Formulation of lipid nanoparticles containing ginsenoside Rg2 and protopanaxadiol for highly efficient delivery of mRNA.

Lipid nanoparticles (LNPs) are widely recognized as crucial carriers of mRNA in therapeutic and vaccine development. The typical lipid composition of mRNA-LNP systems includes an ionizable lipid, a helper lipid, a polyethylene glycol (PEG)-lipid, and cholesterol. Concerns arise regarding cholesterol's susceptibility to oxidation, potentially leading to undesired immunological responses and toxicity. In this study, we formulated novel LNPs by replacing cholesterol with phytochemical-derived compounds, specifically ginsenoside Rg2 and its derivative phytosterol protopanaxadiol (PPD), and validated their efficacy as mRNA delivery systems. The mRNA-LNP complexes were manually prepared through a simple mixing process. The biocompatibility of these Rg2-based LNPs (Rg2-LNP) and PPD-based LNPs (PPD-LNP) was assessed through cell viability assays, while the protective function of LNPs for mRNA was demonstrated by RNase treatment. Enhanced green fluorescent protein (EGFP) mRNA delivery and expression in A549 and HeLa cells were analyzed using optical microscopy and flow cytometry. The expression efficiency of Rg2-LNP and PPD-LNP was compared with that of commercially available LNPs, with both novel formulations demonstrating superior transfection and EGFP expression. Furthermore, in vivo tests following intramuscular (I.M.) injection in hairless mice demonstrated efficient luciferase (Luc) mRNA delivery and effective Luc expression using Rg2-LNP and PPD-LNP compared to commercial LNPs. Results indicated that the efficiency of EGFP and Luc expression in Rg2-LNP and PPD-LNP surpassed that of the cholesterol-based LNP formulation. These findings suggest that Rg2-LNP and PPD-LNP are promising candidates for future drug and gene delivery systems.

Discovery of organosulfur-based selective HDAC8 inhibitors with anti-neuroblastoma activity.

Histone deacetylases (HDACs) are important epigenetic regulators of gene expression and various cellular processes, and are potential targets for anticancer therapy. In particular, HDAC8 is a promising therapeutic target for childhood neuroblastoma. To date, five HDAC inhibitors have been approved as anticancer drugs; however, all are non-selective HDAC inhibitors with various side effects. Furthermore, many promising HDAC inhibitors incorporate hydroxamic acid as a zinc binding group (ZBG), which may be associated with toxicity. Therefore, identification of isoform-selective HDAC inhibitors with novel ZBG is crucial. Here, a series of sulfur-based selective HDAC8 inhibitors featuring a novel ZBG were identified by modifying the early hit, ajoene, a component of garlic. Structure-activity relationship studies uncovered potent and selective HDAC8 inhibitors, and docking studies provided a structural rationale for HDAC8 inhibitory activity. One of the potent compounds, (Z)-1-phenyl-7-(4-methoxyphenyl)-2,3,7-trithiahepta-4-ene-7-oxide (15c), exhibited antiproliferative activity, with a GI50 of 2 µM, against neuroblastoma cell lines. 15c also showed significant in vivo efficacy in a neuroblastoma BE(2)-C xenograft model.

Discovery of the therapeutic potential of PPARδ agonist bearing 1,3,4- thiadiazole in inflammatory disorders.

As a defense mechanism against deleterious stimuli, inflammation plays a vital role in the development of many disorders, including atherosclerosis, inflammatory bowel disease, experimental autoimmune encephalomyelitis, septic and non-septic shock, and non-alcoholic fatty liver disease (NAFLD). Despite the serious adverse effects of extended usage, traditional anti-inflammatory medications, such as steroidal and non-steroidal anti-inflammatory medicines (NSAIDs), are commonly used for alleviating symptoms of inflammation. The PPARδ subtype of peroxisome proliferator-activated receptors (PPARs) has attracted interest because of its potential for reducing inflammation and related disorders. In this study, a series of 1,3,4-thiadiazole derivatives were designed, synthesized, and evaluated. Compound 11 exhibited potent PPARδ agonistic activity with EC50 values 20 nM and strong selectivity over PPARα and PPARγ. Furthermore, compound 11 demonstrated favorable in vitro and in vivo pharmacokinetic properties. In vivo experiments using labeled macrophages and paw thickness measurements confirmed compound 11's potential to reduce macrophage infiltration and alleviate inflammation. These findings highlight compound 11 as a potent and promising therapeutic candidate for the treatment of acute inflammatory diseases and warrant further investigation to explore various biological roles.

