Station-Level Effects of the COVID-19 Pandemic on Subway Ridership in the Seoul Metropolitan Area.

This paper investigates the station-level impacts of the coronavirus disease (COVID-19) pandemic on subway ridership in the Seoul Metropolitan Area. Spatial econometric models are constructed to examine the association between ridership reduction caused by the pandemic and station-level characteristics during the pandemic years 2020 and 2021. The results reveal unequal effects on station-level ridership, based on the pandemic waves, the demographics, and the economic features of pedestrian catchment areas. First, the subway system was severely disrupted by the pandemic, with significant decreases in ridership-by about 27% for each of the pandemic years-compared with the pre-pandemic year (2019). Second, the ridership reduction was sensitive to the three waves in 2020 and responded accordingly; however, it became less sensitive to the waves in 2021, indicating that subway usage was less responsive to pandemic waves during the second year of the pandemic. Third, pedestrian catchment areas with higher numbers of younger residents (in their 20s) and older residents (65 years and older), those with more businesses requiring face-to-face interactions with consumers, and stations located in the employment centers were hit the hardest in ridership reduction caused by the pandemic.

Hederacolchiside A1 Suppresses Autophagy by Inhibiting Cathepsin C and Reduces the Growth of Colon Cancer.

While autophagy degrades non-functional or unnecessary cellular components, producing materials for synthesizing cellular components, it can also provide energy for tumor development. Hederacolchiside A1 (HA1) derived from anemone raddeana has anticancer effects on several carcinomas by inducing apoptosis or exhibiting cytotoxicity, but the relationship with autophagy has not been studied. We investigated the association between HA1 and autophagy and evaluated its anticancer effect on colon cancer. HA1 induced accumulation of the autophagy-related markers LC3B and SQSTM1, with distinct vacuolar formation, unlike other autophagy inhibitors; the effects were similar to those of chloroquine. In addition, HA1 decreased the expression and proteolytic activity of lysosomal protein cathepsin C, reduced the growth of colon cancer cells in vitro, and inhibited tumor growth in vivo. It also reduced the expression of Ki-67 and cathepsin C in mouse tissues and reduced the growth of spheroids and organoids composed of cancer cells. Taken together, these results imply that HA1 regulates cell growth and autophagy and has potential as a promising therapeutic agent in colon cancer.

The Decursin Analog, CYJ-27, Suppresses Inflammation Via the Downregulation of NF-κB and STAT-1.

CYJ-27, a synthetic analog of decursin, prevents the generation of proinflammatory cytokines and oxidative stress. In this study, the effects of CYJ-27 on the regulation of inducible nitric oxide synthase (iNOS), heme oxygenase (HO)-1, and cyclooxygenase (COX-)2 were characterized in lipopolysaccharide (LPS)-treated human umbilical vein endothelial cells (HUVECs). In addition, the effects of CYJ-27 on the production of iNOS and representative proinflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-1ß, were tested in the lung tissues of LPS-treated mice. CYJ-27 promoted the expression of HO-1, suppressed NF-κB-luciferase activity, and reduced COX-2/PGE2 and iNOS/NO, resulting in a diminution in phosphorylated-STAT-1. Furthermore, CYJ-27 promoted the nuclear translocation of Nrf2, enhanced the combination of Nrf2 to antioxidant response elements, and diminished IL-1ß production in LPS-activated HUVECs. CYJ-27-downregulated iNOS/NO expression was rescued after the RNAi suppression of HO-1. In LPS-treated mice, CYJ-27 significantly diminished iNOS production in the lung tissues and TNF-α expression in the bronchoalveolar lavage fluid. These findings indicate that CYJ-27 exerts anti-inflammatory activities by regulating iNOS through downregulation of both NF-κB activation and phosphorylated-STAT-1. Hence, it can act as a template for the development of novel substances to treat inflammatory diseases.

Ginsenoside Rg4 Enhances the Inductive Effects of Human Dermal Papilla Spheres on Hair Growth Via the AKT/GSK-3ß/ß-Catenin Signaling Pathway.

