Upregulation of Chemoresistance by Mg2+ Deficiency through Elevation of ATP Binding Cassette Subfamily B Member 1 Expression in Human Lung Adenocarcinoma A549 Cells

Several anticancer drugs including cisplatin (CDDP) induce hypomagnesemia. However, it remains fully uncertain whether Mg2+ deficiency affects chemosensitivity of cancer cells. Here, we investigated the effect of low Mg2+ concentration (LM) on proliferation and chemosensitivity using human lung adenocarcinoma A549 cells. Cell proliferation was reduced by continuous culture with LM accompanied with the elevation of G1 phase proportion. The amounts of reactive oxygen species (ROS) and stress makers such as phosphorylated-ataxia telangiectasia mutated and phosphorylated-p53 were increased by LM. Cell injury was dose-dependently increased by anticancer drugs such as CDDP and doxorubicin (DXR), which were suppressed by LM. Similar results were obtained by roscovitine, a cell cycle inhibitor. These results suggest that LM induces chemoresistance mediated by ROS production and G1 arrest. The mRNA and protein levels of ATP binding cassette subfamily B member 1 (ABCB1) were increased by LM and roscovitine. The LM-induced elevation of ABCB1 and nuclear p38 expression was suppressed by SB203580, a p38 MAPK inhibitor. PSC833, an ABCB1 inhibitor, and SB203580 rescued the sensitivity to anticancer drugs. In addition, cancer stemness properties were suppressed by SB203580. We suggest that Mg2+ deficiency reduces the chemotherapy sensitivity of A549 cells, although it suppresses cell proliferation

Persistent metamorphopsia associated with branch retinal vein occlusion.

PURPOSE:To investigate longitudinal changes in metamorphopsia associated with branch retinal vein occlusion. METHODS:In this prospective observational case series, we included 32 eyes (32 patients) with branch retinal vein occlusion and acute macular edema. Eyes were treated as needed with intravitreal ranibizumab injections for 12 months. At baseline and 1, 6, and 12 months after initiating treatment, metamorphopsia was quantified using M-CHARTS. Retinal morphology was examined through optical coherence tomography. RESULTS:Logarithm of the minimum angle of resolution visual acuity progressively improved from 0.342 ± 0.304 (Snellen equivalent: 20/44) at baseline to 0.199 ± 0.259 (20/32) and 0.118 ± 0.195 (20/26) at 1 and 12 months, respectively (both P < 0.001). The M-CHARTS score significantly decreased from 0.63 ± 0.61 at baseline to 0.45 ± 0.50 at 1 month (P = 0.044), but no further improvement was achieved with 1 year of additional treatment (6 months: 0.47 ± 0.53 [P = 0.094] and 12 months: 0.50 ± 0.44 [P = 0.173]). Three (13.6%) of 22 eyes with baseline metamorphopsia had complete metamorphopsia resolution. At 12 months, the M-CHARTS score was correlated with baseline foveal thickness (r = 0.373, P = 0.035) and the baseline M-CHARTS score (r = 0.503, P = 0.003). A multiple regression analysis revealed that only the baseline M-CHARTS score was correlated with the 12-month M-CHARTS score (β = 0.460, P = 0.027). CONCLUSIONS:Eyes with branch retinal vein occlusion often have persistent metamorphopsia, even when visual acuity and retinal morphology improve. Metamorphopsia at 12 months was correlated with metamorphopsia and foveal thickness at baseline

Stable isotope-labeled carnitine reveals its rapid transport into muscle cells and acetylation during contraction

Carnitine plays multiple roles in skeletal muscle metabolism, including fatty acid transport and buffering of excess acetyl-CoA in the mitochondria. The skeletal muscle cannot synthesize carnitine; therefore, carnitine must be taken up from the blood into the cytoplasm. Carnitine metabolism, its uptake into cells, and the subsequent reactions of carnitine are accelerated by muscle contraction. Isotope tracing enables the marking of target molecules and monitoring of tissue distribution. In this study, stable isotope-labeled carnitine tracing was combined with matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) imaging to determine carnitine distribution in mouse skeletal muscle tissues. Deuterium-labeled carnitine (d3-carnitine) was intravenously injected into the mice and diffused to the skeletal muscles for 30 and 60 min. To examine whether muscle contraction changes the distribution of carnitine and its derivatives, unilateral in situ muscle contraction was performed; 60 min muscle contraction showed increased d3-carnitine and its derivative d3-acetylcarnitine in the muscle, indicating that carnitine uptake in cells is promptly converted to acetylcarnitine, consequently, buffering accumulated acetyl-CoA. While the endogenous carnitine was localized in the slow type fibers rather than fast type, the contraction-induced distributions of d3-carnitine and acetylcarnitine were not necessarily associated with muscle fiber type. In conclusion, the combination of isotope tracing and MALDI-MS imaging can reveal carnitine flux during muscle contraction and show the significance of carnitine in skeletal muscles

Dupilumab suppresses relapsing chronic eosinophilic pneumonia with severe asthma

Dupilumab-induced hypereosinophilia is mediated by blockade of the IL-4/IL-13 pathway, which reduces eosinophil migration from peripheral blood. The increase in peripheral blood eosinophils may lead to chronic eosinophilic pneumonia (CEP) and/or eosinophilic granulomatosis with polyangiitis, but a direct causal connection between dupilumab and eosinophilic lung diseases has not been established. A 33-year-old Japanese woman with bronchial asthma since age three was treated with fluticasone propionate plus salmeterol twice daily after several asthma exacerbations at age 17. Her course was complicated by CEP at age 33 which resolved without the need for systemic steroids. However, in the four months following resolution of her CEP, the patient had three asthma exacerbations, and a recurrence of CEP, with blood leukocytes of 8500/µL, of which 25.0% were eosinophils. She was treated with prednisolone 50 mg/day, but she could not continue this dose due to the onset of myalgia. Then she had relapsing CEP twice within three months. She was treated with prednisolone 15 mg/day for CEP, but she had persistent asthma for more than one month; dupilumab was added at 600 mg, followed by 300 mg every two weeks. In the first month of treatment with dupilumab, the patient’s asthma symptoms resolved completely, and she had only one relapse of CEP. In 12 months of follow-up, she had neither an asthma exacerbation nor another relapse of CEP. Dupilumab may be a promising treatment for patients with refractory asthma complicated by recurring CEP and undesirable steroid side effects

Determination of the critical chain length for macromolecular crystallization using structurally flexible polyketones

Critical chain length that divides small molecule crystallization from macromolecular crystallization is an important index in macro-organic chemistry to predict chain-length dependent properties of oligomers and polymers. However, extensive research on crystallization behavior of individual oligomers has been inhibited by difficulties in their synthesis and crystallization. Here, we report on the determination of critical chain length of macromolecular crystallization for structurally flexible polyketones consisting of 3,3-dimethylpentane-2,4-dione. Discrete polyketone oligomers were synthesized via stepwise elongation up to 20-mer. Powder and single crystal X-ray diffraction showed that the critical chain length for polyketones existed at an unexpectedly short chain length, 5-mer. While shorter oligomers adopted unique conformations and packing structures in the solid state, higher oligomers longer than 4-mer produced helical conformations and similar crystal packing. The critical chain length helped with understanding the inexplicable changes in melting point in the shorter chain length region resulting from chain conformations and packing styles