Copper is an essential trace element within cells, but it also exerts cytotoxic effects through induction of reactive oxygen species (ROS) production. To determine the mechanisms underlying ...copper-induced ROS production, we examined the effects of copper sulfate in HeLa cells. Exposure to copper sulfate led to dose-dependent decreases in HeLa cell viability, along with increases in the subG1 and G2/M populations and corresponding decreases in the G1 population. Copper sulfate also increased the levels of apoptosis, senescence, mitochondrial dysfunction, autophagy, ROS, and the expression of several stress proteins, including ATF3, c-Fos, DEC1 (differentiated embryonic chondrocyte gene 1), p21, p53, and HIF-1α (hypoxia-inducible factor 1 alpha). The suppression of copper-induced ROS generation by the ROS scavenger
-acetyl cysteine verified copper's functional role, while the suppression of copper's effects by the copper chelator disulfiram, confirmed its specificity. Selective induction of HIF-1α, p53, and phosphorylated ERK proteins by copper was blocked by the knockdown of the transcription factor DEC1, suggesting copper's effects are mediated by DEC1. In addition to HeLa cells, copper also exerted cytotoxic effects in human endometrial (HEC-1-A) and lung (A549) adenocarcinoma cells, but not in normal human kidney (HEK293) or bronchial (Beas-2B) epithelial cells. These findings shed new light on the functional roles of copper within cells.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The anticancer efficacy of TNF‐related apoptosis‐inducing ligand (TRAIL)‐based therapy is limited because of systemic toxicity, poor bioavailability, and development of TRAIL resistance. We developed ...a tumor‐targeted LCPP (lipid/calcium/phosphate/protamine) nanoparticle (NP) to deliver TRAIL plasmid DNA (pDNA) into hepatocellular carcinoma (HCC) cells in a mouse model of HCC. TRAIL pDNA was encapsulated in a pH stimuli‐responsive calcium phosphate (CaP) core, and protamine was added to facilitate nuclear delivery of pDNA. In addition, intracellular release of Ca2+ from the CaP core overcame TRAIL resistance by calcium influx‐dependent DR5 up‐regulation. TRAIL expression also attenuated fibrosis in liver tissues surrounding HCCs by reverting activated hepatic stellate cells (HSCs) to a quiescent state or by directly inducing apoptosis in activated HSCs. Conclusion: TRAIL pDNA delivered by HCC‐targeted LCPP NPs in combination with conventional sorafenib treatment attenuated HCC progression as well as liver fibrosis. Overall, our study presents an effective TRAIL‐based cancer therapy that could be developed for clinical applications. (Hepatology 2018;67:899–913)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
17-4 PH stainless steel rotors used for hemodialysis machines need to meet strict quality requirements because they are subjected to high-speed rotation. The presence of shrinkage, incomplete ...filling, and gas porosity in a rotor might cause creep failure, which can be dangerous during operation. Therefore, computer-aided modeling and experimental verifications are conducted in this work to optimize the investment casting of rotors. Six casting processes and five gating system schemes are designed to optimize the casting qualities. The probability of defect occurrence during casting is assessed based on the retained melt modulus incorporated with the Niyama criterion model. Numerical simulation and experimental results show good agreement. Thermodynamic analysis results show that a high cooling rate increases the flow resistance of molten metal between the dendrite arm spaces, resulting in insufficient feeding in the mushy zone. With proper designs of the runner and riser systems, the problems of flow turbulence and insufficient feeding are almost obviated. Surface sinks and interior shrinkage are also completely eliminated.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The biological activity of the edible basidiomycete Antrodia cinnamomea (AC) has been studied extensively. Many effects, such as anti-cancer, anti-inflammatory, and antioxidant activities, have been ...reported from either crude extracts or compounds isolated from AC. However, research addressing the function of AC in enhancing immunity is rare. The aim of the present study is to investigate the active components and the mechanism involved in the immunostimulatory effect of AC. We found that polysaccharides (PS) in the water extract of AC played a major role in dendritic cell (DC) activation, which is a critical leukocyte in initiating immune responses. We further size purified and identified that the high-molecular weight PS fraction (greater than 100 kDa) exhibited the activating effect. The AC high-molecular weight PSs (AC hmwPSs) promoted pro-inflammatory cytokine production by DCs and the maturation of DCs. In addition, DC-induced antigen-specific T cell activation and Th1 differentiation were increased by AC hmwPSs. In studying the molecular mechanism, we confirmed the activation of the MAPK and NF-κB pathways in DCs after AC hmwPSs treatment. Furthermore, we demonstrated that TLR2 and TLR4 are required for the stimulatory activity of AC hmwPSs on DCs. In a mouse tumor model, we demonstrated that AC hmwPSs enhanced the anti-tumor efficacy of the HER-2/neu DNA vaccine by facilitating specific Th1 responses. Thus, we conclude that hmwPSs are the major components of AC that stimulate DCs via the TLR2/TLR4 and NF-κB/MAPK signaling pathways. The AC hmwPSs have potential to be applied as adjuvants.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Non‐alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Sarcopenia is a syndrome characterized by progressive and generalized loss of ...skeletal muscle mass and strength, which is commonly associated with NAFLD. Adenosine‐to‐inosine editing, catalysed by adenosine deaminase acting on RNA (ADAR), is an important post‐transcriptional modification of genome‐encoded RNA transcripts. Three ADAR gene family members, including ADAR1, ADAR2 and ADAR3, have been identified. However, the functional role of ADAR2 in obesity‐associated NAFLD and sarcopenia remains unclear.
