Magnetically Stimulated Integrin Binding Alters Cell Polarity and Affects Epithelial-Mesenchymal Plasticity in Metastatic Cancer Cells.

Inorganic nanoparticles (NPs) have been widely recognized for their stability and biocompatibility, leading to their widespread use in biomedical applications. Our study introduces a novel approach that harnesses inorganic magnetic nanoparticles (MNPs) to stimulate apical-basal polarity and induce epithelial traits in cancer cells, targeting the hybrid epithelial/mesenchymal (E/M) state often linked to metastasis. We employed mesocrystalline iron oxide MNPs to apply an external magnetic field, disrupting normal cell polarity and simulating an artificial cellular environment. These led to noticeable changes in the cell shape and function, signaling a shift toward the hybrid E/M state. Our research suggests that apical-basal stimulation in cells through MNPs can effectively modulate key cellular markers associated with both epithelial and mesenchymal states without compromising the structural properties typical of mesenchymal cells. These insights advance our understanding of how cells respond to physical cues and pave the way for novel cancer treatment strategies. We anticipate that further research and validation will be instrumental in exploring the full potential of these findings in clinical applications, ensuring their safety and efficacy.

Radotinib attenuates TGFß -mediated pulmonary fibrosis in vitro and in vivo: exploring the potential of drug repurposing.

BACKGROUND: Tyrosine kinase (TK) plays a crucial role in the pathogenesis of idiopathic pulmonary fibrosis. Here, we aimed to investigate whether radotinib (Rb) could inhibit pulmonary fibrosis by inhibiting TK in vitro and in vivo. METHODS: The antifibrotic effects of Rb in transforming growth factor-ß (TGF-ß)1-stimulated A549 cells were determined using real-time polymerase chain reaction, western blotting, and immunocytochemistry assays. Rb inhibition of bleomycin-induced lung fibrosis in Sprague Dawley (SD) rats was determined by histopathological and​ immunohistochemical analyses. Rb-interfering metabolites were analyzed using LC-MS/MS. RESULTS: Rb concentrations of up to 1000 nM did not affect the viability of A549 cells, but Rb (30 nM) significantly reduced expression of TGF-ß1 (10 ng/mL)-induced ECM factors, such as Snail, Twist, and F-actin. Rb also regulated TGF-ß1-overexpressed signal cascades, such as fibronectin and α-smooth muscle actin. Furthermore, Rb attenuated the phosphorylation of Smad2 and phosphorylation of kinases, such as, extracellular signal-regulated kinase, and protein kinase B. In the inhibitory test against bleomycin (5 mg/kg)-induced lung fibrosis, the Rb (30 mg/kg/daily)-treated group showed a half-pulmonary fibrosis region compared to the positive control group. In addition, Rb significantly reduced collagen type I and fibronectin expression in the bleomycin-induced fibrotic region of SD rats. Further, the identified metabolite pantothenic acid was not altered by Rb. CONCLUSION: Taken together, these results indicate that Rb inhibits TGF-ß1-induced pulmonary fibrosis both in vitro and in vivo. These findings suggest that Rb may be an effective treatment for pulmonary fibrosis-related disorders and idiopathic pulmonary fibrosis.

Feasibility of 18F-Fluorocholine PET for Evaluating Skeletal Muscle Atrophy in a Starved Rat Model.

Imaging techniques for diagnosing muscle atrophy and sarcopenia remain insufficient, although various advanced diagnostic methods have been established. We explored the feasibility of 18F-fluorocholine (18F-FCH) positron emission tomography/computed tomography (PET/CT) for evaluating skeletal muscle atrophy, as an imaging technique that tracks choline level changes in muscles. Cell uptake in L6 cells by 18F-FCH was performed in a complete medium containing serum (untreated group, UN) and a serum-free medium (starved group, ST). Small-animal-dedicated PET/CT imaging with 18F-FCH was examined in in-vivo models with rats that were starved for 2 days to cause muscle atrophy. After the hind limbs were dissected, starvation-induced in-vivo models were anatomically confirmed by reverse-transcription polymerase chain reaction to evaluate the expression levels of the atrophy markers muscle RING-finger protein-1 (MuRF-1) and atrogin-1. 18F-FCH uptake was lower in the starvation-induced cells than in the untreated group, and in-vivo PET uptake also revealed a similar tendency (the average standardized uptake value (SUVmean) = 0.26 ± 0.06 versus 0.37 ± 0.07, respectively). Furthermore, the expression levels of MuRF-1 and atrogin-1 mRNA were significantly increased in the starvation-induced muscle atrophy of rats compared to the untreated group. 18F-FCH PET/CT may be a promising tool for diagnosing skeletal muscle atrophy.