Ginsenoside Rg4 is a rare ginsenoside that is naturally found in ginseng, and exhibits a wide range of biological activities including antioxidant and anti-inflammatory properties in several cell types. The purpose of this study was to use an in vivo model of hair follicle (HF)-mimic based on a human dermal papilla (DP) spheroid system prepared by three-dimensional (3D) culture and to investigate the effect of Rg4 on the hair-inductive properties of DP cells. Treatment of the DP spheroids with Rg4 (20 to 50 µg/ml) significantly increased the viability and size of the DP spheres in a dose-dependent manner. Rg4 also increased the mRNA and protein expression of DP signature genes that are related to hair growth including ALP, BMP2, and VCAN in the DP spheres. Analysis of the signaling molecules and luciferase reporter assays further revealed that Rg4 induces the activation of phosphoinositide 3-kinase (PI3K)/AKT and the inhibitory phosphorylation of GSK3ß, which activates the WNT/ß-catenin signaling pathway. These results correlated with not only the increased nuclear translocation of ß-catenin following the treatment of the DP spheres with Rg4 but also the significant elevation of mRNA expression of the downstream target genes of the WNT/ß-catenin pathway including WNT5A, ß-catenin, and LEF1. In conclusion, these results demonstrated that ginsenoside Rg4 promotes the hair-inductive properties of DP cells by activating the AKT/GSK3ß/ß-catenin signaling pathway in DP spheres, suggesting that Rg4 could be a potential natural therapy for hair growth.

Lung-selective 25-hydroxycholesterol nanotherapeutics as a suppressor of COVID-19-associated cytokine storm.

In response to the coronavirus disease-19 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), global efforts are focused on the development of new therapeutic interventions. For the treatment of COVID-19, selective lung-localizing strategies hold tremendous potential, as SARS-CoV-2 invades the lung via ACE2 receptors and causes severe pneumonia. Similarly, recent reports have shown the association of COVID-19 with decreased 25-hydroxycholesterol (25-HC) and increased cytokine levels. This mechanism, which involves the activation of inflammatory NF-κB- and SREBP2-mediated inflammasome signaling pathways, is believed to play a crucial role in COVID-19 pathogenesis, inducing acute respiratory distress syndrome (ARDS) and sepsis. To resolve those clinical conditions observed in severe SARS-CoV-2 patients, we report 25-HC and didodecyldimethylammonium bromide (DDAB) nanovesicles (25-HC@DDAB) as a COVID-19 drug candidate for the restoration of intracellular cholesterol level and suppression of cytokine storm. Our data demonstrate that 25-HC@DDAB can selectively accumulate the lung tissues and effectively downregulate NF-κB and SREBP2 signaling pathways in COVID-19 patient-derived PBMCs, reducing inflammatory cytokine levels. Altogether, our findings suggest that 25-HC@DDAB is a promising candidate for the treatment of symptoms associated with severe COVID-19 patients, such as decreased cholesterol level and cytokine storm.

PEGylated nanoparticle albumin-bound steroidal ginsenoside derivatives ameliorate SARS-CoV-2-mediated hyper-inflammatory responses.

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on a global scale urges prompt and effective countermeasures. Recently, a study has reported that coronavirus disease-19 (COVID-19), the disease caused by SARS-CoV-2 infection, is associated with a decrease in albumin level, an increase in NETosis, blood coagulation, and cytokine level. Here, we present drug-loaded albumin nanoparticles as a therapeutic agent to resolve the clinical outcomes observed in severe SARS-CoV-2 patients. PEGylated nanoparticle albumin-bound (PNAB) was used to promote prolonged bioactivity of steroidal ginsenoside saponins, PNAB-Rg6 and PNAB-Rgx365. Our data indicate that the application of PNAB-steroidal ginsenoside can effectively reduce histone H4 and NETosis-related factors in the plasma, and alleviate SREBP2-mediated systemic inflammation in the PBMCs of SARS-CoV-2 ICU patients. The engineered blood vessel model confirmed that these drugs are effective in suppressing blood clot formation and vascular inflammation. Moreover, the animal model experiment showed that these drugs are effective in promoting the survival rate by alleviating tissue damage and cytokine storm. Altogether, our findings suggest that these PNAB-steroidal ginsenoside drugs have potential applications in the treatment of symptoms associated with severe SARS-CoV-2 patients, such as coagulation and cytokine storm.

