammatory effect of acetylcholine. Recently, combinations of long-acting β2 adrenergic agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) have become available for COPD treatment. These dual long-acting bronchodilators may have synergistic anti-inflammatory effects because stimulation of β2 adrenergic receptors induces inhibitory effects in inflammatory cells via a different signaling pathway from that by antagonizing M3-receptor, though these anti-inflammatory effects have not been clearly demonstrated in COPD patients. In contrast to the pro-inflammatory effects by ACh via muscarinic receptors, it has been demonstrated that the cholinergic anti-inflammatory pathway, which involves the parasympathetic nervous systems, regulates excessive inflammatory responses to protect organs during tissue injury and infection. Stimulation of acetylcholine via the α7 nicotinic acetylcholine receptor (α7nAChR) exerts inhibitory effects on leukocytes including macrophages and type 2 innate lymphoid cells. Although it remains unclear whether the inhibitory effects of acetylcholine via α7nAChR in inflammatory cells can regulate inflammation in COPD, neuroimmune interactions including the cholinergic anti-inflammatory pathway might serve as potential therapeutic targets

Biochemical analyses of lipids deposited on silicone hydrogel lenses

AbstractPurposeThis study was performed to determine the levels of lipids deposited on in vivo worn silicone hydrogel lenses.MethodsThree silicone hydrogel materials, galyfilcon A, senofilcon A, and asmofilcon A, were worn for 2 weeks by 35 normal subjects. Total lipid deposition was determined by the sulfo-phospho-vanillin reaction. Cholesterol was estimated by a colorimetric probe through enzymatic oxidation. Phospholipid level was estimated by determining phosphorus with ammonium molybdate through enzymatic digestion.ResultsThe total lipid content recovered from galyfilcon A, senofilcon A, and asmofilcon A was 32.9 ± 33.8, 42.1 ± 14.0, and 36.6 ± 31.9 μg/lens, respectively. The cholesterol content recovered from galyfilcon A, senofilcon A, and asmofilcon A was 26.2 ± 26.9, 28.6 ± 19.4, and 31.1 ± 21.1 μg/lens, respectively. There were no statistically significant differences in total lipids and cholesterol among the contact lens types. However, the quantity of phospholipid recovered from the asmofilcon A (7.0 ± 5.5 μg/lens) lenses was significantly higher than from galyfilcon A (1.1 ± 0.8 μg/lens) and senofilcon A (2.4 ± 0.8 mg/lens) lenses (p < 0.05, Mann-Whitney test).ConclusionsThe quantity of total lipid and cholesterol deposited on the 3 silicone hydrogel lenses tested did not differ. However, there were significant differences in the amounts of phospholipid deposited among the 3 silicone hydrogel lenses, of which clinical significance should be explored in the future study

A case of Langerhans cell sarcoma on the scalp: Whole‐exome sequencing reveals a role of ultraviolet in the pathogenesis

Langerhans cell sarcoma (LCS) is a high‐grade neoplasm with overtly malignant cytological features and a Langerhans cell phenotype. The underlying genetic features are poorly understood, and only a few alterations, such as those of the MARK pathway‐related genes, CDKN2A and TP53 have been reported. Here we present a 70‐year‐old male with LCS on the scalp and pulmonary metastasis. The multinodular tumor, 3.0 cm in diameter, consisted of diffusely proliferated pleomorphic cells with numerous mitoses (53/10 HPFs). Immunohistochemically, the tumor cells were positive for CD1a, Langerin and PD‐L1, and the Ki‐67 labeling index was 50%. These pathological features were consistent with LCS, and were also observed in the metastatic tumor. Whole‐exome sequencing revealed that both the primary and metastatic tumors harbored a large number of mutations (>20 mutations/megabase), with deletion of CDKN2A and TP53 mutation, and highlighted that the mutational signature was predominantly characteristic of ultraviolet (UV) exposure (W = 0.828). Our results suggest, for the first time, that DNA damage by UV could accumulate in Langerhans cells and play a role in the pathogenesis of LCS. The high mutational burden and PD‐L1 expression in the tumor would provide a rationale for the use of immune checkpoint inhibitors for treatment of unresectable LCS

Preparations of melatonin and 1-hydroxymelatonin, and its novel nucleophilic dimerization to (±)-3a,3a\u27-bispyrrolo[2,3-b]indoles

金沢大学大学院自然科学研究科生理活性物質科学金沢大学薬学部A unique synthetic method for melatonin was established through biologically promising synthetic intermediates. 1-Hydroxymelatonin was prepared as crystals for the first time. It reacted with 85% formic acid to give (±)-3a,3a\u27-bispyrrolo[2,3-b]indole compound, whose structure was unequivocally determined by X-Ray crystallographic analysi

A novel methodology for preparing 5-chloro- and 5-bromotryptamines and tryptophans, and its application to the synthesis of (±)-bromochelonin B

金沢大学大学院自然科学研究科生理活性物質科学金沢大学薬学部A novel methodology for introducing chlorine or bromine into the 5- position of tryptamines was found through 1-hydroxytryptamines. The chemistry was applied to the syntheses of (±)-5-chloro-, -5-bromotryptophan derivatives, and (±)-bromochelonin B