Lysosomes are organelles surrounded by membranes that contain acid hydrolases; they degrade proteins, macromolecules, and lipids. According to nutrient conditions, lysosomes act as signaling hubs that regulate intracellular signaling pathways and are involved in the homeostasis of cells. Therefore, the lysosomal dysfunction occurs in various diseases, such as lysosomal storage disease, neurodegenerative diseases, and cancers. Multiple forms of stress can increase lysosomal membrane permeabilization (LMP), resulting in the induction of lysosome-mediated cell death through the release of lysosomal enzymes, including cathepsin, into the cytosol. Here we review the molecular mechanisms of LMP-mediated cell death and the enhancement of sensitivity to anticancer drugs. Induction of partial LMP increases apoptosis by releasing some cathepsins, whereas massive LMP and rupture induce non-apoptotic cell death through release of many cathepsins and generation of ROS and iron. Cancer cells have many drug-accumulating lysosomes that are more resistant to lysosome-sequestered drugs, suggesting a model of drug-induced lysosome-mediated chemoresistance. Lysosomal sequestration of hydrophobic weak base anticancer drugs can have a significant impact on their subcellular distribution. Lysosome membrane damage by LMP can overcome resistance to anticancer drugs by freeing captured hydrophobic weak base drugs from lysosomes. Therefore, LMP inducers or lysosomotropic agents can regulate lysosomal integrity and are novel strategies for cancer therapy.
COP9 signalosome (CSN), which is originally identified as the regulator of the photomorphogenic development in plant, is highly conserved protein complex in diverse eukaryotic organisms. Most eukaryotic CSN complex is composed of 8 subunits, which is structurally and functionally similar to the lid subunit of 26S proteasome and eIF3 translation initiation complex. CSN play important functions in the regulation of cell cycle and checkpoint response by controlling Cullin-Ring E3 ubiquitin ligases (CRL) activities. CSN exhibits an isopeptidase activity which cleaves the neddylated moiety of cullin components. In fission yeast, S-phase cell cycle progression was delayed and the sensitivity to g-ray or UV was increased in CSN1 and CSN2 deletion mutants, indicating that yeast CSN is also involved in the checkpoint regulation. CSN in fungal system more closely resembles that of the higher organisms in the structure and assembly of their components. Functionally, CSN is associated with the regulation of conidiation rhythms in Neurospora crassa and the sexual development in Aspsergillus nidulans. Recent studies also revealed that CSN functions as an essential cell cycle regulator, playing key roles in the regulation of DNA replication and DNA damage response in Aspergillus. Overall, CSN of microorganisms, such as fission yeast and fungi, share functionally common aspects with higher organisms, implying that they can be useful tools to study the role of CSN in the CRL-mediated diverse cellular activities.
Commercial formulation of fungicides was studied in vitro for sensitivity against Typhula species causal agents of Typhula blight. Efficacies of fungicides application, spray volume, nozzle types and fungicides applied time (early fall and late fall) were evaluated for their influence on the chemical control of Typhula blight of turfgrass during the winter season in Wisconsin. All fungicides effectively reduced the mycelial growth of eight isolates of Typhula spp. in vitro on potato dextrose agar (PDA) media. For inhibitory effects on mycelial growth of eight isolates, propiconazole was the most effective at $1.0{\mu}g$ active ingredient (a.i) / ml of PDA. Typhula incarnata two isolates were significantly more sensitive to all fungicides of PDA than six isolates of three varieties of T. ishikariensis. For 2 years in field experiment, unsprayed control has significantly more disease severity than seven fungicides were applied to field plots at two locations. Propiconazole was the most effective for controlling Typhula blight, at two locations in both years. The level of disease control was not dependent on fungicides spray volume or nozzle types at two locations. The disease damage treated with triadimefon applied time (early fall and late fall) was not significantly different at two location for two years.
Cervical cancer is associated with low antioxidant status. It has a high prevalence especially amongst woman in Asia and is a leading cause of cancer death. Cancer chemotherapy in vivo improved in cases with high p53 expression in the tumor tissue. The restoration of p53 levels could be a potential strategy to increase chemoresponsiveness. Under circumstances where damage is extensive, p53 plays a direct role in trigering apoptosis. To investigate the effect of curcumin (CMN) as an antioxidant agent on anticancer agent 5-fluorouracil (5FU) induced apoptosis and p53 expression, HPV-18 positive HeLa cells were treated with noncytotoxic amounts of antioxidant. Curcumin induced apoptosis in cervical cancer cells. Morphological hallmarks of apoptosis such as nuclear fragmentation and internucleosomal fragmentation of DNA were observed. CMN caused upregulation of p53 expression, evident from Western blotting data and also increased the susceptibility/apoptosis induced by 5FU. These results show that increasing drug sensitivity of cervical cancer cells by upregulation of p53 using CMN is novel approach and could have a possible therapeutic potential in cervical cancer.