Anti-photoaging effect of skin cream manufactured with ziyuglycoside I isolated from Sanguisorba officinalis on ultraviolet B-induced hairless mice.

In this study, skin cream containing ziyuglycoside I isolated from Sanguisorba officinalis was manufactured and examined the protective effects of the skin cream against UVB-induced hairless mice. UVB-induced hairless mice were topically treated with the skin cream once a day for 5 weeks. Application of the skin cream did not exhibit side effect on body growth showing normal body weight and food efficiency in the mice. The skin cream treatment also was inhibited mRNA expression of interleukin (IL)-1ß, matrix metalloproteinase (MMP)-2, MMP-9, and MMP-2 protein expression in the mice. Furthermore, the skin cream treatment inhibits epidermal wrinkle formation, wrinkle depth, wrinkle thickness, and collagen degradation in UVB-induced hairless mice. Therefore, the skin cream was able to play a role in the attenuation of photoaging caused by UVB irradiation via downregulation of mRNA expression of inflammatory cytokine IL-1ß, MMP-2, MMP-9, and suppression of MMP-2 proteins expression.

Capsosiphon fulvescens extracts improve obesity-associated metabolic disorders and hepatic steatosis in high-fat diet-induced obese mice.

Herbal dietary supplements have attracted more and more attention owing to their relative effectiveness in obesity -related metabolic disorders and diseases. This study investigated the therapeutic effects and underlying mechanisms of Capsosiphon fulvescens (CF) extracts on obesity, their associated metabolic disorders and hepatic steatosis in high-fat diet (HFD)-induced obese mice. Male C57BL/6 mice were fed with normal, HFD/Vehicle and HFD/CF (orally 300 mg/kg/day for CF). After 12 weeks, CF blocked HFD-induced body weight, food intake, liver weight, hepatic triglyceride (TG), fat mass (weight of abdominal subcutaneous fat and epididymal adipose tissue) and biochemical parameters (total cohlesterol, glucose, TG, creatinine, high-density lipoproteins cholesterol and low-density lipoprotein cholesterol) of serum. CF also had improved serum levels of adiponectin, leptin and insulin-like growth factor-1 in HFD/CF mice. Moreover, CF ameliorated the hepatic steatosis-reducing size of white adipose tissue. These results indicate that CF have anti-obesity effects and are effective for reducing metabolic risk and hepatic steatosis.

Synthesis and evaluation of (+)-decursin derivatives as inhibitors of the Wnt/ß-catenin pathway.

We synthesized (+)-decursin derivatives substituted with cinnamoyl- and phenyl propionyl groups originating from (+)-CGK062 and screened them using a cell-based assay to detect relative luciferase reporter activity. Of this series, compound 8b, in which a 3-acetoxy cinnamoyl group was introduced, most potently inhibited (97.0%) the Wnt/ß-catenin pathway. Specifically, compound 8b dose-dependently inhibited Wnt3a-induced expression of the ß-catenin response transcription (CRT) and increased ß-catenin degradation in HEK293 reporter cells. Furthermore, compound 8b suppressed expression of the downstream ß-catenin target genes cyclin D1 and c-myc and suppressed PC3 cell growth in a concentration-dependent manner.

Mitomycin C and doxorubicin elicit conflicting signals by causing accumulation of cyclin E prior to p21WAF1/CIP1 elevation in human hepatocellular carcinoma cells.

