Although much is known regarding intestinal stem cell (ISC) self-renewal and differentiation, the specific mechanisms used for their elimination is unclear. We recently discovered that the pro-apoptotic protein ARTS, a isoform, interacts with X-linked inhibitor of apoptosis (XIAP) in the ISC niche to regulate stem cell survival during intestinal homeostasis and regeneration. These findings point to an intriguing avenue of translational research, examining how manipulation of stem cell apoptosis through the ARTS/XIAP module can affect stem-cell-dependent processes.
Iron overload is a major complication in transfusion-dependent thalassemia (TDT) patients. Chronic oxidative stress from iron overload may lead to cellular damage and viability. This is a cross-sectional study. Transfusion-dependent thalassemia patients aged ⩾18 years old were enrolled. Transfusion-dependent thalassemia patient’s serum and normal volunteer’s serum were separately incubated with healthy peripheral blood mononuclear cells (PBMCs). The cell viability was measured by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay at 24, 48, and 72 hours. Sixty-nine TDT patients and 22 healthy controls were enrolled. The mean of PBMCs viability after incubation with serum from TDT patients was lower than that with the controls (88.65% vs 103.56% at 24 hours, 78.77% vs 112.04%% at 48 hours, and 71.18% vs 132.16%% at 72 hours, respectively). High serum ferritin level (correlation −0.29, P < .05) and white blood cell (WBC) count negatively affected cell viability (correlation −2.86, P = .05). From multivariate analysis, serum ferritin level is the only significant risk factor that is independently associated with cell viability (correlation −11.42, P < .001). Our findings showed that TDT patient’s serum causes decreased cell viability. Serum ferritin level was a significant independent factor influencing cell viability.
Iron overload is a major complication in transfusion-dependent thalassemia (TDT) patients. Chronic oxidative stress from iron overload may lead to cellular damage and viability. This is a cross-sectional study. Transfusion-dependent thalassemia patients aged ⩾18 years old were enrolled. Transfusion-dependent thalassemia patient's serum and normal volunteer's serum were separately incubated with healthy peripheral blood mononuclear cells (PBMCs). The cell viability was measured by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay at 24, 48, and 72 hours. Sixty-nine TDT patients and 22 healthy controls were enrolled. The mean of PBMCs viability after incubation with serum from TDT patients was lower than that with the controls (88.65% vs 103.56% at 24 hours, 78.77% vs 112.04%% at 48 hours, and 71.18% vs 132.16%% at 72 hours, respectively). High serum ferritin level (correlation -0.29, < .05) and white blood cell (WBC) count negatively affected cell viability (correlation -2.86, = .05). From multivariate analysis, serum ferritin level is the only significant risk factor that is independently associated with cell viability (correlation -11.42, < .001). Our findings showed that TDT patient's serum causes decreased cell viability. Serum ferritin level was a significant independent factor influencing cell viability.
Active caspase-3-mediated apoptosis has been implicated in the pathogenesis of harmaline-induced tremor. The aim of this study is to illustrate the impact of tremor induction on the expression of factors mediating the cell surface death receptor–dependent apoptosis. A total of 20 normal Wistar rats were randomly selected and equally divided into control and experimental groups. Tremor was induced in the experimental group by injecting the rats with a single dose of harmaline (50 mg/kg). After that, cerebellar tissues were evaluated by immunohistochemistry to examine the expression of tumor necrosis factor α (TNF-α) and active caspase-8 in the 2 groups of animals. TNF-α and active caspase-8 expression was significantly higher in cerebella from experimental rats compared with that in those from the control rats (P value < .01). Thus, our present data suggest the association of tremor induction with the cerebellar overexpression of TNF-α and active caspase-8, correlative with Purkinje cell (PC) loss indicated by loss of calbindin immunoreactivity, indicating the induction of the cell surface death receptor–mediated apoptosis.
Postoperative cognitive dysfunction (POCD) has been one of the most common problems in elderly patients following surgery. But the specific mechanism of POCD is still not clear. To further understand the reason of these postoperative behavioral deficits, we evaluated the spatial learning memory of both adult (3 months) and aged (18 months) male mice, 3 or 28 days after isoflurane (Iso) exposure for two hours or appendectomy (App). Hippocampal microglia activation and IL-1β, TNF-α, and IFN-γ expression were also evaluated at day 3, day 14 and day 28 after Iso exposure or appendectomy. Results showed that spatial learning memory of aged, but not adult, mice was impaired after Iso exposure or appendectomy, accompanied with more hippocampal microglia activation and IL-1β, TNF-α, and IFN-γ overexpression. These findings suggest that the cognitive deficits of elderly patients who have undergone surgeries are quite possibly caused by hippocampal microglia overactivation and the subsequent inflammation.