To examine the antitumor effect of proso millet grains, whether proso millet grains exert apoptotic activity against human cancer cells was investigated. When the cytotoxicity of 80% ethanol (EtOH) extract of proso millet grains was tested against various cancer cells using MTT assay, more potent cytotoxicity was observed against human breast cancer MDA-MB-231 cells than against other cancer cells. When the EtOH extract was evaporated to dryness, dissolved in water, and then further fractionated by sequential extraction using four organic solvents (n-hexane, methylene chloride, ethyl acetate, and n-butanol), the BuOH fraction exhibited the highest cytotoxicity against MDA-MB-231 cells. Along with the cytotoxicity, TUNEL-positive apoptotic nucleosomal DNA fragmentation and several apoptotic responses including BAK/BAX activation, mitochondria membrane potential (Δψm) loss, mitochondrial cytochrome c release into the cytosol, activation of caspase-8/-9/-3, and degradation of poly (ADP-ribose) polymerase (PARP) were detected. However, human normal mammary epithelial MCF-10A cells exhibited a significantly lesser extent of sensitivity compared to malignant MDA-MB-231 cells. Irrespective of Fas-associated death domain (FADD)-deficiency or caspase-8-deficiency, human T acute lymphoblastic leukemia Jurkat cells displayed similar sensitivities to the cytotoxicity of BuOH fraction, excluding an involvement of extrinsic apoptotic mechanism in the apoptosis induction. These results demonstrate that the cytotoxicity of BuOH fraction from proso millet grains against human breast cancer MDA-MB-231 cells is attributable to intrinsic apoptotic cell death resulting from BAK/BAX activation, and subsequent mediation of mitochondrial damage-dependent activation of caspase cascade.
Journal of the korean academy of Pediatric Dentistry
/
v.28
no.3
/
pp.480-487
/
2001
In children and adolescents, oral and maxillofacial trauma is one of the most common causes of dental and periodontal damage, which often induces crown fracture of the permanent anterior teeth. Frequently, these traumatized teeth lose their vitality, and require routine endodontic treatment if their root apices are closed. However if their apices are not fully closed, further root formation should be promoted by apexification or apexogenesis. Calcium hydroxide is a biocompatible & bacteriostatic material, and is widely used for apexification. However it has several disadvantages which include the need for multiple visits and patient cooperation, low strength and technical sensitivity in a broad apex. In one-visit apexification using IRM or SuperEBA, patient's visits can be minimized. However, their biocompatibility is questionable. Mineral trioxide aggregate(MTA) is a relatively new material. It is considered biocompatible with periapical hard tissue and has good marginal sealing ability. MTA is also known to help facillitate the growth of the cementum around it. In this case report, apexification with MTA was attempted on traumatized maxillary central incisors with immature root apices, and favorable clinical results were achieved.
Vulnerability assessment has been required for establish climate adaptation plan to prevent damage from climate change. In this study we assessed vulnerability with 1 km resolution and determined which sectors have the highest priority in each municipality of Gangwon province based on the result of vulnerability assessment. All sectors of vulnerability assessment are composed of three criteria; sensitivity, exposure and adaptation capacity. And suitable indicators of each sector were selected and spatial data set was prepared using GIS. Priority of vulnerability was classified with the degree of vulnerability in present and variation in vulnerability between present and future. The results of vulnerability assessment were different among municipalities due to the contribution of indicators. Present and future trends in vulnerability showed similar results but high vulnerable area was predicted to expand in the future. In addition increase in temperature led whole area to be more vulnerable generally. The result of prioritizing sectors of vulnerability indicated the most considerable sectors within a municipality. Also, the municipalities which have similar geographic, climatic and social conditions tended to be classified as the same priority class. The method of vulnerability assessment and determining priorities suggested in this study could be used to support decision makers to establish adaptation plan of local area.