Monoamine oxidase-A targeting probe for prostate cancer imaging and inhibition of metastasis.

Mitochondrial enzyme monoamine oxidase (MAO-A) is known to be overexpressed in prostate cancer (PCa) cells. Herein, we have developed a two-photon probe (PCP-1) for selectively targeting and imaging the MAO-A in PCa. Supported by enzymatic docking and in vitro experiments, PCP-1 showed efficiency to visualize MAO-A overexpressing cells and inhibit their growth and metastasis potential.

Combined Amelioration of Ginsenoside (Rg1, Rb1, and Rg3)-enriched Korean Red Ginseng and Probiotic Lactobacillus on Non-alcoholic Fatty Liver Disease.

BACKGROUND: Red ginseng is a traditional medicine that has been used to treat numerous metabolic and inflammatory diseases. Probiotic administration has been established to have beneficial effects in non-alcoholic fatty liver disease (NAFLD). The purpose of this study was to determine whether a combination of Korean red ginseng (KRG) and probiotics could synergistically reduce NAFLD and liver inflammation compared with the effects reported for each individual product. METHOD: db/db and C57BL/6 mice were fed a normal chow diet and high-fat diet (HFD), respectively, and were treated with KRG, probiotics, or both. Samples were examined for lipid content, kinase protein phosphorylation, and gene expression patterns. RESULTS: KRG- and probiotic-treated HFD-fed mice exhibited a reduction in body weight and a decrease in inflammatory cytokine secretion compared with the non-treated control mice. The same treatment was less successful in improving NAFLD parameters in the db/db mice while the combination of both products did not enhance their therapeutic potential. CONCLUSION: The results of this study indicate that KRG and probiotics administration ameliorated NAFLD symptoms in a mouse model of dyslipidemia by reducing weight gain and liver inflammation. Coadministration of both products did not enhance their efficacy, and further research should be conducted to clarify their mechanisms of action.

The organization of tyrosine hydroxylase-immunopositive cells in the sparrow retina.

The purpose of this study was to identify tyrosine hydroxylase-immunopositive (TH+) cells in the sparrow retina using immunocytochemistry and quantitative analysis. All TH+ cells were conventional amacrine cells. Based on dendritic morphology, at least two types were observed. The first type had a single thick primary process that descended from the cell body and many densely beaded processes in substrata (s) 1, less beaded processes in s3, and spiny processes in s4/5 of the inner plexiform layer. The dendrites of the second type appeared similar in each layer, but it displayed several primary processes that spread laterally away from the soma before descending to the inner plexiform layer. The average density of TH+ cells was 37.48 ± 1.97 cells/mm2 (mean ± standard deviation; n = 4), and the estimated total number of TH+ cells was 3,061.25 ± 192.79. The highest and lowest densities of TH+ cells were located in the central dorsotemporal retina and periphery of the ventronasal retina, respectively. TH+ cells did not express calbindin-D28 K, calretinin, or parvalbumin. These results suggest that all TH+ cells in specific amacrine cell subpopulations are involved in retinal information processing in both the ON and OFF sublaminae in sparrow retina.

Identification of protein kinase C α- and tyrosine hydroxylase-immunoreactive cells in the microbat retina.

A growing number of studies have revealed the functional neuroarchitecture of the microbat retina and suggested that microbats can see using their eyes. To better understand the organization of the microbat retina, quantitative analysis of protein kinase C alpha (PKCα)- and tyrosine hydroxylase (TH)-immunoreactive (IR) cells was conducted on the greater horseshoe bat (Rhinolophus ferrumequinum) retina. As a result, PKCα immunoreactivity was observed in rod bipolar cells, consistent with previous studies on other mammalian retinas. PKCα-IR cell distribution in the inner nuclear layer showed regional differences in density, with the highest density found in the nasal retina. The average density of PKCα-IR cells was 10,487±441 cells/mm² (mean ± S.D.; n=4), with a total of 43,077±1,843 cells/retina. TH-IR cells in the Rhinolophus ferrumequinum retina could be classified into four types based on soma location and ramification in the inner plexiform layer: conventional amacrine, displaced amacrine, interplexiform, and intercalated cells. The majority of TH-IR cells were conventional amacrine cells. TH-IR cells were nonrandomly distributed at low density over the retina. The average density was 29.7±3.1 cells/mm² (mean ± S.D.; n=3), with a total of 124.0±11.3 cells/retina. TH-IR processes showed varicosities and formed ring-like structures encircling AII amacrine cells. Our study provides the foundation for understanding the neurochemical architecture of the microbat retina and supports the notion that the eyes do play a role in the visual system of microbats.