Patients with chronic hepatitis C virus (HCV) infection risk complications of cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Previously, our proteomic examination of hepatocytes carrying a HCV-replicon revealed that deregulation of cytoskeletal dynamics may be a potential mechanism of viral-induced HCC growth. Here, we demonstrate the effect of HCV replication on the microtubule regulator stathmin (STMN1) in HCC cells. We further explore how the altered activity or synthesis of stathmin affects cellular proliferation and sensitivity to apoptosis in control HCC cells (Huh7.5) and experimental HCV-replicon harboring HCC cells (R-Huh7.5). The HCV-replicon harboring HCC cells (R-Huh 7.5) lack viral structural genes/proteins for acute infectivity and thus is the standard model for in vitro chronic infection study. Knockdown of endogenous stathmin reduced sensitivity to apoptosis in replicon cells. Meanwhile, constitutively active stathmin increased sensitivity to apoptosis in replicon cells. In addition, overexpression of constitutively active stathmin reduced cell proliferation in both control and replicon cells. These findings implicate, for the first time, a novel role for stathmin in viral replication–related apoptosis. Stathmin’s potential role in HCV replication and HCC make it a candidate for the future study of viral-induced malignancies.
Neisseria gonorrhoeae, the human obligate pathogen responsible for the sexually transmitted disease gonorrhea, has evolved several mechanisms to evade the host immune response. One such mechanism is the modulation of host cell death pathways. In this study, we defined cell death pathways induced by N gonorrhoeae in human monocyte-derived macrophages (MDMs). In a dose-dependent manner, N gonorrhoeae stimulation of MDMs resulted in caspase 1 and 4–dependent cell deaths, indicative of canonical and noncanonical pyroptosis, respectively. Internalization of bacteria or stimulation with lipooligosaccharide (LOS) specifically induced pyroptosis in MDMs and increased secretion of IL-1β. Collectively, our results demonstrate that N gonorrhoeae induces inflammatory pyroptosis in human macrophages due in part to intracellular LOS. We propose that this in turn may exacerbate inflammatory outcomes observed during mucosal infection.
Programmed cell death (PCD) is genetically regulated phenomenon of selective elimination of target cells that are either under pathological conditions or unwanted for organism’s normal growth and development due to other reasons. The process although being genetically controlled is physiological in nature that renders some hallmarks like blebs in the cell membrane, lobe formation in nuclear membrane, DNA nicks resulting to DNA ladder of 200 bp, and downstream activation of caspases. Moreover, as the process refers to the death of “targeted cell”, the term is exclusively suitable for multicellular organisms. Number of reports advocate similar type of cell death process in unicellular organisms. As cell death in unicellular organisms is also reflected by the signature of PCD obtained in metazoans, such cell death has been grouped under the broad category of PCD. It is pertinent to mention that by definition a unicellular organism is made of a single cell wherein it carries out all of its life processes. Using the term “Programmed Cell Death” with a preset “survival strategy of the organism” for unicellular organisms looks misnomer. Therefore, this correspondence argues and requests recommendation committee on cell death to revisit for the nomenclature of the cell death process in the unicellular organisms.
The use of generic drugs has been increasing. However, studies of the safety of generic cisplatin (CDDP) for the treatment of head and neck cancer (HNC) have not been reported. This study investigated the treatment completion rates and incidence of CDDP-related adverse events in patients with advanced HNC treated with concurrent chemoradiotherapy (CRT) using generic CDDP. This study included 72 patients who received concurrent CRT using generic CDDP. The number of courses of CDDP was 3 in 45 patients, 2 in 19 patients, and 1 in 8 patients. During 154 courses of 80 mg/m2 generic CDDP, grade 3/4 leukopenia in 21 (14%), neutropenia in 18 (12%), and hypochromia in 8 (5%) cases were reported. Grade 2 elevated serum creatinine occurred in 4 cases (3%), but no grade 3/4 elevated serum creatinine was reported. These results suggest that CRT using generic CDDP is well tolerated in patients with HNC.
Objective: Although safety concerns still remain among patients undergoing unanticipated noncardiac surgery after prior percutaneous coronary intervention (PCI), it has not been directly compared with coronary artery bypass grafting (CABG). The objective of this study was to compare clinical outcomes after noncardiac surgery in patients with prior (>6 months) coronary revascularization by PCI or CABG. Methods: From February 2010 to December 2015, 413 patients with a history of coronary revascularization, scheduled for noncardiac surgery were identified. Patients were divided into PCI group and CABG group and postoperative clinical outcome was compared between 2 groups. The primary outcome was composite of all-cause death, myocardial infarction, and stroke in 1-year follow-up. Results: The 413 patients were divided according to prior coronary revascularization types: 236 (57.1%) into PCI and 177 (42.9%) into CABG group. In multivariate analysis within 1-year follow-up, there was no significant difference in clinical outcome which was composite of all-cause death, myocardial infarction, and stroke (hazard ratio [HR]: 1.50; 95% confidence interval [CI]: 0.76-2.93; P = .24). The same result was present in propensity-matched population analysis (HR: 1.43; 95% CI: 0.68-3.0; P = .34). Conclusions: In patients undergoing noncardiac surgery with prior coronary revascularization by PCI or CABG performed on an average of 42 months after PCI and 50 months after CABG, postoperative clinical outcome at 1-year follow-up is comparable.