To evaluate if the apoptotic fragment assay could be used to estimate the dose prediction after radiation exposure, we examined apoptotic mouse crypt cells per 1,000 cells after whole body $^{60}Co$$\gamma$-rays and 50MeV ($p{\rightarrow}Be^+$) cyclotron fast neutron irradiation in the range of 0.25 to 1 Gy, respectively. The incidence of apoptotic cell death rose steeply at very low doses up to 1 Gy, and radiation at all doses tigger rapid changes in crypt cells in stem cell region. These data suggest that apoptosis may play an important role in homeostasis of damaged radiosensitive target organ by removing damaged cells. The curve of dose-effect relationship for the data of apoptotic fragments was obtained by the linear-quadratic model $y=0.18+(9.728{\pm}0.887)D+(-4.727{\pm}1.033)D^2$ ($r^2=0.984$) after $\gamma$-rays irradiation, while $y=0.18+(5.125{\pm}0.601)D+(-2.652{\pm}0.7000)D^2$ ($r^2=0.970$) after neutrons in mice. The dose-response curves were linear-quadratic, and a significant dose-response relationship was found between the frequency of apoptotic cell and dose. These data show a trend towards increase of the numbers of apoptotic crypt cells with increasing dose. Both the time course and the radiation dose-response curve for high and low linear energy transfer (LET) radiation modalities were similar. The relative biological effectiveness (RBE) value for crypt cells was 2.072. In addition, there were significant peaks on apoptosis induction at 4 and 6h after irradiation, and the morpholoigcal findings of the irradiated groups were typical apoptotic fragments in crypt cells that were hardly observed in the control group. Thus, apoptosis in crypt cells could be a useful in vivo model for studying radio-protective drug sensitivity or screening test, microdosimetric indicator and radiation-induced target organ injury. Since the apoptotic fragment assay is simple, rapid and reproducible in the range of 0.25 to 1 Gy, it will also be a good tool for evaluating the dose response of radiation-induced organ damage in vivo and provide a potentially valuable biodosimetry for the early dose prediction after accidental exposure.
There is a growing voice that medical information should be shared because it can prepare for genetic diseases or cancer by analyzing and utilizing medical information in big data or artificial intelligence to develop medical technology and improve patient care. The utilization and protection of patients' personal information are the same as two sides of the same coin. Medical institutions or medical personnel should take extra caution in handling personal information with high environmental distinct characteristics and sensitivity, which is different from general information processors. In general, the patient's personal information is processed by medical personnel or medical institutions through the processes of collection, creation, and destruction. Still, the use of terms related to personal information in the Medical Service Act is jumbled, or the scope of application is unclear, so it relies on the interpretation of precedents. For the medical personnel or the founder of the medical institution, in the case of infringement of Article 24(4), it cannot be regarded that it means only medical treatment information among personal information, whether or not it should be treated the same as the personal information under Article 23, because the sensitive information of patients is recorded, saved, and stored in electronic medical records. Although the prohibition of information leakage under Article 19 of the Medical Service Act has a revision; 'secret' that was learned in business was revised to 'information', but only the name was changed, and the benefit and protection of the law is the same as the 'secret' of the criminal law, such that the patient's right to self-determination of personal information is not protected. The Privacy Law and the Local Health Act consider the benefit and protection of the law in 'information learned in business' as the right to self-determination of personal information and stipulate the same penalties for personal information infringement such as leakage, forgery, alteration, and damage. The privacy regulations of the Medical Service Act require that the terms be adjusted uniformly because the jumbled use of terms can confuse information subjects, information processors, and shows certain limitations on the protection of personal information because the contents or scope of the regulations of the Medical Service Law for special corporations and the Privacy Law may cause confusion in interpretation. The patient's personal information is sensitive and must be safely protected in its use and processing. Personal information must be processed in accordance with the protection principle of Privacy Law, and the rights such as privacy, freedom, personal rights, and the right to self-determination of personal information of patients or guardians, the information subject, must be guaranteed.
1. In order to obtain useful mutants such as early maturity, resistance to lodging, high protein and oil content, and capability of high yield, dormant seeds of two soybean varieties, Jang Dan Baik Mok and Clark, were treated with ${\gamma}$-ray, Ethyl Methane Sulfonate(EMS), Ethylene Imine(EI)and combinations of ${\gamma}$-ray and EMS or EI. 2. The germination rate and survival rate in a variety Jang Dan Baik Mok were significantly decreased with ${\gamma}$-ray treatment while it was not the same in the Clark variety. A significant decrease for seedling height measured at 14 and 21 days after sowing was found with the increase of ${\gamma}$-ray dose in both varieties. 3. Germination rates in both varieties were significantly decreased as EI concentration increases, particularly severe damage in germination was observed at 0.008 Mo. concentration. Germination rate damages were found with EMS concentration increases in the variety Jang Dan Baik Mok while no regular responses in seedling height were observed in the variety Clark. 4. Germination rate was significantly lowered with the combined treatment of EMS and ${\gamma}$-ray 24KR than that of EMS alone. In the treatments of ${\gamma}$-ray with three levels of EI concentration, the combined treatments except 24KR+EI 0.002 Mol. resulted in better germination than of EI alone. In both varieties, significant reduction in seedling height was observed in the combined treatments of ${\gamma}$-ray with various concentrations of EMS, whereas stimulation effect on seedling height was found with treatment of ${\gamma}$-ray EI +0.08Mol. 5. Germination rate, survival rate, and plant height as criteria of radio sensitivity, variety Jang Dan Baik Mok is moze sensitive to ${\gamma}$-ray, EMS, and EI than the variety Clark, and the varietal difference in responsibility to mutagen may be due to the genetic-constitution of the varieties.
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