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In this study, high particulate matter (PM2.5) pollution episodes were examined in Seoul, the capital city of South Korea, which, based on the episode characteristics, were influenced by a distinct meteorological mode, long-range transport (LRT), from two-level meteorological observations: surface and 850-500 hPa level. We performed two-step statistical analysis including principal component (PC) analysis of meteorological variables based on the observation data, followed by multiple linear regression (MLR). The meteorological variables included surface temperature (Tsfc), wind speed (WSsfc), and the east–west (usfc) and north– south (vsfc) components of wind speed, as well as wind components at 850 hPa geopotential height (u850 and v850, respectively) and the vertical temperature gradient between 850 and 500 hPa. Our two-step analysis of data collected during 2018–2019 revealed that the dominant factors influencing high-PM2.5 days in Seoul (129 days) were upper wind characteristics in winter, including positive u850 and negative v850, that were controlled by the presence of continental anticyclones that increased the likelihood of LRT of PM2.5 pollutants. Regional-scale meteorological variables, including surface and upper meteorological variables on normal and high-PM2.5 days, showed distinct covariation over Seoul, a megacity in the eastern part of northeast Asia with large anthropogenic emissions. Although this study examined only two atmospheric layers (surface and 500-850 hPa), our results clearly detected high-PM2.5 episodes with LRT characteristics, suggesting the importance of considering both geographical distinctiveness and seasonal meteorological covariability when scaling down continental-to-local response to emission reduction.

Background Reducing salt intake helps prevent complications of cerebrovascular disease. To help patients accept a low-sodium diet, the salty taste test is used to evaluate how much salt an individual actually consumes. The aim of this study was to help patients with hypertension reduce their salt intake by helping them recognize the difference between their subjective perception of saltiness and the objective test results. Methods We enrolled workers who visited a local occupational health institution in the period from April to August 2019. Demographic and physical characteristics were recorded. Blood pressure measurement and use of medication were also recorded. A questionnaire was used to investigate whether people liked or disliked salty food, i.e., preference for saltiness, and whether they usually ate salty, normal, or fresh food, i.e., the subjective perception of saltiness. Subsequently, the taste determination kit provided by the Ministry of Food and Drug Safety was used to objectively test saltiness at various salty taste concentrations. The Ministry of Food and Drug Safety program (No. 10-093760) was used as the salty taste judgment tool. Results A total of 86 workers were surveyed. Eleven of 18 workers (61.1%) who reported usually eating fresh food actually ate normal or salty food. Thirteen of 37 workers (35.1%) who reported eating normal food actually ate salty food. Thirteen of 31 workers (41.9%) who reported eating salty food actually ate fresh or normal food. Of 46 workers who reported disliking salty food, 14 (30.4%) actually ate salty food, while 20 (43.5%) ate normal food. The subjective perception and preference for saltiness were not significantly correlated with the objective test results (P = ​​0.085 and P = 0.110, respectively). As for the subjective perception and preference for saltiness, Cohen’s weighted kappa for the taste judgment result were 0.23 and 0.22, respectively, indicating a low degree of agreement. Conclusions In dietary counseling to prevent cerebrovascular and cardiovascular diseases, rather than relying on the subjective perception of saltiness, a salty taste test should be performed such that people can recognize their salty food eating habits through objective evaluation.

Diabetic nephropathy (DN) is associated with kidney fibrosis. A previous study revealed that periostin (POSTN) contributes to kidney fibrosis. This study examined the role of POSTN in DN. The urinary concentrations of POSTN and TNC increased according to the severity of DN in human samples. Streptozotocin (STZ) was administered after unilateral nephrectomy (UNXSTZ) to induce DN in both wild-type and Postn-null mice. Four experimental groups were generated: wild-type sham (WT sham), wild-type UNXSTZ (WT STZ), Postn-null sham (KO sham), Postn-null UNXSTZ (KO STZ). After 20 weeks, the KO STZ group had lower urine albumin excretion, glomerular sclerosis, and interstitial fibrosis than the WT STZ group. Also, it had lower expression of fibrosis markers, including TNC. The KO STZ group showed better glucose regulation than the WT STZ model. Furthermore, the KO STZ group preserved pancreatic islet integrity and insulin expression significantly. We stimulated INS-1 cells with streptozotocin and evaluated the viability of these cells. The anti-POSTN antibody treatment of INS-1 cells with streptozotocin resulted in higher cell viability than treatment with streptozotocin alone. The absence of POSTN in DN contributes to renal fibrosis alleviation by improving pancreatic β-cell function. Additionally, there is an association between POSTN and TNC.

PDF file - 194K, S1. Validation of knockdowns. S2. Regulation of K-RAS acetylation and oncogenicity by HDAC1/6. S3. SIRT2 regulates K-RAS acetylation and oncogenicity.