Remodeling of sorafenib as an orally bioavailable ferroptosis inducer for Lung Cancer by chemical modification of adenine-binding motif.

Sorafenib (BAY 43-9006) was developed as a multi-kinase inhibitor to treat advanced renal cell, hepatocellular, and thyroid cancers. The cytotoxic effect of sorafenib on cancer cells results from not only inhibiting the MEK/ERK signaling pathway (the on-target effect) but also inducing oxidative damage (the off-target effect). The inhibitory effect of sorafenib on system Xc- (xCT), a cystine/glutamate antiporter, promotes ferroptosis induction and accounts for oxidative damage. While emerging studies on ferroptosis in cancers have garnered increasing attention, the lack of consideration for ferroptosis inducers (FINs) with favorable pharmacokinetics could be problematic. Herein, we remodeled the chemical structure of sorafenib, of which pharmacokinetics and safety are already assured, to customize the off-target effect (i.e., ferroptosis induction) to on-target by disrupting the adenine-binding motif. JB3, a sorafenib derivative (i.e., JB compounds), with a tenfold higher IC50 toward RAF1 because of chemical remodeling, induced strong cytotoxicity in the elastin-sensitive lung cancer cells, while it was markedly reduced by ferrostatin-1. The 24% oral bioavailability of JB3 in rats accounted for a significant anti-tumor effect of orally administrated JB3 in xenograft models. These results indicate that JB3 could be further developed as an orally bioavailable FIN in novel anti-cancer therapeutics.

Optimizing Embryo Collection for Application of CRISPR/Cas9 System and Generation of Fukutin Knockout Rat Using This Method.

Rat animal models are widely used owing to their relatively superior cognitive abilities and higher similarity compared with mouse models to human physiological characteristics. However, their use is limited because of difficulties in establishing embryonic stem cells and performing genetic modifications, and insufficient embryological research. In this study, we established optimal superovulation and fertilized-egg transfer conditions, including optimal hormone injection concentration (≥150 IU/kg of PMSG and hCG) and culture medium (mR1ECM), to obtain high-quality zygotes and establish in vitro fertilization conditions for rats. Next, sgRNA with optimal targeting activity was selected by performing PCR analysis and the T7E1 assay, and the CRISPR/Cas9 system was used to construct a rat model for muscular dystrophy by inducing a deficiency in the fukutin gene without any off-target effect detected. The production of fukutin knockout rats was phenotypically confirmed by observing a drop-in body weight to one-third of that of the control group. In summary, we succeeded in constructing the first muscular dystrophy disease rat model using the CRISPR/CAS9 system for increasing future prospects of producing various animal disease models and encouraging disease research using rats.

Discovery and Feasibility Study of Medical Fluorophore 33 as a Novel Theranostic Agent.

Fluorescent dyes have garnered significant attention as theranostic platforms owing to their inherent characteristics. In this study, we present the discovery of Medical Fluorophore 33 (MF33), a novel and potent theranostic agent with a phenaleno-isoquinolinium salt structure that can serve as a cancer therapeutic strategy. The synthesis of MF33 is readily achievable through a simple Rh(III)-catalyzed reaction. Moreover, MF33 displayed strong fluorescence signals, excellent microsomal stability, and high biocompatibility in vivo. It induces significant apoptosis in cancer cells via the p53/p21/caspase-3 signaling pathway, leading to selective cytotoxicity in various cancer cells. In vivo fluorescence imaging with MF33 enabled the visualization of sentinel lymph nodes in living mice. Notably, repeated intraperitoneal administration of MF33 resulted in antitumor activity in mice with colorectal cancer. Collectively, our findings suggest that phenaleno-isoquinolinium salt-based MF33 is a viable theranostic agent for biomedical imaging and cancer treatment.

