Supramolecular Senolytics via Intracellular Oligomerization of Peptides in Response to Elevated Reactive Oxygen Species Levels in Aging Cells.

Senolytics, which eliminate senescent cells from tissues, represent an emerging therapeutic strategy for various age-related diseases. Most senolytics target antiapoptotic proteins, which are overexpressed in senescent cells, limiting specificity and inducing severe side effects. To overcome these limitations, we constructed self-assembling senolytics targeting senescent cells with an intracellular oligomerization system. Intracellular aryl-dithiol-containing peptide oligomerization occurred only inside the mitochondria of senescent cells due to selective localization of the peptides by RGD-mediated cellular uptake into integrin αvß3-overexpressed senescent cells and elevated levels of reactive oxygen species, which can be used as a chemical fuel for disulfide formation. This oligomerization results in an artificial protein-like nanoassembly with a stable α-helix secondary structure, which can disrupt the mitochondrial membrane via multivalent interactions because the mitochondrial membrane of senescent cells has weaker integrity than that of normal cells. These three specificities (integrin αvß3, high ROS, and weak mitochondrial membrane integrity) of senescent cells work in combination; therefore, this intramitochondrial oligomerization system can selectively induce apoptosis of senescent cells without side effects on normal cells. Significant reductions in key senescence markers and amelioration of retinal degeneration were observed after elimination of the senescent retinal pigment epithelium by this peptide senolytic in an age-related macular degeneration mouse model and in aged mice, and this effect was accompanied by improved visual function. This system provides a strategy for the treatment of age-related diseases using supramolecular senolytics.

The Role of Diffusion-Weighted Imaging Based on Maximum-Intensity Projection in Young Patients with Marked Background Parenchymal Enhancement on Contrast-Enhanced Breast MRI.

Diffusion-weighted imaging (DWI) utilizing maximum-intensity projection (MIP) was suggested as a cost-effective alternative tool without the risk of gadolinium-based contrast agents. The purpose of this study was to investigate whether DWI MIPs played a supportive role in young (≤60) patients with marked background parenchymal enhancement (BPE) on contrast-enhanced MRI (CE-MRI). The research included 1303 patients with varying degrees of BPE, and correlations between BPE on CE-MRI, the background diffusion signal (BDS) on DWI, and clinical parameters were analyzed. Lesion detection scores were compared between CE-MRI and DWI, with DWI showing higher scores. Among the 186 lesions in 181 patients with marked BPE on CE-MRI, the main lesion on MIPs of CE-MRI was partially or completely seen in 88.7% of cases, while it was not seen in 11.3% of cases. On the other hand, the main lesion on MIPs of DWI was seen in 91.4% of cases, with only 8.6% of cases showing no visibility. DWI achieved higher scores for lesion detection compared to CE-MRI. The presence of a marked BDS was significantly associated with a lower likelihood of a higher DWI score (p < 0.001), and non-mass lesions were associated with a decreased likelihood of a higher DWI score compared with mass lesions (p = 0.196). In conclusion, the inclusion of MIPs of DWI in the preoperative evaluation of breast cancer patients, particularly young women with marked BPE, proved highly beneficial in improving the overall diagnostic process.

Spatiotemporal Self-Assembly of Peptide Amphiphiles by Carbonic Anhydrase IX-Targeting Induces Cancer-Lysosomal Membrane Disruption.

To achieve spatiotemporal control, an enzyme-instructed self-assembly system is widely used, but this approach typically has a small effect on cellular fate. In this study, we show that the intralysosomal assembly by a carbonic anhydrase IX (CAIX)-targeting peptide amphiphile (Pep-AT) can control cellular fate with a low therapeutic dose by tuning the surface charge based on pH change. Pep-AT self-assembles into a fibrous aggregate with a negative surface charge in an extracellular environment near CAIX. During endocytosis, it changes into a nanofiber with a positive surface charge at the lysosome. Then, it can disrupt the lysosomal membrane and induce cellular apoptosis. This study demonstrates that a spatiotemporal assembly induced by a cancer enzyme and specific organelle can control the cellular fate of cancer.

Retrospective clinical study of mandible fractures.

