• Advances in nano research
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• v.13 no.1
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• pp.87-96
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• 2022

Drug self-delivery systems can easily realize combination drug therapy and avoid carrier-induced toxicity and immunogenicity because they do not need non-therapeutic carrier materials. So, designing appropriate drug self-delivery systems for specific diseases can settle most of the problems existing in traditional drug delivery systems. Retinal pigment epithelium is very important for the homeostasis of retina. However, it is vulnerable to oxidative damage and difficult to repair. Worse still, the antioxidants can hardly reach the retina by non-invasive administration routes due to the ocular barriers. Herein, the targeted group (folic acid) and antioxidant (melatonin) have been grafted on the surface of ZnO quantum dots to fabricate a new kind of drug self-delivery systems as a protectant via eyedrops. In this study, the negative nanoparticles with size ranging in 4~6 nm were successfully synthesized. They could easily and precisely deliver drugs to retinal pigment epithelium via eyedrops. And they realized acid degradation to controlled release of melatonin and zinc in retinal pigment epithelium cells. Consequently, the structure of retinal pigment epithelium cells were stabilized according to the expression of ZO-1 and β-catenin. Moreover, the antioxidant capacity of retinal pigment epithelium were enhanced both in health mice and photic injury mice. Therefore, such new drug self-delivery systems have great potential both in prevention and treatment of oxidative damage induced retinal diseases.

• The Korean Journal of Physiology and Pharmacology
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• v.26 no.5
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• pp.367-375
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• 2022

Gastric cancer stem cells (GCSCs) are a major cause of radioresistance and chemoresistance in gastric cancer (GC). Therefore, targeting GCSCs is regarded as a powerful strategy for the effective treatment of GC. Atorvastatin is a widely prescribed cholesterol-lowering drug that inhibits 3-hydroxy-3-methylglutaryl-coenzyme A reductase, a rate-limiting enzyme in the mevalonate pathway. The anticancer activity of atorvastatin, a repurposed drug, is being investigated; however, its therapeutic effect and molecular mechanism of action against GCSCs remain unknown. In this study, we evaluated the anticancer effects of atorvastatin on MKN45-derived GCSCs. Atorvastatin significantly inhibited the proliferative and tumorsphere-forming abilities of MKN45 GCSCs in a mevalonate pathway-independent manner. Atorvastatin induced cell cycle arrest at the G0/G1 phase and promoted apoptosis by activating the caspase cascade. Furthermore, atorvastatin exerted an antiproliferative effect against MKN45 GCSCs by inhibiting the expression of cancer stemness markers, such as CD133, CD44, integrin α6, aldehyde dehydrogenase 1A1, Oct4, Sox2, and Nanog, through the downregulation of β-catenin, signal transducer and activator of transcription 3, and protein kinase B activities. Additionally, the combined treatment of atorvastatin and sorafenib, a multi-kinase targeted anticancer drug, synergistically suppressed not only the proliferation and tumorsphere formation of MKN45 GCSCs but also the in vivo tumor growth in a chick chorioallantoic membrane model implanted with MKN45 GCSCs. These findings suggest that atorvastatin can therapeutically eliminate GCSCs.

• Molecules and Cells
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• v.45 no.12
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• pp.935-949
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• 2022

Liver cancer has a high prevalence, with majority of the cases presenting as hepatocellular carcinoma (HCC). The prognosis of metastatic HCC has hardly improved over the past decade, highlighting the necessity for liver cancer research. Studies have reported the ability of the KiSS1 gene to inhibit the growth or metastasis of liver cancer, but contradictory research results are also emerging. We, therefore, sought to investigate the effects of KiSS1 on growth and migration in human HCC cells. HepG2 human HCC cells were infected with lentivirus particles containing KiSS1. The overexpression of KiSS1 resulted in an increased proliferation rate of HCC cells. Quantitative polymerase chain reaction and immunoblotting revealed increased Akt activity, and downregulation of the G1/S phase cell cycle inhibitors. A significant increase in tumor spheroid formation with upregulation of β-catenin and CD133 was also observed. KiSS1 overexpression promoted the migratory, invasive ability, and metastatic capacity of the hepatocarcinoma cell line, and these effects were associated with changes in the expressions of epithelial mesenchymal transition (EMT)- related genes such as E-cadherin, N-cadherin, and slug. KiSS1 overexpression also resulted in dramatically increased tumor growth in the xenograft mouse model, and upregulation of proliferating cell nuclear antigen (PCNA) and Ki-67 in the HCC tumors. Furthermore, KiSS1 increased the angiogenic capacity by upregulation of the vascular endothelial growth factor A (VEGF-A) and CD31. Based on these observations, we infer that KiSS1 not only induces HCC proliferation, but also increases the metastatic potential by increasing the migratory ability and angiogenic capacity.