Methods
ADAR2+/+/GluR‐BR/R mice (wild type WT) and ADAR2−/−/GluR‐BR/R mice (ADAR2 knockout KO) were subjected to feeding with standard chow or high‐fat diet (HFD) for 20 weeks at the age of 5 weeks. The metabolic parameters, hepatic lipid droplet, grip strength test, rotarod test, muscle weight, fibre cross‐sectional area (CSA), fibre types and protein associated with protein degradation were examined. Systemic and local tissues serum amyloid A1 (SAA1) were measured. The effects of SAA1 on C2C12 myotube atrophy were investigated.
Results
ADAR2 KO mice fed with HFD exhibited lower body weight (−7.7%, P < 0.05), lower liver tissue weight (−20%, P < 0.05), reduced liver lipid droplets in concert with a decrease in hepatic triglyceride content (−24%, P < 0.001) and liver injury (P < 0.01). ADAR2 KO mice displayed protection against HFD‐induced glucose intolerance, insulin resistance and dyslipidaemia. Skeletal muscle mass (P < 0.01), muscle strength (P < 0.05), muscle endurance (P < 0.001) and fibre size (CSA; P < 0.0001) were improved in ADAR2 KO mice fed with HFD compared with WT mice fed with HFD. Muscle atrophy‐associated transcripts, such as forkhead box protein O1, muscle atrophy F‐box/atrogin‐1 and muscle RING finger 1/tripartite motif‐containing 63, were decreased in ADAR2 KO mice fed with HFD compared with WT mice fed with HFD. ADAR2 deficiency attenuates HFD‐induced local liver and skeletal muscle tissue inflammation. ADAR2 deficiency abolished HFD‐induced systemic (P < 0.01), hepatic (P < 0.0001) and muscular (P < 0.001) SAA1 levels. C2C12 myotubes treated with recombinant SAA1 displayed a decrease in myotube length (−37%, P < 0.001), diameter (−20%, P < 0.01), number (−39%, P < 0.001) and fusion index (−46%, P < 0.01). Myogenic markers (myosin heavy chain and myogenin) were decreased in SAA1‐treated myoblast C2C12 cells.
Conclusions
These results provide novel evidence that ADAR2 deficiency may be important in obesity‐associated sarcopenia and NAFLD. Increased SAA1 might be involved as a regulatory factor in developing sarcopenia in NAFLD.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Viral- and host-targeted traditional Chinese medicine (TCM) formulae NRICM101 and NRICM102 were administered to hospitalized patients with COVID-19 during the mid-2021 outbreak in Taiwan. We report ...the outcomes by measuring the risks of intubation or admission to intensive care unit (ICU) for patients requiring no oxygen support, and death for those requiring oxygen therapy.
This multicenter retrospective study retrieved data of 840 patients admitted to 9 hospitals between May 1 and July 26, 2021. After propensity score matching, 302 patients (151 received NRICM101 and 151 did not) and 246 patients (123 received NRICM102 and 123 did not) were included in the analysis to assess relative risks.