BACKGROUND: As society becomes more complex, the incidence of mandibular fractures is increasing. This study aimed to analyze the incidence and type and identify etiological factors of mandibular fractures to use them in future treatments. MATERIAL AND METHODS: Data were collected from 224 patients who visited the department of oral and maxillofacial surgery at the Kyung Hee Medical Center dental hospital during a 6-year period (2016 to 2021). A logistic regression model was used for data analysis. RESULTS: In a total of 224 patients, 362 fractures were appeared. The average age of the patients was 34.1 years, with the highest incidence in the 20s. And the ratio between male and female was 4.09:1. Symphysis fractures were the most prevalent of all patients (52.7%), followed by unilateral condyle (37.1%), angle (36.2%), bilateral condyle (9.4%), body (8%), and coronoid (2.2%). The most common cause of fracture was daily-life activity (57.6%), followed by violence (30.4%), traffic accidents (8.5%), and syncope (3.6%). Patients with symphysis fracture were at low risk (OR < 1) of angle, body, and unilateral condyle fractures. Similarly, patients with unilateral fracture were at low risk (OR < 1) of symphysis, angle, body, and others site fractures. In contrast, patient with bilateral condyle fracture were at high risk (OR > 1) of coronoid fractures. And younger patients were high risk of mandibular angle fractures. CONCLUSION: Through this study, it was confirmed that etiological factors of mandibular fractures were like those of previous studies.

Intramitochondrial co-assembly between ATP and nucleopeptides induces cancer cell apoptosis.

Mitochondria are essential intracellular organelles involved in many cellular processes, especially adenosine triphosphate (ATP) production. Since cancer cells require high ATP levels for proliferation, ATP elimination can be a unique target for cancer growth inhibition. We describe a newly developed mitochondria-targeting nucleopeptide (MNP) that sequesters ATP by self-assembling with ATP inside mitochondria. MNP interacts strongly with ATP through electrostatic and hydrogen bonding interactions. MNP exhibits higher binding affinity for ATP (-637.5 kJ mol-1) than for adenosine diphosphate (ADP) (-578.2 kJ mol-1). To improve anticancer efficacy, the small-sized MNP/ADP complex formed large assemblies with ATP inside cancer cell mitochondria. ATP sequestration and formation of large assemblies of the MNP/ADP-ATP complex inside mitochondria caused physical stress by large structures and metabolic disorders in cancer cells, leading to apoptosis. This work illustrates a facile approach to developing cancer therapeutics that relies on molecular assemblies.

[The Effects of Utilizing Smartphone Application Peer Support on Health Behavior and Body Mass Index among Breast Cancer Survivors].

PURPOSE: This study aimed to identify the effects of utilizing Smartphone Application Peer Support (SAPS) on health behavior and body mass index (BMI) among overweight or obese breast cancer survivors (BCS). METHODS: A nonequivalent control group with a non-synchronized design was utilized and 36 participants (experimental group 14, control group 22) were recruited from August 2017 to September 2018. Participants were 40~65 years old, overweight or obese, had completed primary cancer treatment within the 12 months prior to the study, and had not done regular exercise during the last 6 months. The 3-month SAPS consisted of exercise and diet education (once p/2 weeks), peer support (once p/week), and self-monitoring using smartphone applications (5 times p/week). All participants underwent assessments at baseline, right after SAPS, and at 3 months after SAPS. Data were analyzed using repeated measures ANOVA. RESULTS: At the completion of SAPS significant differences were found between groups in motivation for exercise (t=-3.24, p=.005), physical activity (t=-4.15, p<.001), total calorie intake (t=3.42, p=.002), calories from fat (t=-3.01, p=.005), intake of vegetables (t=-2.83, p=.008), and BMI (t=5.21, p<.001). Significant differences in BMI (t=4.13, p<.001) remained up to 3 months after SAPS completion. No significant differences was shown between groups in self-efficacy for exercise, either immediately after or 3 months after SAPS. CONCLUSION: The SAPS has the potential to improve motivation for exercise, health behavior, and BMI of BCS. However, special efforts are required to encourage participants to complete the intervention and maintain long-term effects for future trials.

Endoscopic Findings of Enteropathy-Associated T-Cell Lymphoma Type II: A Case Series.