Visualizing mast cell migration to tumor sites using sodium iodide symporter of nuclear medicine reporter gene.

PURPOSE: Owing to the close relationship between mast cells and cancer progression, an imaging technique that can be applied in a clinical setting to explore the biological behavior of mast cells in the tumor microenvironment is needed. In this study, we visualized mast cell migration to lung tumor lesions in live mice using sodium iodide symporter (NIS) as a nuclear medicine reporter gene. EXPERIMENTAL DESIGN: The murine mast cell line MC-9 was infected with retrovirus including NIS, luciferase (as a surrogate marker for NIS), and Thy1.1 to generate MC-9/NFT cells. Radioiodine uptake was measured in MC-9/NFT cells, and an inhibition assay of radioiodine uptake using KCLO4 was also performed. Cell proliferation and FcεRI expression was examined in MC-9 and MC-9/NFT cells. The effect of mast cell-conditioned media (CM) on the proliferation of Lewis lung cancer (LLC) cells was examined. The migration level of MC-9/NFT cells was confirmed in the presence of serum-free media (SFM) and CM of cancer cells. After intravenous injection of MC-9/NFT cells into mice with an LLC tumor, I-124 PET/CT and biodistribution analysis was performed. RESULTS: MC-9/NFT cells exhibited higher radioiodine avidity compared to parental MC-9 cells; this increased radioiodine avidity in MC-9/NFT cells was reduced to basal level by KCLO4. Levels of FcεRI expression and cell proliferation were not different in parental MC-9 cell and MC-9/ NFT cells. The CM of MC-9/NFT cells increased cancer cell proliferation relative to that of the SFM. The migration level of MC-9/NFT cells was higher in the CM than the SFM of LLC cells. PET/CT imaging with I-124 clearly showed infiltration of reporter mast cells in lung tumor at 24 h after transfer, which was consistent with the findings of the biodistribution examination. CONCLUSION: These findings suggest that the sodium iodide symporter can serve as a reliable nuclear medicine reporter gene for non-invasively imaging the biological activity of mast cells in mice with lung tumors. Visualizing mast cells in the tumor microenvironment via a nuclear medicine reporter gene would provide valuable insights into their biological functions.

Upregulation of the ERRγ-VDAC1 axis underlies the molecular pathogenesis of pancreatitis.

Emerging evidence suggest that transcription factors play multiple roles in the development of pancreatitis, a necroinflammatory condition lacking specific therapy. Estrogen-related receptor γ (ERRγ), a pleiotropic transcription factor, has been reported to play a vital role in pancreatic acinar cell (PAC) homeostasis. However, the role of ERRγ in PAC dysfunction remains hitherto unknown. Here, we demonstrated in both mice models and human cohorts that pancreatitis is associated with an increase in ERRγ gene expression via activation of STAT3. Acinar-specific ERRγ haploinsufficiency or pharmacological inhibition of ERRγ significantly impaired the progression of pancreatitis both in vitro and in vivo. Using systematic transcriptomic analysis, we identified that voltage-dependent anion channel 1 (VDAC1) acts as a molecular mediator of ERRγ. Mechanistically, we showed that induction of ERRγ in cultured acinar cells and mouse pancreata enhanced VDAC1 expression by directly binding to specific site of the Vdac1 gene promoter and resulted in VDAC1 oligomerization. Notably, VDAC1, whose expression and oligomerization were dependent on ERRγ, modulates mitochondrial Ca2+ and ROS levels. Inhibition of the ERRγ-VDAC1 axis could alleviate mitochondrial Ca2+ accumulation, ROS formation and inhibit progression of pancreatitis. Using two different mouse models of pancreatitis, we showed that pharmacological blockade of ERRγ-VDAC1 pathway has therapeutic benefits in mitigating progression of pancreatitis. Likewise, using PRSS1R122H-Tg mice to mimic human hereditary pancreatitis, we demonstrated that ERRγ inhibitor also alleviated pancreatitis. Our findings highlight the importance of ERRγ in pancreatitis progression and suggests its therapeutic intervention for prevention and treatment of pancreatitis.