• Journal of Digestive Cancer Research
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• v.4 no.1
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• pp.1-9
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• 2016

The abundance of multi-drug resistance ATPase binding cassette and deranged self-renewal pathways shown in cancer stem cells (CSCs) played a crucial role in tumorigenesis, tumor resistance, tumor recurrence, and tumor metastasis. Therefore, elucidation of CSCs biology can improve diagnosis, enable targeted treatment, and guide the follow up of GI cancer patients. In order to achieve chemoquiescence, seizing cancer through complete ablation of CSCs, CSCs are rational targets for the design of interventions that will enhance responsiveness to traditional therapeutic strategies and contribute in the prevention of local recurrence as well as metastasis. However, current cancer treatment strategies fail to either detect or differentiate the CSCs from their non-tumorigenic progenies mostly due to the absence of specific biomarkers and potent agents to kill CSCs. Recent advances in knowledge of CSCs enable to produce several candidates to ablate CSCs in gastrointestinal (GI) cancers, especially cancers originated from inflammation-driven mutagenesis such as Barrett's esophagus (BE), Helicobacter pylori-associated gastric cancer, and colitis-associated cancer (CAC). Our research teams elucidated through revisiting old drugs that proton pump inhibitor (PPI) and potassium competitive acid blocker (p-CAB) beyond authentic acid suppression, chloroquine for autophage inhibition, sonic hedgehog (SHH) inhibitors, and Wnt/β-catenin/NOTCH inhibitor can ablate CSCs specifically and efficiently. Furthermore, nanoformulations of these molecules could provide an additional advantage for more selective targeting of the pathways existing in CSCs just like current molecular targeted therapeutics and sustained action, while normal stem cells intact. In this review article, the novel approach specifically to ablate CSCs existing in GI cancers will be introduced with the introduction of explored mode of action.

• Food Science of Animal Resources
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• v.44 no.1
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• pp.204-215
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• 2024

This study was designed to examine the effect of Lactilactobacillus curvatus LB-P9 on hair regeneration. The treatment of LB-P9 conditioned medium increased the proliferation of both hair follicle dermal papilla cells and hair germinal matrix cells (hGMCs). Moreover, the expression levels of hair growth factors such as vascular endothelial growth factor (VEGF) and fibroblast growth factor 7 were significantly elevated in hGMCs co-cultured with LB-P9. After time-synchronized depilation, mice were orally administered with either 4×10⁷ colony forming unit (CFU) of LB-P9 (low dose) or 4×10⁸ CFU of LB-P9 (high dose), once daily for 4 weeks. Compared with the vehicle (phosphate-buffered saline)-administrated group, the LB-P9-treated groups exhibited accelerated hair regrowth rate and enhanced hair thickness in a dose-dependent manner. Supporting this observation, both hair follicle numbers and the dermal thickness in skin tissues of the LB-P9-treated groups were increased, compared to those of the vehicle-treated group. These results might be explained by the increased level of β-catenin and number of hair follicle stem cells (CD34⁺ CD49f⁺ cells) in the skin tissues of mice administered with LB-P9, compared to the vehicle-treated mice. Also, increased serum levels of hair growth factors such as VEGF and insulin-like growth factor-1, and superoxide dismutase were found in the LB-P9-treated groups, compared to those of the vehicle-treated group. Taken together, these results might demonstrate that the oral administration of LB-P9 promotes hair regeneration by the enhancement of dermal papilla proliferation through the stimulation of hair growth factor production.