Enteropathy-associated T-cell lymphoma (EATL) is a rare extranodal T-cell lymphoma arising from the intestine. Two types of EATL have been reported. In contrast to the classic EATL type I, EATL type II occurs sporadically, is unrelated to celiac disease, and comprises 10% to 20% of all EATL cases. A total of five cases of EATL type II were diagnosed at our clinic from January 2009 to September 2012. Four of the five patients were diagnosed with the help of endoscopy. Among the four patients, two of the cases involved both the small and large intestines, whereas in the other two patients, EATL was limited to the small intestine. Common endoscopic findings included innumerable fine granularities (also called mosaic mucosal patterns) and diffuse thickening of the mucosa with a semicircular shallow ulceration in the lesions of the small bowel. In contrast, the endoscopic findings of the colon were nonspecific and could not distinguish EATL type II from other diseases. There are only few published reports regarding the representative endoscopic findings of EATL. Here, we present the clinical and endoscopic findings of four cases of EATL type II diagnosed by endoscopy.

Brown Pine Leaf Extract and Its Active Component Trans-Communic Acid Inhibit UVB-Induced MMP-1 Expression by Targeting PI3K.

Japanese red pine (Pinus densiflora) is widely present in China, Japan, and Korea. Its green pine leaves have traditionally been used as a food as well as a coloring agent. After being shed, pine leaves change their color from green to brown within two years, and although the brown pine leaves are abundantly available, their value has not been closely assessed. In this study, we investigated the potential anti-photoaging properties of brown pine leaves for skin. Brown pine leaf extract (BPLE) inhibited UVB-induced matrix metalloproteinase-1 (MMP-1) expression to a greater extent than pine leaf extract (PLE) in human keratinocytes and a human skin equivalent model. HPLC analysis revealed that the quantity of trans-communic acid (TCA) and dehydroabietic acid (DAA) significantly increases when the pine leaf color changes from green to brown. BPLE and TCA elicited reductions in UVB-induced MMP-1 mRNA expression and activator protein-1 (AP-1) transactivation by reducing DNA binding activity of phospho-c-Jun, c-fos and Fra-1. BPLE and TCA also inhibited UVB-induced Akt phosphorylation, but not mitogen activated protein kinase (MAPK), known regulators of AP-1 transactivation. We additionally found that BPLE and TCA inhibited phosphoinositide 3-kinase (PI3K), the upstream kinase of Akt, in vitro. In summary, both BPLE and its active component TCA exhibit protective effects against UVB-induced skin aging. Taken together, these findings underline the potential for BPLE and TCA to be utilized as anti-wrinkling agents and cosmetic ingredients, as they suppress UVB-induced MMP-1 expression.

20-O-ß-D-glucopyranosyl-20(S)-protopanaxadiol suppresses UV-Induced MMP-1 expression through AMPK-mediated mTOR inhibition as a downstream of the PKA-LKB1 pathway.

Various health effects have been attributed to the ginsenoside metabolite 20-O-ß-D-glucopyranosyl-20(S)-protopanaxadiol (GPD); however, its effect on ultraviolet (UV)-induced matrix metalloproteinase (MMP)-1 expression and the mechanism underlying this effect are unknown. We examined the inhibitory effect of GPD on UV-induced MMP-1 expression and its mechanisms in human dermal fibroblasts (HDFs). GPD attenuated UV-induced MMP-1 expression in HDFs and suppressed the UV-induced phosphorylation of mammalian target of rapamycin (mTOR) and p70(S6K) without inhibiting the activity of phosphatidylinositol 3-kinase and Akt, which are well-known upstream kinases of mTOR. GPD augmented the phosphorylation of liver kinase B1 (LKB1) and adenosine monophosphate-activated protein kinase (AMPK), which are inhibitors of mTOR, to a greater extent than UV treatment alone. Similar to GPD, 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranosyl 5'-monophosphate (AICAR), an activator of AMPK, augmented UV-induced AMPK phosphorylation to a greater extent than UV treatment alone, resulting in the inhibition of MMP-1 expression. AICAR also decreased the phosphorylation of mTOR and p70(S6K). However, compound C, an antagonist of AMPK, increased MMP-1 expression. In HDF cells with AMPK knock-down using shRNA, MMP-1 expression was increased. These results indicate that AMPK activation plays a key role in MMP-1 suppression. Additionally, the cAMP-dependent protein kinase (PKA) inhibitor, H-89, antagonized GPD-mediated MMP-1 suppression via the inhibition of LKB1. Our results suggest that the suppressive activity of GPD on UV-induced MMP-1 expression is due to the activation of AMPK as a downstream of the PKA-LKB1 pathway.