N-methyl-D-aspartate receptors induce M1 polarization of macrophages: Feasibility of targeted imaging in inflammatory response in vivo.

BACKGROUND: N-methyl-D-aspartate receptors (NMDARs) are considered to be involved in several physiological and pathophysiological processes in addition to the progression of neurological disorders. However, how NMDARs are involved in the glycolytic phenotype of M1 macrophage polarization and the possibility of using them as a bio-imaging probe for macrophage-mediated inflammation remain unclear. METHODS: We analyzed cellular responses to NMDAR antagonism and small interfering RNAs using mouse bone marrow-derived macrophages (BMDMs) treated with lipopolysaccharide (LPS). An NMDAR targeting imaging probe, N-TIP, was produced via the introduction of NMDAR antibody and the infrared fluorescent dye FSD Fluor™ 647. N-TIP binding efficiency was tested in intact and LPS-stimulated BMDMs. N-TIP was intravenously administered to mice with carrageenan (CG)- and LPS-induced paw edema, and in vivo fluorescence imaging was conducted. The anti-inflammatory effects of dexamethasone were evaluated using the N-TIP-mediated macrophage imaging technique. RESULTS: NMDARs were overexpressed in LPS-treated macrophages, subsequently inducing M1 macrophage polarization. Mechanistically, NMDAR-mediated Ca2+ accumulation resulted in LPS-stimulated glycolysis via upregulation of PI3K/AKT/mTORC1 signaling. In vivo fluorescence imaging with N-TIP showed LPS- and CG-induced inflamed lesions at 5 h post-inflammation, and the inflamed lesions could be detected until 24 h. Furthermore, our N-TIP-mediated macrophage imaging technique helped successfully visualize the anti-inflammatory effects of dexamethasone in mice with inflammation. CONCLUSION: This study demonstrates that NMDAR-mediated glycolysis plays a critical role in M1 macrophage-related inflammation. Moreover, our results suggest that NMDAR targeting imaging probe may be useful in research on inflammatory response in vivo.

An Inverse Agonist of Estrogen-Related Receptor Gamma, GSK5182, Enhances Na+/I- Symporter Function in Radioiodine-Refractory Papillary Thyroid Cancer Cells.

Previously, we reported that an inverse agonist of estrogen-related receptor gamma (ERRγ), GSK5182, enhances sodium iodide (Na+/I-) symporter (NIS) function through mitogen-activated protein (MAP) kinase signaling in anaplastic thyroid cancer cells. This finding helped us to further investigate the effects of GSK5182 on NIS function in papillary thyroid cancer (PTC) refractory to radioactive iodine (RAI) therapy. Herein, we report the effects of ERRγ on the regulation of NIS function in RAI-resistant PTC cells using GSK5182. RAI-refractory BCPAP cells were treated with GK5182 for 24 h at various concentrations, and radioiodine avidity was determined with or without potassium perchlorate (KClO4) as an NIS inhibitor. We explored the effects of GSK5182 on ERRγ, the mitogen-activated protein (MAP) kinase pathway, and iodide metabolism-related genes. We examined whether the MAP pathway affected GSK5182-mediated NIS function using U0126, a selective MEK inhibitor. A clonogenic assay was performed to evaluate the cytotoxic effects of I-131. GSK5182 induced an increase in radioiodine avidity in a dose-dependent manner, and the enhanced uptake was completely inhibited by KClO4 in BCPAP cells. We found that ERRγ was downregulated and phosphorylated extracellular signal-regulated kinase (ERK)1/2 was upregulated in BCPAP cells, with an increase in total and membranous NIS and iodide metabolism-related genes. MEK inhibitors reversed the increase in radioiodine avidity induced by GSK5182. Clonogenic examination revealed the lowest survival in cells treated with a combination of GSK5182 and I-131 compared to those treated with either GSK518 or I-131 alone. We demonstrate that an inverse agonist of ERRγ, GSK5182, enhances the function of NIS protein via the modulation of ERRγ and MAP kinase signaling, thereby leading to increased responsiveness to radioiodine in RAI-refractory papillary thyroid cancer cells.

