RAS proteins play critical roles in various cellular processes, including growth and transformation. RAS proteins are subjected to protein stability regulation via the Wnt/β‐catenin pathway, and ...glycogen synthase kinase 3 beta (GSK3β) is a key player for the phosphorylation‐dependent RAS degradation through proteasomes. GSK3β‐mediated RAS degradation does not occur in cells that express a nondegradable mutant (MT) β‐catenin. Here, we show that β‐catenin directly interacts with RAS at the α‐interface region that contains the GSK3β phosphorylation sites, threonine 144 and threonine 148 residues. Exposure of these sites by prior β‐catenin degradation is required for RAS degradation. The introduction of a peptide that blocks the β‐catenin‐RAS interaction by binding to β‐catenin rescues the GSK3β‐mediated RAS degradation in colorectal cancer (CRC) cells that express MT β‐catenin. The coregulation of β‐catenin and RAS stabilities by the modulation of their interaction provides a mechanism for Wnt/β‐catenin and RAS‐ERK pathway cross‐talk and the synergistic transformation of CRC by both APC and KRAS mutations.
Synopsis
GSK3β promotes phosphorylation‐ and polyubiquitination‐dependent proteasomal RAS degradation. β‐Catenin directly interacts with RAS, thereby preventing GSK3β‐dependent phosphorylation and degradation, defining the basis for the synergistic effect of β‐catenin and RAS on cancer growth.
β‐Catenin directly interacts with RAS at the α‐interface that contains GSK3β phosphorylation sites.
β‐Catenin degradation is required for subsequent GSK3β‐mediated RAS degradation.
Targeting both β‐catenin and RAS for degradation is a potential approach against colorectal cancer.
GSK3β promotes phosphorylation‐ and polyubiquitination‐dependent proteasomal RAS degradation. β‐Catenin directly interacts with RAS, thereby preventing GSK3β‐dependent phosphorylation and degradation, defining the basis for the synergistic effect of β‐catenin and RAS on cancer growth.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Antiplatelet therapy has shown protective effects against hepatocellular carcinoma (HCC) in preclinical studies. However, it is unclear whether antiplatelet therapy lowers the risk of HCC in patients ...with chronic hepatitis B. A retrospective analysis was conducted of data from 1,674 chronic hepatitis B patients, enrolled between January 2002 and May 2015, whose serum hepatitis B virus DNA levels were suppressed by antivirals to <2,000 IU/mL. The primary and secondary outcomes were development of HCC and bleeding events, respectively. Risk was compared between patients with antiplatelet treatment (aspirin, clopidogrel, or both; antiplatelet group) and patients who were not treated (non‐antiplatelet group) using a time‐varying Cox proportional hazards model for total population and propensity score–matching analysis. The antiplatelet group included 558 patients, and the non‐antiplatelet group had 1,116 patients. During the study period, 63 patients (3.8%) developed HCC. In time‐varying Cox proportional analyses, the antiplatelet group showed a significantly lower risk of HCC (hazard ratio HR, 0.44; 95% confidence interval CI, 0.23–0.85; P = 0.01), regardless of antiplatelet agent. In propensity score–matched pairs, antiplatelet therapy significantly reduced the risk of HCC (HR, 0.34; 95% CI, 0.15‐0.77; P = 0.01). However, the overall risk of bleeding was higher in the antiplatelet group (HR, 3.28; 95% CI, 1.98‐5.42; P < 0.001), particularly for clopidogrel with or without aspirin. Treatment with aspirin alone was not associated with a higher bleeding risk (HR, 1.11; 95% CI, 0.48‐2.54; P = 0.81). Conclusion: Antiplatelet therapy reduces the risk of HCC in chronic hepatitis B patients whose hepatitis B virus is effectively suppressed. However, antiplatelet therapy containing clopidogrel may increase the risk of bleeding. (Hepatology 2017;66:1556–1569)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Since the global outbreak of coronavirus disease-2019 (COVID-19), plastic surgeons were forced to transition from traditional didactics to virtual lectures to practice “social distancing.” As this ...method of education continues to be widely used, understanding the current trend of its usage is critical. In this study, we performed a survey study of virtual lecture attendees and presenters to determine current usage and general consensus on virtual lectures in plastic surgery education.
