Cystamine induces AIF-mediated apoptosis through glutathione depletion

AbstractCystamine and its reduced form cysteamine showed protective effects in various models of neurodegenerative disease, including Huntington's disease and Parkinson's disease. Other lines of evidence demonstrated the cytotoxic effect of cysteamine on duodenal mucosa leading to ulcer development. However, the mechanism for cystamine cytotoxicity remains poorly understood. Here, we report a new pathway in which cystamine induces apoptosis by targeting apoptosis-inducing factor (AIF). By screening of various cell lines, we observed that cystamine and cysteamine induce cell death in a cell type-specific manner. Comparison between cystamine-sensitive and cystamine-resistant cell lines revealed that cystamine cytotoxicity is not associated with unfolded protein response, reactive oxygen species generation and transglutaminase or caspase activity; rather, it is associated with the ability of cystamine to trigger AIF nuclear translocation. In cystamine-sensitive cells, cystamine suppresses the levels of intracellular glutathione by inhibiting γ-glutamylcysteine synthetase expression that triggers AIF translocation. Conversely, glutathione supplementation completely prevents cystamine-induced AIF translocation and apoptosis. In rats, cysteamine administration induces glutathione depletion and AIF translocation leading to apoptosis of duodenal epithelium. These results indicate that AIF translocation through glutathione depletion is the molecular mechanism of cystamine toxicity, and provide important implications for cystamine in the neurodegenerative disease therapeutics as well as in the regulation of AIF-mediated cell death

Etomidate Should be Used Carefully for Emergent Endotracheal Intubation in Patients with Septic Shock

Etomidate and midazolam are the most popular drugs among the induction agents for emergent endotracheal intubation. The purpose of this study was to compare the incidence of adrenal insufficiency and mortality between the septic shock patients who received etomidate (ETM group) and those who received midazolam (MDZ group). Between November 2004 and September 2006, 65 patients were analyzed in this study. The hospital mortality rate was 36% in the ETM group (n=25) and 50% in the MDZ group (n=40), which was not statistically significant (p=0.269). The incidence of relative adrenal insufficiency was significantly higher in the ETM group than in the MDZ group (84% and 48%, respectively; p=0.003). On multivariate analysis, the use of etomidate was the only significant factor affecting the incidence of relative adrenal insufficiency (odds radio, 5.59; 95% confidence interval, 1.61-19.4). In conclusion, we think that physicians who treat patients with septic shock should be aware that etomidate can cause adrenal insufficiency, and should start corticosteroids if etomidate is administered

Radiosensitization with combined use of olaparib and PI-103 in triple-negative breast cancer

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.Abstract Background Triple-negative breast cancer (TNBC) shows aggressive clinical behavior, but the treatment options are limited due to lack of a specific target. TNBC shares many clinical and pathological similarities with BRCA-deficient breast cancer, for which poly(ADP-ribose) polymerase (PARP) inhibitor is effective, but PARP inhibitor alone failed to show clinical effects in patients with sporadic TNBC. Radiation induces DNA double-strand breaks, and the phosphoinositide 3-kinase (PI3K) signaling pathway has been known to regulate steady-state levels of homologous recombination. A recent preclinical study showed that PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient TNBC to PARP inhibition. Therefore, we assessed the radiosensitizing effect, and the underlying mechanism of combination treatment with PARP inhibitor olaparib and PI3K inhibitor PI-103 in BRCA-proficient TNBC cells. Methods MDA-MB-435S cells were divided into four treatment groups, irradiation (IR) alone, olaparib plus IR, PI-103 plus IR, and olaparib plus PI-103 plus IR. Cells were exposed to the drugs for 2 hours prior to irradiation, and the cell survival curve was obtained using a clonogenic assay. Western blotting and immunofluorescent detection of γH2AX foci were performed. Xenograft and bioluminescence imaging were carried out to assess in vivo radiosensitivity. Results Combined use of olaparib and PI-103 enhanced radiation-induced death of MDA-MB-435S (sensitizer enhancement ratio[SER]0.05,1.7) and MDA-MB-231-BR (SER0.05,2.1) cells and significantly reduced tumor volume in a xenograft models (P < 0.001). Treatment with PI-103 showed persistent γH2AX foci, indicating delayed repair of DNA strand breaks. PI-103 alone increased levels of poly(ADP-ribose) and phosphorylated extracellular signal-regulated kinase, and downregulated BRCA1. Conclusions Combined use of olaparib and PI-103 enhanced radiation-induced cell death in BRCA-proficient MDA-MB-435S and MDA-MB-231-BR cells and xenografts. TNBC patients have high incidences of locoregional relapse and distant metastasis, and radiation therapy targets both locoregional control and treatment of distant recurrences such as brain metastasis or other oligometastasis. Targeting of the PI3K signaling pathway combined with PARP inhibition maybe a feasible approach to enhance effects of radiation in BRCA-proficient TNBC

Establishing molecular pathology curriculum for pathology trainees and continued medical education: a collaborative work from the Molecular Pathology Study Group of the Korean Society of Pathologists

Background The importance of molecular pathology tests has increased during the last decade, and there is a great need for efficient training of molecular pathology for pathology trainees and as continued medical education. Methods The Molecular Pathology Study Group of the Korean Society of Pathologists appointed a task force composed of experienced molecular pathologists to develop a refined educational curriculum of molecular pathology. A 3-day online educational session was held based on the newly established structure of learning objectives; the audience were asked to score their understanding of 22 selected learning objectives before and after the session to assess the effect of structured education. Results The structured objectives and goals of molecular pathology was established and posted as a web-based interface which can serve as a knowledge bank of molecular pathology. A total of 201 pathologists participated in the educational session. For all 22 learning objectives, the scores of self-reported understanding increased after educational session by 9.9 points on average (range, 6.6 to 17.0). The most effectively improved items were objectives from next-generation sequencing (NGS) section: ‘NGS library preparation and quality control’ (score increased from 51.8 to 68.8), ‘NGS interpretation of variants and reference database’ (score increased from 54.1 to 68.0), and ‘whole genome, whole exome, and targeted gene sequencing’ (score increased from 58.2 to 71.2). Qualitative responses regarding the adequacy of refined educational curriculum were collected, where favorable comments dominated. Conclusions Approach toward the education of molecular pathology was refined, which would greatly benefit the future trainees