Programmed cell death (PCD) is genetically regulated phenomenon of selective elimination of target cells that are either under pathological conditions or unwanted for organism's normal growth and development due to other reasons. The process although being genetically controlled is physiological in nature that renders some hallmarks like blebs in the cell membrane, lobe formation in nuclear membrane, DNA nicks resulting to DNA ladder of 200 bp, and downstream activation of caspases. Moreover, as the process refers to the death of "targeted cell", the term is exclusively suitable for multicellular organisms. Number of reports advocate similar type of cell death process in unicellular organisms. As cell death in unicellular organisms is also reflected by the signature of PCD obtained in metazoans, such cell death has been grouped under the broad category of PCD. It is pertinent to mention that by definition a unicellular organism is made of a single cell wherein it carries out all of its life processes. Using the term "Programmed Cell Death" with a preset "survival strategy of the organism" for unicellular organisms looks misnomer. Therefore, this correspondence argues and requests recommendation committee on cell death to revisit for the nomenclature of the cell death process in the unicellular organisms.
Intraventricular hemorrhage (IVH) is a devastating morbidity in preterm infants and can result in poor neurodevelopmental outcomes. Intraventricular hemorrhage usually occurs within 72 hours after birth; post–acute-phase IVH (>1 week after birth) is uncommon. Development of the hemostatic system in fetuses and neonates is an age-dependent evolving process, and the neonatal hemostatic system is characterized by low levels of vitamin K–dependent factors, with further reduction caused by prematurity. Importantly, a severe coagulation deficiency can be a major contributing factor of IVH. Active maternal Crohn disease (CD) during pregnancy causes malnutrition via enteral malabsorption; this may include vitamin K deficiency, resulting in fetal vitamin K deficiency. We herein describe a preterm infant who was born to a mother with CD and developed post–acute-phase IVH due to coagulopathy despite vitamin K administration.
Spleen tyrosine kinase (SYK) is a cytoplasmic enzyme that promotes survival and proliferation of B cells. SYK inhibition has shown promising results in the treatment of arthritis and chronic lymphocytic leukemia (CLL). However, in other context, it has been shown that SYK overexpression in epithelial cancer cells induced senescence in p53-dependent mechanism, which underscored its antineoplastic activity in vitro. Here, we show that SYK was induced in response of DNA damage in parallel with p53 levels. In addition, using chemical inhibitors of SYK reduced p53 levels in HCT116 and HT1080 cell lines, which underlines the role of SYK inhibition on p53 activity. Furthermore, SYK inhibition modulated the cell growth, which resulted in a decreasing in cell death. Interestingly, SYK expression showed a positive prognosis in patients with solid tumors in correlations with their survival rates, as expected negative correlation was seen between SYK expression and survival rate of patients with CLL. In conclusion, these findings demonstrate that SYK inhibition modulates p53 expression and activity in HCT116 and HT1080 cells. Reconsidering using of SYK inhibitors in clinical setting in the future should be evaluated carefully in accordance with these findings to prevent the formation of secondary malignancies.
7-Oxysterols are major toxic components in oxidized low-density lipoprotein and human atheroma lesions, which cause lysosomal membrane permeabilization (LMP) and cell death. Autophagy may function as a survival mechanism in this process. Here, we investigated whether 7-oxysterols mixed in an atheroma-relevant proportion induce autophagy, whether autophagy induction influences 7-oxysterol-mediated cell death, and the underlying mechanisms, by focusing on cellular lipid levels, oxidative stress, and LMP in 7-oxysterol-treated macrophages. We found that 7-oxysterols induced cellular lipid accumulation, autophagy dysfunction, and cell death in the form of both apoptosis and necrosis. Exposure to 7-oxysterols induced autophagic vacuole synthesis in the form of increased autophagy marker microtubule-associated protein 1A/1B-light chain 3 (LC3) and LC3-phosphatidylethanolamine conjugate (LC3-II) and autophagic vacuole formation. This led to an accumulation of p62, indicating a reduction in autophagic vacuole degradation. Importantly, autophagy induction significantly reduced 7-oxysterol-mediated cell death by diminishing LMP and oxidative stress. Moreover, autophagy induction minimized cellular lipid accumulation induced by 7-oxysterols. These findings highlight the importance of autophagy in combating cellular stress, LMP, and cell death in atherosclerosis. Therefore, activation of the autophagy pathway may be a potential therapeutic strategy for prevention of necrotic core formation in atherosclerotic lesions.