An electronic survey was sent to attendees and presenters of virtual lectures using Google Forms. Demographic data, webinar usage patterns, and views on virtual lectures were collected.
A total of 417 surveys were received. Prior to the COVID-19 era, 39.1percent of attendees did not use virtual lectures and 45.6percent of presenters did not give webinars at all. Both groups reported that the lack of opportunities and need were the most common cause of no use of lectures or webinars. After the outbreak, 35.4percent of attendees now use virtual lectures daily and 51.4percent of presenters give lectures weekly. Over 90percent of the study population reported a positive experience with the virtual lectures due to increased interaction, convenience, outreach, and usability. Finally, over 75percent stated that virtual lectures might replace classroom lectures in the future.
Our study shows that a majority of plastic surgeons have begun to use and give virtual lectures daily after the COVID-19 outbreak. Virtual education is a powerful and versatile tool that has great potentials, and it may continue to serve as a part of surgical training in the future.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Human pluripotent stem cell (hPSC)-derived intestinal organoids (hIOs) form 3D structures organized into crypt and villus domains, making them an excellent in vitro model system for studying human ...intestinal development and disease. However, hPSC-derived hIOs still require in vivo maturation to fully recapitulate adult intestine, with the mechanism of maturation remaining elusive. Here, we show that the co-culture with human T lymphocytes induce the in vitro maturation of hIOs, and identify STAT3-activating interleukin-2 (IL-2) as the major factor inducing maturation. hIOs exposed to IL-2 closely mimic the adult intestinal epithelium and have comparable expression levels of mature intestinal markers, as well as increased intestine-specific functional activities. Even after in vivo engraftment, in vitro-matured hIOs retain their maturation status. The results of our study demonstrate that STAT3 signaling can induce the maturation of hIOs in vitro, thereby circumventing the need for animal models and in vivo maturation.
Ginseng, refering to the roots of the species of the genus
Panax ginseng, has been widely used in traditional oriental medicine for its wide spectrum of medicinal effects, such as anti-inflammatory, ...anti-tumorigenic, adaptogenic, and anti-aging activities. Many of its medicinal effects are attributed to the triterpene glycosides known as ginsenosides. In this study, we report a novel anti-apoptotic activity of 20(
S)-ginsenoside Rg3 ((20S)Rg3) and its underlying molecular mechanism in human endothelial cells (ECs). ECs undergo apoptosis associated with increased LEHDase (caspase-9) and DEVDase (caspase-3) activity and DNA fragmentation after 24
h of serum deprivation. These apoptotic markers were suppressed by the addition of (20S)Rg3. (20S)Rg3 increased the expression of Bax and conversely decreased Bcl-2. (20S)Rg3 potently induced a rapid and sustained Akt activation and Bad phosphorylation, resulting in the inhibition of mitochondrial cytochrome
c release. These anti-apoptotic activities of (20S)Rg3 were significantly abrogated in cells expressing dominant negative Akt. Taken together, our results suggest that (20S)Rg3 prevents EC apoptosis via Akt-dependent inhibition of the mitochondrial apoptotic signaling pathway. The novel property of (20S)Rg3 may be valuable for developing new pharmaceutical means that will control unwanted endothelial cell death at the site of vascular injury.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Protein disulfide isomerase (PDI) participates in the pathogenesis of numerous diseases. Increasing evidence indicates that intravascular cell-derived PDI plays an important role in the initiation ...and progression of cardiovascular diseases, including thrombosis and vascular inflammation. Recent studies with PDI conditional knockout mice have advanced our understanding of the function of cell-specific PDI in disease processes. Furthermore, the identification and development of novel small-molecule PDI inhibitors has led into a new era of PDI research that transitioned from the bench to bedside. In this review, we will discuss recent findings on the regulatory role of PDI in cardiovascular disease.