Association of weekend catch-up sleep ratio and subjective sleep quality with depressive symptoms and suicidal ideation among Korean adolescents.

Circadian misalignment caused by differences in sleep duration between weekends and weekdays may be associated with adolescent mental health and sleep quality may be able to compensate for this problem. This study aimed to investigate the association between weekend catch-up sleep (CUS) ratio and sleep quality with depressive symptoms and suicidal ideation among South Korean adolescents. We used data from the Korea Youth Risk Behavior Web-based Survey 2015-2019 involving 270,619 adolescents. The weekend CUS ratio was calculated by dividing the average weekend sleep duration by the average weekday sleep duration (< 1.00, 1.00 ≤ CUS < 1.50, or ≥ 1.50). Subjective sleep quality was categorized as poor, moderate, or good. Multiple logistic regression analyses were performed. A weekend CUS ratio of < 1.00 and poor sleep quality was significantly associated with mental health. Absolutely short sleep duration (CUS < 1.00 and weekday sleep duration < 5 h) was most associated with depressive symptoms and suicidal ideation. Furthermore, adolescents with a CUS ratio of ≥ 1.50 showed increased odds of depressive symptoms despite having good sleep quality. Appropriate weekend CUS may benefit adolescents' mental health. When investigating the relationship between adolescents' sleep and mental health, a weekend CUS ratio should be considered in addition to sleep quality and duration.

Discovery of novel phenaleno isoquinolinium-based fluorescence imaging agents for sentinel lymph node mapping.

Fluorescence imaging agents have recently received huge attention due to their important role in disease diagnostics. However, the intrinsic problems of these probes, such as complex synthetic routes and high molecular weight, remain challenging. Here, we developed novel phenaleno isoquinolinium-based fluorescent agents, Medical Fluorophores 37-41 (MF37-41), applicable to the quantitative and sensitive detection of sentinel lymph nodes (SLNs). These imaging agents showed no adverse effects on the proliferation of immune and normal cells and did not induce in vivo toxicity. In vivo fluorescence lifetime imaging demonstrated the accumulation of phenaleno isoquinolinium salts in the SLNs of nude mice within 15 min postinjection, consistent with our biodistribution findings. These results suggest that phenaleno isoquinolinium salts are feasible fluorescence imaging agents that can be used as potential lymphatic tracers.

Targeting the Nuclear Receptor-Binding SET Domain Family of Histone Lysine Methyltransferases for Cancer Therapy: Recent Progress and Perspectives.

Nuclear receptor-binding SET domain (NSD) proteins are a class of histone lysine methyltransferases (HKMTases) that are amplified, mutated, translocated, or overexpressed in various types of cancers. Several campaigns to develop NSD inhibitors for cancer treatment have begun following recent advances in knowledge of NSD1, NSD2, and NSD3 structures and functions as well as the U.S. FDA approval of the first HKMTase inhibitor (tazemetostat, an EZH2 inhibitor) to treat follicular lymphoma and epithelioid sarcoma. This perspective highlights recent findings on the structures of catalytic su(var), enhancer-of-zeste, trithorax (SET) domains and other functional domains of NSD methyltransferases. In addition, recent progress and efforts to discover NSD-specific small molecule inhibitors against cancer-targeting catalytic SET domains, plant homeodomains, and proline-tryptophan-tryptophan-proline domains are summarized.

Pyruvate dehydrogenase kinase 1 and 2 deficiency reduces high-fat diet-induced hypertrophic obesity and inhibits the differentiation of preadipocytes into mature adipocytes.