• IMMUNE NETWORK
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• v.20 no.5
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• pp.36.1-36.13
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• 2020

Hippo signaling pathways are evolutionarily conserved signal transduction mechanisms mainly involved in organ size control, tissue regeneration, and tumor suppression. However, in mammals, the primary role of Hippo signaling seems to be regulation of immunity. As such, humans with null mutations in STK4 (mammalian homologue of Drosophila Hippo; also known as MST1) suffer from recurrent infections and autoimmune symptoms. Although dysregulated T cell homeostasis and functions have been identified in MST1-deficient human patients and mouse models, detailed cellular and molecular bases of the immune dysfunction remain to be elucidated. Although the canonical Hippo signaling pathway involves transcriptional co-activator Yes-associated protein (YAP) or transcriptional coactivator with PDZ motif (TAZ), the major Hippo downstream signaling pathways in T cells are YAP/TAZ-independent and they widely differ between T cell subsets. Here we will review Hippo signaling mechanisms in T cell immunity and describe their implications for immune defects found in MST1-deficient patients and animals. Further, we propose that mutual inhibition of Mst and Akt kinases and their opposing roles on the stability and function of forkhead box O and β-catenin may explain various immune defects discovered in mutant mice lacking Hippo signaling components. Understanding these diverse Hippo signaling pathways and their interplay with other evolutionarily-conserved signaling components in T cells may uncover molecular targets relevant to vaccination, autoimmune diseases, and cancer immunotherapies.

• BMB Reports
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• v.55 no.2
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• pp.98-103
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• 2022

Increased mRNA levels of cancer upregulated gene (CUG)2 have been detected in many different tumor tissues using Affymetrix microarray. Oncogenic capability of the CUG2 gene has been further reported. However, the mechanism by which CUG2 overexpression promotes cancer stem cell (CSC)-like phenotypes remains unknown. With recent studies showing that pyruvate kinase muscle 2 (PKM2) is overexpressed in clinical tissues from gastric, lung, and cervical cancer patients, we hypothesized that PKM2 might play an important role in CSC-like phenotypes caused by CUG2 overexpression. The present study revealed that PKM2 protein levels and translocation of PKM2 into the nucleus were enhanced in CUG2-overexpressing lung carcinoma A549 and immortalized bronchial BEAS-2B cells than in control cells. Expression levels of c-Myc, CyclinD1, and PKM2 were increased in CUG2-overexpressing cells than in control cells. Furthermore, EGFR and ERK inhibitors as well as suppression of Yap1 and NEK2 expression reduced PKM2 protein levels. Interestingly, knockdown of β-catenin expression failed to reduce PKM2 protein levels. Furthermore, reduction of PKM2 expression with its siRNA hindered CSC-like phenotypes such as faster wound healing, aggressive transwell migration, and increased size/number of sphere formation. The introduction of mutant S37A PKM2-green fluorescence protein (GFP) into cells without ability to move to the nucleus did not confer CSC-like phenotypes, whereas forced expression of wild-type PKM2 promoted such phenotypes. Overall, CUG2-induced increase in the expression of nuclear PKM2 contributes to CSC-like phenotypes by upregulating c-Myc and CyclinD1 as a co-activator.

• Animal Bioscience
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• v.37 no.4
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• pp.609-621
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• 2024

Objective: Hair follicle stem cells (HFSCs) differentiation is a critical physiological progress in skin hair follicle (HF) formation. Goat HFSCs differentiation is one of the essential processes of superior-quality brush hair (SQBH) synthesis. However, knowledge regarding the functions and roles of miR-133a-3p and miR-145-5p in differentiated goat HFSCs is limited. Methods: To examine the significance of chi-miR-133a-3p and chi-miR-145-5p in differentiated HFSCs, overexpression and knockdown experiments of miR-133a-3p and miR-145-5p (Mimics and Inhibitors) separately or combined were performed. NANOG, SOX9, and stem cell differentiated markers (β-catenin, C-myc, Keratin 6 [KRT6]) expression levels were detected and analyzed by using real-time quantitative polymerase chain reaction, western blotting, and immunofluorescence assays in differentiated goat HFSCs. Results: miR-133a-3p and miR-145-5p inhibit NANOG (a gene recognized in keeping and maintaining the totipotency of embryonic stem cells) expression and promote SOX9 (an important stem cell transcription factor) expression in differentiated stem cells. Functional studies showed that miR-133a-3p and miR-145-5p individually or together overexpression can facilitate goat HFSCs differentiation, whereas suppressing miR-133a-3p and miR-145-5p or both inhibiting can inhibit goat HFSCs differentiation. Conclusion: These findings could more completely explain the modulatory function of miR-133a-3p and miR-145-5p in goat HFSCs growth, which also provide more understandings for further investigating goat hair follicle development.