Purpose: Oral care in hospitalized patients with psychiatric disorders is important. However, some patients with psychiatric disorders cannot undergo oral care because of psychiatric symptoms and cognitive decline. The effect of a standardized oral hygiene intervention on the prevention of pneumonia in hospitalized patients with psychiatric disorders was investigated. Method: Patients were divided into 2 groups: control group (N = 259), patients without standardized intervention who were enrolled on April 2014 as the time point of baseline, and intervention group (N = 263), patients with standardized intervention who were enrolled on April 2015 as the time point of baseline. Two end points were evaluated: (1) pneumonia onset within 1 year after the enrollment and (2) no pneumonia for 1 year after the enrollment. The following parameters were compared between the groups: sex, age, psychiatric disorders, past history of diseases of the respiratory system, hypertension, diabetes, hyperlipidemia, heart impairment, and pneumonia. Results: No statistically significant differences were found between the 2 groups in the distributions of characteristics except pneumonia by univariate analysis. The presence of pneumonia was significantly associated with age and the absence of the standardized oral hygiene intervention by multivariate logistic regression analysis. Conclusions: The standardized oral hygiene intervention appears to be effective for preventing pneumonia in patients with psychiatric disorders.
We report an elderly male patient with hyperammonemia induced by intrahepatic portal-systemic shunt without cirrhosis (IPSSwoC). The occasional emergence of his erratic behaviors was misdiagnosed as a psychiatric disorder. Regardless of his uneven symptoms, IPSSwoC was suspected due to his hyperammonemia. The contrast computed tomography of the abdomen revealed a congenital type of IPSSwoC. As blood ammonia levels are inconstant, repeated blood tests are recommended when this disease is suspected in elderly patients with psychiatric symptoms.
The patient was a 66-year-old woman, G2P2. The patient presented a chief complaint of irregular postmenopausal bleeding 1 month ago. A transvaginal ultrasonography showed that bilateral ovaries were not enlarged and uterine endometrium was thickened, measuring at 9 mm. As a result of endometrial curettage, the simple endometrial hyperplasia was revealed. A blood examination showed an elevated estradiol level of 67 pg/mL, an elevated level of testosterone 0.64 ng/mL, and a slightly suppressed follicle-stimulating hormone (FSH) level of 34.86 mIU/mL. We conducted laparoscopic hysterectomy and bilateral salpingo-oophorectomy because the patient strongly suggested less invasive surgery. The result of pathological diagnosis was Sertoli-Leydig cell tumor (SLCT) in moderately differentiation. A blood examination after a month postoperatively revealed an elevated FSH level of 85.59 mIU/mL, depressed estradiol level of less than 10 pg/mL, and testosterone level of less than 0.03 ng/mL. There was no evidence of recurrence in the first year of follow-up.
Background: Chorioamnionitis (CAM) is an important risk factor for the development of bronchopulmonary dysplasia (BPD) in preterm infants. Objectives: To evaluate the effects of CAM on the development of BPD using interleukin 6 (IL-6), Krebs von den Lungen 6 (KL-6), and transforming growth factor β 1 (TGF-β 1 ) in the amniotic fluid as markers for inflammation, lung injury, and fibrosis/remodeling, respectively. Methods: Amniotic fluid concentrations of IL-6, KL-6, and TGF-β 1 were measured with enzyme-linked immunosorbent assay or electrochemiluminescence immunoassay. Results: Of the 36 preterm infants, 18 were exposed to histologically confirmed CAM. Of these, 12 were later diagnosed as having BPD. The IL-6, KL-6, and TGF-β 1 levels in the amniotic fluid significantly increased with increasing histologic severity of CAM. Moreover, these markers were higher in the BPD group with histologic CAM than those without. Conclusions: Our study suggests that CAM is likely to induce inflammatory, injury, and remodeling processes in the fetal lung.
KillerRed (KR) is a recently discovered fluorescent protein that, when activated with green light, releases reactive oxygen species (ROS) into the cytoplasm, triggering apoptosis in a KR-expressing cell. This property allows for the use of KR as a means of killing cells in an organism with great temporal and spatial specificity, while minimizing the nonspecific effects that can result from mechanical or chemical exposure damage techniques. Such optogenetic control of cell death, and the resulting ability to induce the targeted death of specific tissues, is invaluable for regeneration/repair studies–-particularly in Xenopus laevis, where apoptosis plays a key role in regeneration and repair. We here describe a method by which membrane-bound KR, introduced to Xenopus embryos by mRNA microinjection, can be activated with green light to induce apoptosis in specific organs and tissues, with a focus on the developing eye and pronephric kidney.