Proteins involved in the G1 phase of the cell cycle are aberrantly expressed, sometimes in mutated forms, in human cancers including human hepatocellular carcinoma. Upon attack by a DNA-damaging anticancer drug, a cell arrests at the G1 phase; this is a safety feature prohibiting entry of DNA-damaged cells into S-phase. p21WAF1/CIP1 prevents damaged cells from progressing to the next cell cycle. Here, we show that, in response to mitomycin C and doxorubicin, human hepatocellular carcinoma cells generate conflicting signals, mediated by cyclin E and p21WAF1/CIP1, which respectively accelerates and represses cell cycle transition. Exposure to these anticancer drugs led to rapid accumulation of cyclin E in both p53-proficient HepG2 and p53-deficient Hep3B cells. Such anticancer drug-induced cyclin E accumulation influenced the G1-S-phase transition, but not DNA fragmentation-mediated death. In p53-proficient HepG2 cells, accumulation of cyclin E was followed by an increase in the level of p53-dependent p21WAF1/CIP1, thereby inhibiting further the G1-S-phase transition. Sublethal drug concentrations also induced rapid accumulation of cyclin E, but p21WAF1/CIP1 accumulation was delayed, further facilitating the G1-S-phase transition. Eventually, most cells arrested in G2/M. Thus, mitomycin C- or doxorubicin-induced conflicting signals, mediated by cyclin E and p21WAF1/CIP1, are in play in human hepatocellular carcinoma cells. Damaged G1 cells either immediately enter S-phase, or do not do so at all, depending on the extent of DNA damage.

Therapeutic effects of Baicalein on atopic dermatitis-like skin lesions of NC/Nga mice induced by dermatophagoides pteronyssinus.

The present study was conducted to investigate the effects of Baicalein (BE), which is hydrolyzed product of Baicalin (BA), on atopic dermatitis (AD). AD was induced in NC/Nga mice by DPE treatment. BE hydrogels treatment reduced the levels of skin severity scores. BE hydrogels treatment also decreased inflammatory cytokines such as TNF-alpha, IL-6, and its level in the serum. BE hydrogels treatment elevated IFN-gamma level in the spleenocyte culture supernatant. Cell numbers in the skin positive to CD3+/CD69+, CCR3+, CD11b+/Gr-1+, B220+/IgE+ all of which were up-regulated in AD-induced mice were decreased and returned to normal levels. Histological examination showed that infiltration levels of immune cells in the skin of AD-induced NC/Nga mice were much improved by BE hydrogels treatment. These results thus suggest that BE can regulate molecular mediators and immune cells that are functionally associated with atopic dermatitis induced in NC/Nga mice, and may play an important role in recovering AD symptoms.

Murrayafoline A attenuates the Wnt/beta-catenin pathway by promoting the degradation of intracellular beta-catenin proteins.

Molecular lesions in Wnt/beta-catenin signaling and subsequent up-regulation of beta-catenin response transcription (CRT) occur frequently during the development of colon cancer. To identify small molecules that suppress CRT, we screened natural compounds in a cell-based assay for detection of TOPFalsh reporter activity. Murrayafoline A, a carbazole alkaloid isolated from Glycosmis stenocarpa, antagonized CRT that was stimulated by Wnt3a-conditioned medium (Wnt3a-CM) or LiCl, an inhibitor of glycogen synthase kinase-3beta (GSK-3beta), and promoted the degradation of intracellular beta-catenin without altering its N-terminal phosphorylation at the Ser33/37 residues, marking it for proteasomal degradation, or the expression of Siah-1, an E3 ubiquitin ligase. Murrayafoline A repressed the expression of cyclin D1 and c-myc, which is known beta-catenin/T cell factor (TCF)-dependent genes and thus inhibited the proliferation of various colon cancer cells. These findings indicate that murrayafoline A may be a potential chemotherapeutic agent for use in the treatment of colon cancer.

The effects of ketorolac tromethamine and baicalein on the levels of inflammatory factors in human synoviocytes.