Association between Aspirin Therapy and Clinical Outcomes in Patients with Non-Obstructive Coronary Artery Disease: A Cohort Study.

BACKGROUND: Presence of non-obstructive coronary artery disease (CAD) is associated with increased prescription of cardiovascular preventive medications including aspirin. However, the association between aspirin therapy with all-cause mortality and coronary revascularization in this population has not been investigated. METHODS AND FINDINGS: Among the cohort of individuals who underwent coronary computed tomography angiography (CCTA) from 2007 to 2011, 8372 consecutive patients with non-obstructive CAD (1-49% stenosis) were identified. Patients with statin or aspirin prescription before CCTA, and those with history of revascularization before CCTA were excluded. We analyzed the differences of all-cause mortality and a composite of mortality and late coronary revascularization (> 90 days after CCTA) between aspirin users (n = 3751; 44.8%) and non-users. During a median of 828 (interquartile range 385-1,342) days of follow-up, 221 (2.6%) mortality cases and 295 (3.5%) cases of composite endpoint were observed. Annualized mortality rates were 0.97% in aspirin users versus 1.28% in non-users, and annualized rates of composite endpoint were 1.56% versus 1.48%, respectively. Aspirin therapy was associated with significantly lower risk of all-cause mortality (adjusted HR 0.649; 95% CI 0.492-0.857; p = 0.0023), but not with the composite endpoint (adjusted HR 0.841; 95% CI 0.662-1.069; p = 0.1577). Association between aspirin and lower all-cause mortality was limited to patients with age ≥ 65 years, diabetes, hypertension, decreased renal function, and higher levels of coronary artery calcium score, low-density lipoprotein cholesterol and high-sensitivity C-reactive protein. CONCLUSIONS: Among the patients with non-obstructive CAD documented by CCTA, aspirin is associated with lower all-cause mortality only in those with higher risk.

Statin therapy is associated with lower all-cause mortality in patients with non-obstructive coronary artery disease.

OBJECTIVE: Non-obstructive coronary artery disease (CAD) is a frequent clinical condition and is associated with an increase in cardiovascular events. However, appropriate medical therapy for this population is not known. We investigated the association between statin use and risk of all-cause mortality and coronary revascularization in patients with non-obstructive CAD. METHODS: From 2007 to 2011, we identified 8372 consecutive patients with non-obstructive CAD (1-49% stenosis) documented by coronary computed tomography angiography (CCTA) from 3 medical centers. Patients with statins or aspirin use before CCTA, and a history of revascularization before initial CCTA were excluded. All-cause mortality and a composite of mortality and late coronary revascularization (>90 days after CCTA) were analyzed according to the use of statins. RESULTS: Mean age of the study population was 61.4 ± 10.9 years and 70.3% were male. Statins were prescribed to 1983 (23.7%) patients. During 828 days of follow-up (IQR 385-1342), 221 (2.6%) cases of all-cause mortality and 295 (3.5%) cases of the composite endpoint were observed. Statin therapy was associated with lower risks of all-cause mortality (adjusted HR 0.397; 95% CI 0.262-0.602; p < 0.0001) and composite endpoint (adjusted HR 0.430; 95% CI 0.310-0.597; p < 0.0001). Association between statin therapy and better clinical outcomes was regardless of age, sex, presence of hypertension or diabetes, coronary artery calcium score, low-density lipoprotein cholesterol levels, high-sensitivity C-reactive protein levels, or glomerular filtration rate. CONCLUSIONS: Statin therapy was associated with a lower risk of all-cause mortality in patients with non-obstructive CAD documented by CCTA, regardless of combined clinical risk factors.