During the 30-day observation period, no endpoint occurred in the patients receiving NRICM101 plus usual care while 14 (9.27%) in the group receiving only usual care were intubated or admitted to ICU. The numbers of deceased patients were 7 (5.69%) in the group receiving NRICM102 plus usual care and 27 (21.95%) in the usual care group. No patients receiving NRICM101 transitioned to a more severe status; NRICM102 users were 74.07% less likely to die than non-users (relative risk= 25.93%, 95% confidence interval 11.73%-57.29%).
NRICM101 and NRICM102 were significantly associated with a lower risk of intubation/ICU admission or death among patients with mild-to-severe COVID-19. This study provides real-world evidence of adopting broad-spectrum oral therapeutics and shortening the gap between outbreak and effective response. It offers a new vision in our preparation for future pandemics.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Animal cells and cell lines, such as HEK-293 cells, are commonly cultured at 37°C. These cells are often used to express recombinant proteins. Having a higher expression level or a higher protein ...yield is generally desirable. As we demonstrate in this study, dropping culture temperature to 33°C, but not lower, 24 hours after transient transfection in HEK-293S cells will give rise to ~1.5-fold higher expression of green fluorescent protein (GFP) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. By following the time course of the GFP-expressing cells growing at 37°C and 33°C from 24 hours after transfection (including 19 hours recovery at 37°C in the normal growth medium), we found that a mild hypothermia (i.e., 33°C) reduces the growth rate of HEK-293S cells, while increasing cellular productivity of recombinant proteins. As a result, green cells remain undivided in a longer period of time. Not surprisingly, the property of a recombinant protein expressed in the cells grown at 33°C is unaffected, as shown by the use of AMPA receptors. We further demonstrate with the use of PC12 cells that this method may be especially useful when a recombinant protein is difficult to express using a chemical-based, transient transfection method.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A cationic liposome-PEG-PEI complex (LPPC) was employed as a carrier for achieving targeted delivery of drug to human epidermal growth factor receptor-2 (HER2/neu)-expressing breast cancer cells. ...LPPC can be easily loaded with an anti-tumor drug and non-covalently associated with an anti-tumor antibody such as Herceptin that is clinically used to rapidly form immunoparticles within 1 h.
Drug-loaded LPPC have an average size about 250 nm and a zeta potential of about 40 mV. Herceptin was complexed onto surface of the LPPC to form the drug/LPPC/Herceptin complexes. The size of curcumin/LPPC/Herceptin complexes were 280 nm and the zeta potentials were about 23 mV. Targeting ability of this delivery system was demonstrated through specific binding on surface of cells and IVIS images in vivo, which showed specific binding in HER2-positive SKBR3 cells as compared to HER2-negative Hs578T cells. Only the drug/LPPC/Herceptin complexes displayed dramatically increased the cytotoxic activity in cancer cells. Both in vitro and in vivo results indicated that Herceptin adsorbed on LPPC directed the immunocomplex towards HER2/neu-positive cells but not HER2/neu-negative cells. The complexes with either component (curcumin or doxorubicin) used in the LPPC-delivery system provided a better therapeutic efficacy compared to the drug treatment alone and other treatment groups, including clinical dosages of Herceptin and LipoDox, in a xenografted model.
LPPC displays important clinical implications by easily introducing a specific targeting characteristic to drugs utilized for breast cancer therapy.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Objective
To investigate the suicide risk factors among caregivers of individuals with depression who may develop suicidal ideation due to the ongoing challenges of managing the patient's mood ...fluctuations.
Methods
This cross-sectional study enrolled dyads of patients with depression and their caregivers from a medical centre. The assessment included a psychiatric diagnostic interview, the Hospital Anxiety and Depression Scale, the List of Threatening Experiences, Benefit Finding Scale, Numerical Pain Rating Scale, Stigma Subscale of the Explanatory Model Interview Catalogue, Big Five Inventory-10, the Family APGAR Index and the Suicide Assessment Scale. Univariate and multivariate regression analysis were used to explore the interrelationship between the mental health of patients and caregivers.
Results
Among the 125 caregivers, 60.0% (n = 75) were females. The most common psychiatric diagnoses were depressive disorders (33 of 125; 26.4%), followed by anxiety disorders (21 of 125; 16.8%) and insomnia disorder (19 of 125; 15.2%). There was a significant association between the stressful life events of depressive patients and the suicide risk of their caregivers. The severity of anxiety and depression in caregivers was significantly associated with the suicide risk among the caregivers.
Conclusion
A relationship may exist between the psychological well-being of patients with depression and their caregivers.
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