This study examined the effects of ketorolac tromethamine (KT) and baicalein (BE) on the levels of inflammatory factors in human synoviocytes. The fibroblast-like synoviocytes (FLS) cells were used to determine the possible regulatory effects of KT and BE (KTBE) on the levels of inflammatory factors in FLS cells. In addition, the levels of TNF-alpha, IL-6, and IL-1beta mRNA expression in FLS cells induced by a TNF-alpha and IL-1beta co-treatment were largely inhibited by a KTBE treatment. The level of FLS cells proliferation was increased by IL-1beta and TNF-alpha, and strongly inhibited by KTBE treatment. The production of oxygen species (ROS) was inhibited by KTBE in FLS cells. KTBE appears to regulate the levels of mRNA that are important for regulating RA progression.

Preparation and evaluation of ketorolac tromethamine gel containing genipin for periodontal diseases.

Ketorolac tromethamine gel (KT gel) and ketorolac tromethamine gel containing genipin (KTG gel) were prepared and their therapeutic effects on periodontitis were evaluated. The skin permeation rate of ketorolac from the KT gel and KTG gel was 5.75+/-0.53 and 5.82 +/- 0.74 microg/cm2/ h, respectively. The skin permeation rate of genipin from the KTG gel was 10.13 +/- 1.47 microg/ cm2/h. The tensile strength of the KTG gel was larger than the KT gel. After 4 weeks, the periodontal pocket depth of the KTG gel group (3.22 +/- 0.20 mm) significantly decreased compared with the non-treated group (4.50 +/- 0.25 mm) and the KT group (3.84 +/- 00.26 mm). The KTG gel did not induce separation of the stratum corneum and subcutaneous tissue, and the collagen layers of the corium were closer, more fibrous, and showed longer connections than in the other groups. The KTG gel appears to be effective against gingivitis in the periodontal pocket through its increased anti-inflammatory activity and the crosslinking of genipin with the biological tissue.

Cytotoxic isoquinoline alkaloids from the aerial parts of Corydalis incisa.

Three known isoquinoline alkaloids were isolated from the chloroform-soluble fraction of the methanolic extract of the aerial parts of Corydalis incisa (Papaveraceae) through repeated column chromatography. Their chemical structures were elucidated as corynoline (1), corynoloxine (2) and 6-oxocorynoline (3) using spectroscopic analysis. Compounds 1-3 exhibited cytotoxicity against human A549, SK-OV-3, SK-MEL-2 and HCT15 tumor cells.

Transdermal delivery system of triamcinolone acetonide from a gel using phonophoresis.

Triamcinolone acetonide (TA) is a corticosteroid that is used in the systemic and topical treatment of many inflammatory diseases. In this study, a phonophoretic drug delivery system was designed to enhance the TA permeability and the influence of ultrasound was examined. In order to establish the transdermal delivery system for TA, a hydrophilic carbopol gel containing TA was prepared after adopting phonophoresis. A permeation study through mouse skin was performed at 37 degrees C using a Franz diffusion cell, and the ultrasound treatment was carried out for 10 h. The level of TA permeation through the skin was evaluated under various ultrasound conditions including the frequency (1.0, 3.0 MHz), intensity (1.0, 2.5 W/cm2), and duty cycle (continuous, pulse mode) using a 0.5% TA gel. The highest permeation was observed under the ultrasound treatment conditions of low frequency, high intensity, and in continuous mode.

5-Arylidene-2(5H)-furanone derivatives: synthesis and structure-activity relationship for cytotoxicity.

Thirty-eight 5-arylidene-2(5H)-furanone derivatives possessing halo-, methoxy-, oxo-, dioxo-, and thiophenyl groups as well as anthraquinone and naphthquinone moieties were synthesized, and their cytotoxicity was evaluated against various cancer cell lines. The introduction of halogen atoms or nitro group at aromatic ring of 5-arylidene-2(5H)-furanone was shown to increase the cytotoxicity with 5-(3-nitrobenzylidene)-2(5H)-furanone (21) being the most potent. Among anthracenyl or naphthalenyl derivatives, (E)-5-[2-(1,4-dimethoxy-9,10-dioxo) anthracenyl]-2(5H)-furanone (34) showed the most potent cytotoxic activity.