Minimizing blood loss during surgery is critical, and many modalities have been used to decrease unwanted surgical bleeding. Among many methods, use of pharmacologic agents such as antifibrinolytic ...drugs has been shown to significantly reduce blood loss and the rates of postoperative blood transfusion in many articles. Tranexamic acid is an antifibrinolytic agent that has been widely used in other surgical specialties, especially in cardiac, orthopedic, and trauma surgery. Despite its known benefits, the use of tranexamic acid in plastic surgery is extremely limited, primarily because most plastic surgery procedures do not involve the extent of blood loss that can lead to anemia and the need for blood transfusion, as is common in major orthopedic and cardiac surgery procedures. Nevertheless, there are significant benefits to be gained from the use of antifibrinolytic drugs in the full range of plastic surgery. In this article, the authors introduce the benefits, dosages, and technical considerations of using tranexamic acid in plastic surgery procedures.
The disruption of the retinal pigment epithelium (RPE), for example, through oxidative damage, is a common factor underlying age-related macular degeneration (AMD). Aberrant autophagy also ...contributes to AMD pathology, as autophagy maintains RPE homeostasis to ensure blood-retinal barrier (BRB) integrity and protect photoreceptors. Thioredoxin-interacting protein (TXNIP) promotes cellular oxidative stress by inhibiting thioredoxin reducing capacity and is in turn inversely regulated by reactive oxygen species levels; however, its role in oxidative stress-induced RPE cell dysfunction and the mechanistic link between TXNIP and autophagy are largely unknown. Here, we observed that TXNIP expression was rapidly downregulated in RPE cells under oxidative stress and that RPE cell proliferation was decreased. TXNIP knockdown demonstrated that the suppression of proliferation resulted from TXNIP depletion-induced autophagic flux, causing increased p53 activation via nuclear localization, which in turn enhanced AMPK phosphorylation and activation. Moreover, TXNIP downregulation further negatively impacted BRB integrity by disrupting RPE cell tight junctions and enhancing cell motility by phosphorylating, and thereby activating, Src kinase. Finally, we also revealed that TXNIP knockdown upregulated HIF-1α, leading to the enhanced secretion of VEGF from RPE cells and the stimulation of angiogenesis in cocultured human retinal microvascular endothelial cells. This suggests that the exposure of RPE cells to sustained oxidative stress may promote choroidal neovascularization, another AMD pathology. Together, these findings reveal three distinct mechanisms by which TXNIP downregulation disrupts RPE cell function and thereby exacerbates AMD pathogenesis. Accordingly, reinforcing or restoring BRB integrity by targeting TXNIP may serve as an effective therapeutic strategy for preventing or attenuating photoreceptor damage in AMD.
Edible insects have received global attention as an alternative protein-rich food. However, their structural characteristics make them difficult to digest. To overcome this obstacle, we assessed the ...techno-functional properties of three protein concentrates from the cricket
. Freeze-dried
powder was defatted using ethanol, hexene, or acetone as solvents, and the techno-functional properties (protein solubility, water and oil holding capacity, foaming properties, emulsion capacity, and gel formation) of the protein concentrates were determined. Freeze-dried
powder comprised approximately 17.3% crude fat and 51.3% crude protein based on dry weight. Ethanol was the most effective solvent for reducing the fat content (from 17.30% to 0.73%) and increasing the protein content (from 51.3% to 62.5%) of the concentrate. Techno-functionality properties drastically differed according to the defatting solvent used and foaming properties were most affected. Thus, the techno-functional and whole properties must be considered for proper application of edible insects to achieve global food sustainability.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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