Obesity is now recognized as a disease. This study revealed a novel role for pyruvate dehydrogenase kinase (PDK) in diet-induced hypertrophic obesity. Mice with global or adipose tissue-specific PDK2 deficiency were protected against diet-induced obesity. The weight of adipose tissues and the size of adipocytes were reduced. Adipocyte-specific PDK2 deficiency slightly increased insulin sensitivity in HFD-fed mice. In studies with 3T3-L1 preadipocytes, PDK2 and PDK1 expression was strongly increased during adipogenesis. Evidence was found for epigenetic induction of both PDK1 and PDK2. Gain- and loss-of-function studies with 3T3-L1 cells revealed a critical role for PDK1/2 in adipocyte differentiation and lipid accumulation. PDK1/2 induction during differentiation was also accompanied by increased expression of hypoxia-inducible factor-1α (HIF1α) and enhanced lactate production, both of which were absent in the context of PDK1/2 deficiency. Exogenous lactate supplementation increased the stability of HIF1α and promoted adipogenesis. PDK1/2 overexpression-mediated adipogenesis was abolished by HIF1α inhibition, suggesting a role for the PDK-lactate-HIF1α axis during adipogenesis. In human adipose tissue, the expression of PDK1/2 was positively correlated with that of the adipogenic marker PPARγ and inversely correlated with obesity. Similarly, PDK1/2 expression in mouse adipose tissue was decreased by chronic high-fat diet feeding. We conclude that PDK1 and 2 are novel regulators of adipogenesis that play critical roles in obesity.

Escherichia coli adhesin protein-conjugated thermal responsive hybrid nanoparticles for photothermal and immunotherapy against cancer and its metastasis.

BACKGROUND: Advanced cancer therapy is targeted at primary tumors and also recurrent or metastatic cancers. Combinational cancer treatment has recently shown high efficiency against recurrent and metastatic cancers. In this study, we synthesized a thermal responsive hybrid nanoparticle (TRH) containing FimH, an immune stimulatory recombinant protein, for the induction of a combination of photothermal therapy (PTT) and immunotherapy against cancer and its metastasis. METHODS: The hybrid nanoparticle was incorporated with a near-infrared (NIR) absorbent, indocyanine green, and decorated with FimH on its surface to form F-TRH. F-TRH was evaluated for its anticancer and antimetastatic effects against CT-26 carcinoma in mice by combining PTT and immunotherapy. RESULTS: NIR laser irradiation elicited an elevation of temperature in F-TRH, which induced apoptosis in CT-26 carcinoma cells in vitro. In addition, F-TRH and NIR laser irradiation promoted photothermal-mediated therapeutic effects against CT-26 and 4T1 tumors in mice. The release of FimH from F-TRH in response to elevated temperature and apoptotic bodies of cancer cells via PTT elicited dendritic cell-mediated cancer antigen-specific T-cell responses, which subsequently inhibited the second challenge of CT-26 and 4T1 cell growth in the lung. CONCLUSIONS: These data demonstrate the potential use of F-TRH for immuno-photothermal therapy against cancer and its recurrence and metastasis.

Novel quinoline-based fluorescent bioimaging probe, KSNP117, for sentinel lymph node mapping.

Fluorescent imaging agents with biocompatibility and high sensitivity are urgently required for the accurate detection of sentinel lymph nodes (SLNs). Herein, we report the design of a novel quinoline-based fluorescent probe, designated KSNP117, which can be applied as a biomedical imaging agent in the sensitive and quantitative detection of SLNs. KSNP117 exerted no adverse effects on the proliferation of ovary and immune cells and also showed excellent serum stability with photo-brightening effects. In vivo fluorescent imaging revealed the accumulation of KSNP117 in the SLNs of nude mice within 10 min post injection, without in vivo toxicity, which was consistent with the findings of ex vivo imaging. These results support the potential of KSNP117 as a promising lymphatic tracer for biomedical imaging applications.