Activating point mutations in K-RAS are extremely common in cancers of the lung, colon, and pancreas and are highly predictive of poor therapeutic response. One potential strategy for overcoming the deleterious effects of mutant K-RAS is to alter its posttranslational modification. Although therapies targeting farnesylation have been explored, and have ultimately failed, the therapeutic potential of targeting other modifications remains to be seen. Recently, it was shown that acetylation of lysine 104 attenuates K-RAS transforming activity by interfering with GEF-induced nucleotide exchange. Here, the deacetylases HDAC6 and SIRT2 were shown to regulate the acetylation state of K-RAS in cancer cells. By extension, inhibition of either of these enzymes has a dramatic impact on the growth properties of cancer cells expressing activation mutants of K-RAS. These results suggest that therapeutic targeting of HDAC6 and/or SIRT2 may represent a new way to treat cancers expressing mutant forms of K-RAS.Implications: This study suggests that altering K-RAS acetylation is a feasible approach to limiting tumorigenic potential. Mol Cancer Res; 11(9); 1072–7. ©2013 AACR.

Transcriptome profiling of tubulointerstitial tissue in glomerulonephritis may reveal a potential tubulointerstitial injury-related biomarker. We profiled manually microdissected tubulointerstitial tissue from biopsy cores of 65 glomerulonephritis cases, including 43 patients with IgA nephropathy, 3 with diabetes mellitus nephropathy, 3 with focal segmental glomerulosclerosis, 3 with lupus nephritis, 4 with membranous nephropathy and 9 with minimal change disease, and additional 22 nephrectomy controls by RNA sequencing. A potential biomarker was selected based on the false discovery rate, and experiments were performed in TNF-α-stimulated primary cultured human tubular epithelial cells (hTECs). We identified 3037 genes with low expression and 2852 genes with high expression in the disease samples compared to the controls. Dual-specificity phosphatase 1 (DUSP1) exhibited universal low expression in various diseases (log2 fold change, -3.87), with the lowest false discovery rate (7.03E-132). In further experimental validation study, DUSP1 overexpression ameliorated inflammatory markers related to MAP kinase pathways in hTECs, while pharmacologic inhibition of DUSP1 increased these markers. The combination of DUSP1 overexpression with low-concentration corticosteroid treatment resulted in more potent suppression of inflammation than high-concentration corticosteroid treatment alone. The profiled transcriptomes provide insights into the pathophysiology of tubulointerstitial injury in kidney diseases and may reveal a potential therapeutic biomarker.

Legends for Supplemental Figures S1-S4.

Supplemental Figure S1. VEGF-A silencing in WM1617, C8161 and A2058 melanoma cells by plasmid-based shRNA (sh2).

A highly contagious virus, severe acute respiratory syndrome coronavirus 2, caused the coronavirus disease 19 (COVID-19) pandemic (SARS-CoV-2). SARS-CoV-2 genetic variants have been reported to circulate throughout the COVID-19 pandemic. COVID-19 symptoms include respiratory symptoms, fever, muscle pain, and breathing difficulty. In addition, up to 30% of COVID-19 patients experience neurological complications such as headaches, nausea, stroke, and anosmia. However, the neurotropism of SARS-CoV-2 infection remains largely unknown. This study investigated the neurotropic patterns between the B1.617.2 (Delta) and Hu-1 variants (Wuhan, early strain) in K18-hACE2 mice. Despite both the variants inducing similar pathogenic patterns in various organs, B1.617.2-infected K18-hACE2 mice demonstrated a higher range of disease phenotypes such as weight loss, lethality, and conjunctivitis when compared to those in Hu-1-infected mice. In addition, histopathological analysis revealed that B1.617.2 infects the brain of K18-hACE2 mice more rapidly and effectively than Hu-1. Finally, we discovered that, in B1.617.2-infected mice, the early activation of various signature genes involved innate cytokines and that the necrosis-related response was most pronounced than that in Hu-1-infected mice. The present findings indicate the neuroinvasive properties of SARS-CoV-2 variants in K18-hACE2 mice and link them to fatal neuro-dissemination during the disease onset.

Brassinin (BSN), a potent phytoalexin found in cruciferous vegetables, has been found to exhibit diverse anti-neoplastic effects on different cancers. However, the impact of BSN on chronic myelogenous leukemia (CML) cells and the possible mode of its actions have not been described earlier. We investigated the anti-cytotoxic effects of BSN on the KBM5, KCL22, K562, and LAMA84 CML cells and its underlying mechanisms of action in inducing programmed cell death. We noted that BSN could induce apoptosis, autophagy, and paraptosis in CML cells. BSN induced PARP cleavage, subG1 peak increase, and early apoptosis. The potential action of BSN on autophagy activation was confirmed by an LC3 expression and acridine orange assay. In addition, BSN induced paraptosis through increasing the reactive oxygen species (ROS) production, mitochondria damage, and endoplasmic reticulum (ER) stress. Moreover, BSN promoted the activation of the MAPK signaling pathway, and pharmacological inhibitors of this signaling pathway could alleviate all three forms of cell death induced by BSN. Our data indicated that BSN could initiate the activation of apoptosis, autophagy, and paraptosis through modulating the MAPK signaling pathway.