Immunophenotyping of COVID-19 and influenza highlights the role of type I interferons in development of severe COVID-19

Although most SARS-CoV-2-infected individuals experience mild coronavirus disease 2019 (COVID-19), some patients suffer from severe COVID-19, which is accompanied by acute respiratory distress syndrome and systemic inflammation. To identify factors driving severe progression of COVID-19, we performed single-cell RNA-seq using peripheral blood mononuclear cells (PBMCs) obtained from healthy donors, patients with mild or severe COVID-19, and patients with severe influenza. Patients with COVID-19 exhibited hyper-inflammatory signatures across all types of cells among PBMCs, particularly up-regulation of the TNF/IL-1 beta-driven inflammatory response as compared to severe influenza. In classical monocytes from patients with severe COVID-19, type I IFN response co-existed with the TNF/IL-1 beta-driven inflammation, and this was not seen in patients with milder COVID-19. Interestingly, we documented type I IFN-driven inflammatory features in patients with severe influenza as well. Based on this, we propose that the type I IFN response plays a pivotal role in exacerbating inflammation in severe COVID-19

Identification of a novel antiapoptotic protein that antagonizes ASK1 and CAD activities

Diverse stimuli initiate the activation of apoptotic signaling pathways that often causes nuclear DNA fragmentation. Here, we report a new antiapoptotic protein, a caspase-activated DNase (CAD) inhibitor that interacts with ASK1 (CIIA). CIIA, by binding to apoptosis signal-regulating kinase 1 (ASK1), inhibits oligomerization-induced ASK1 activation. CIIA also associates with CAD and inhibits the nuclease activity of CAD without affecting caspase-3–mediated ICAD cleavage. Overexpressed CIIA reduces H2O2- and tumor necrosis factor-α–induced apoptosis. CIIA antisense oligonucleotides, which abolish expression of endogenous CIIA in murine L929 cells, block the inhibitory effect of CIIA on ASK1 activation, deoxyribonucleic acid fragmentation, and apoptosis. These findings suggest that CIIA is an endogenous antagonist of both ASK1- and CAD-mediated signaling

CIIA functions as a molecular switch for the Rac1-specific GEF activity of SOS1

CIIA mediates the TGF-β–induced activation of SOS1–Rac1 signaling and cell migration

The effectiveness of moxibustion for the treatment of functional constipation: a randomized, sham-controlled, patient blinded, pilot clinical trial

<p>Abstract</p> <p>Background</p> <p>Moxibustion is an ancient traditional medicine using burning mugworts to stimulate acupuncture points. The aim of this study was to investigate the safety and efficacy of moxibustion for the treatment of constipation using a randomized, sham-controlled, participant-blinded, pilot trial.</p> <p>Methods</p> <p>Twenty-six participants (identified with either qi (vital energy) deficiency or qi excess syndrome) were randomly divided into either a moxibustion or sham group. Participants were treated with real or sham moxibustion at 4 acupuncture points, ST23 and ST27, bilaterally, 3 times per week for four weeks. The primary outcome was the frequency of defecations; secondary outcomes were the Bristol stool form scale (BSS) and the constipation assessment scale (CAS).</p> <p>Results</p> <p>Of the 26 participants that were randomized, 24 completed the study. Defecation frequency, BSS, and CAS showed no difference between the moxibustion and sham groups. The differences were -0.25 (95% CI: -2.08, 1.58, p = 0.78), -1.22 (95% CI: -2.7, 0.26, p = 0.1), 0.91 (95% CI: -1.46, 3.28, p = 0.44) in defecation frequency, BSS, CAS, respectively. The defecation frequency increased from an average of 3.3 to 4.6 times per week in the moxibustion group (1.5[-0.5, 2], <it>p </it>= 0.06) and from 2.7 to 3.7 stools per week in the sham group (1[-1, 2], <it>p </it>= 0.15) after four weeks of treatment. The difference between participants with a deficiency or an excess syndrome, determined based on assessment of sweat, facial features, pain, body energy, and pulse type, was significant in only defecation frequency. The difference was 3.3 (95% CI: 0.41, 6.19, <it>p </it>= 0.03).</p> <p>Conclusion</p> <p>Moxibustion treatment appears safe, but showed no positive effect on constipation. The effectiveness of moxibustion treatment may depend on the syndrome pattern, and further long-term studies with a larger number of subjects are warranted.</p> <p>Trial registration</p> <p>Clinical Research Information Service, KCT0000168</p

Spin crossover in the cyanide-bridged Mo(V)Mn(III) single-chain magnet containing Fe(II) cations

A 1D Mo(V)Mn(III) chain compound balanced by {Fe[ HC(3,5-Me(2)pz)(3)](2)}(2+) dications was prepared. This complex displays a typical single-chain magnet character associated with the Mo(V)Mn(III) chain and a spin crossover phenomenon arising from cationic Fe(II) subunits. The spin crossover behavior tends to slightly affect single-chain magnetic properties at low temperature.National Research Foundation of Korea; Korean Government[2011-0003264]; Ministry of Education, Science and Technology[NRF20110018396