Repositioning Trimebutine Maleate as a Cancer Treatment Targeting Ovarian Cancer Stem Cells.

The overall five-year survival rate for late-stage patients of ovarian cancer is below 29% due to disease recurrence and drug resistance. Cancer stem cells (CSCs) are known as a major contributor to drug resistance and recurrence. Accordingly, therapies targeting ovarian CSCs are needed to overcome the limitations of present treatments. This study evaluated the effect of trimebutine maleate (TM) targeting ovarian CSCs, using A2780-SP cells acquired by a sphere culture of A2780 epithelial ovarian cancer cells. TM is indicated as a gastrointestinal motility modulator and is known to as a peripheral opioid receptor agonist and a blocker for various channels. The GI50 of TM was approximately 0.4 µM in A2780-SP cells but over 100 µM in A2780 cells, demonstrating CSCs specific growth inhibition. TM induced G0/G1 arrest and increased the AV+/PI+ dead cell population in the A2780-SP samples. Furthermore, TM treatment significantly reduced tumor growth in A2780-SP xenograft mice. Voltage gated calcium channels (VGCC) and calcium-activated potassium channels (BKCa) were overexpressed on ovarian CSCs and targeted by TM; inhibition of both channels reduced A2780-SP cells viability. TM reduced stemness-related protein expression; this tendency was reproduced by the simultaneous inhibition of VGCC and BKCa compared to single channel inhibition. In addition, TM suppressed the Wnt/ß-catenin, Notch, and Hedgehog pathways which contribute to many CSCs characteristics. Specifically, further suppression of the Wnt/ß-catenin pathway by simultaneous inhibition of BKCa and VGCC is necessary for the effective and selective action of TM. Taken together, TM is a potential therapeutic drug for preventing ovarian cancer recurrence and drug resistance.

Visualization of platelet recruitment to tumor lesions using highly sensitive and stable radioiodine studded gold nanoprobes.

In vivo imaging of platelets will provide a better understanding of their critical roles in arterial cardiovascular disease, hemostasis, inflammation, and cancer. Here, we demonstrate the feasibility of using radioiodine studded gold nanoprobes (RIS-GNPs) as a platelet tracker for nuclear medicine imaging in tumor-bearing mice using positron emission tomography and computed tomography (PET/CT). Platelet labeling with RIS-GNPs did not alter the platelet functions, such as cellular proliferation and aggregation. PET/CT imaging clearly revealed the migration of platelets into tumor sites at 1 to 5 h post-transfer of RIS-GNP-labeled platelets, which was consistent with the biodistribution data. Our findings suggest that the imaging approach using RIS-GNPs makes it feasible to visualize the biological behavior of platelets in living organisms with cancer.

Tunicamycin as a Novel Redifferentiation Agent in Radioiodine Therapy for Anaplastic Thyroid Cancer.

The silencing of thyroid-related genes presents difficulties in radioiodine therapy for anaplastic thyroid cancers (ATCs). Tunicamycin (TM), an N-linked glycosylation inhibitor, is an anticancer drug. Herein, we investigated TM-induced restoration of responsiveness to radioiodine therapy in radioiodine refractory ATCs. 125I uptake increased in TM-treated ATC cell lines, including BHT101 and CAL62, which was inhibited by KClO4, a sodium-iodide symporter (NIS) inhibitor. TM upregulated the mRNA expression of iodide-handling genes and the protein expression of NIS. TM blocked pERK1/2 phosphorylation in both cell lines, but AKT (protein kinase B) phosphorylation was only observed in CAL62 cells. The downregulation of glucose transporter 1 protein was confirmed in TM-treated cells, with a significant reduction in 18F-fluorodeoxyglucose (FDG) uptake. A significant reduction in colony-forming ability and marked tumor growth inhibition were observed in the combination group. TM was revealed to possess a novel function as a redifferentiation inducer in ATC as it induces the restoration of iodide-handling gene expression and radioiodine avidity, thereby facilitating effective radioiodine therapy.