We aimed to determine the metabolomic profile of kidney cells under high glucose conditions and following sodium-glucose cotransporter 2 (SGLT2) inhibitor treatment. Targeted metabolomics using the Absolute IDQ-p180 kit was applied to quantify metabolites in kidney cells stimulated with high glucose (25 and 50 mM) and treated with SGLT2 inhibitor, dapagliflozin (2 µM). Primary cultured human tubular epithelial cells and podocytes were used to identify the metabolomic profile in high glucose conditions following dapagliflozin treatment. The levels of asparagine, PC ae C34:1, and PC ae C36:2 were elevated in tubular epithelial cells stimulated with 50 mM glucose and were significantly decreased after 2 µM dapagliflozin treatment. The level of PC aa C32:0 was significantly decreased after 50 mM glucose treatment compared with the control, and its level was significantly increased after dapagliflozin treatment in podocytes. The metabolism of glutathione, asparagine and proline was significantly changed in tubular epithelial cells under high-glucose stimulation. And the pathway analysis showed that aminoacyl-tRNA biosynthesis, arginine and proline metabolism, glutathione metabolism, valine, leucine and isoleucine biosynthesis, phenylalanine, tyrosine, and tryptophan biosynthesis, beta-alanine metabolism, phenylalanine metabolism, arginine biosynthesis, alanine, aspartate and glutamate metabolism, glycine, serine and threonine metabolism were altered in tubular epithelial cells after dapagliflozin treatment following 50 mM glucose compared to those treated with 50 mM glucose.

In breast cancer (BC), STAT3 is hyperactivated. This study explored the design of imidazopyridine-tethered pyrazolines as a de novo drug strategy for inhibiting STAT3 phosphorylation in human BC cells. This involved the synthesis and characterization of two series of compounds namely, 1-(3-(2,6-dimethylimidazo [1,2-a]pyridin-3-yl)-5-(3-nitrophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-(4-(substituted)piperazin-1-yl)ethanone and N-substituted-3-(2,6-dimethylimidazo[1,2-a]pyridin-3-yl)-5-(3-nitrophenyl)-4,5-dihydro-1H-pyrazoline-1-carbothioamides. Compound 3f with 2,3-dichlorophenyl substitution was recognized among the tested series as a lead structure that inhibited the viability of MCF-7 cells with an IC50 value of 9.2 μM. A dose- and time-dependent inhibition of STAT3 phosphorylation at Tyr705 and Ser727 was observed in MCF-7 and T47D cells when compound 3f was added in vitro. Calculations using density functional theory showed that the title compounds HOMOs and LUMOs are situated on imidazopyridine-pyrazoline and nitrophenyl rings, respectively. Hence, compound 3f effectively inhibited STAT3 phosphorylation in MCF-7 and T47D cells, indicating that these structures may be an alternative synthon to target STAT3 signaling in BC.

Corilagin (CLG) is a hydrolyzable tannin and possesses various pharmacological activities. Here, we investigated the impact of CLG as an anti-tumor agent against human gastric tumor cells. We observed that CLG could cause negative regulation of JAKs-Src-STAT3/5 signaling axis in SNU-1 cells, but did not affect these pathways in SNU-16 cells. Interestingly, CLG promoted the induction of mitogen-activated protein kinases (MAPKs) signaling pathways in only SNU-16 cells, but not in the SNU-1 cells. CLG exhibited apoptotic effects that caused an increased accumulation of the cells in sub-G1 phase and caspase-3 activation in both SNU-1 and SNU-16 cell lines. We also noticed that CLG and docetaxel co-treatment could exhibit significantly enhanced apoptotic effects against SNU-1 cells. Moreover, the combinations treatment of CLG and docetaxel markedly inhibited cell growth, phosphorylation of JAK-Src-STAT3 and induced substantial apoptosis. Additionally, pharmacological inhibition of JNK, p38, and ERK substantially blocked CLG-induced activation of MAPKs, cell viability, and apoptosis, thereby implicating the pivotal role of MAPKs in the observed anti-cancer effects of CLG. Taken together, our data suggest that CLG could effectively block constitutive STAT3/5 activation in SNU-1 cells but induce sustained MAPKs activation in SNU-16 cells.