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1.
Cancer Cell Int ; 24(1): 156, 2024 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-38704578

RESUMEN

BACKGROUND: Identifying molecular biomarkers for predicting responses to anti-cancer drugs can enhance treatment precision and minimize side effects. This study investigated the novel cancer-targeting mechanism of combining SH003, an herbal medicine, with docetaxel in non-small cell lung cancer (NSCLC) cells. Also, the present study aimed to identify the genetic characteristics of cancer cells susceptible to this combination. METHODS: Cell viability was analyzed by WST-8 assay. Apoptosis induction, BrdU incorporation, and cell cycle analysis were performed using flow cytometry. Metabolites were measured by LC-MS/MS analysis. Real-time PCR and western blotting evaluated RNA and protein expression. DNA damage was quantified through immunofluorescence. cBioPortal and GEPIA data were utilized to explore the mutual co-occurrence of TP53 and UMPS and UMPS gene expression in NSCLC. RESULTS: The combination treatment suppressed de novo pyrimidine nucleotide biosynthesis by reducing the expression of related enzymes. This blockade of pyrimidine metabolism led to DNA damage and subsequent apoptosis, revealing a novel mechanism for inducing lung cancer cell death with this combination. However, some lung cancer cells exhibited distinct responses to the combination treatment that inhibited pyrimidine metabolism. The differences in sensitivity in lung cancer cells were determined by the TP53 gene status. TP53 wild-type lung cancer cells were effectively inhibited by the combination treatment through p53 activation, while TP53 mutant- or null-type cells exhibited lower sensitivity. CONCLUSIONS: This study, for the first time, established a link between cancer cell genetic features and treatment response to simultaneous SH003 and docetaxel treatment. It highlights the significance of p53 as a predictive factor for susceptibility to this combination treatment. These findings also suggest that p53 status could serve as a crucial criterion in selecting appropriate therapeutic strategies for targeting pyrimidine metabolism in lung cancer.

2.
Int J Mol Sci ; 24(4)2023 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-36835418

RESUMEN

Costunolide (CTL), an active compound isolated from Saussurea lappa Clarke and Laurus nobilis L, has been shown to induce apoptosis via reactive oxygen species (ROS) generation in various types of cancer cells. However, details of molecular mechanisms underlying the difference in sensitivity of cancer cells to CTL are still largely unknown. Here, we tested the effect of CTL on the viability of breast cancer cells and found that CTL had a more efficient cytotoxic effect against SK-BR-3 cells than MCF-7 cells. Mechanically, ROS levels were significantly increased upon CTL treatment only in SK-BR-3 cells, which leads to lysosomal membrane permeabilization (LMP) and cathepsin D release, and subsequent activation of the mitochondrial-dependent intrinsic apoptotic pathway by inducing mitochondrial outer membrane permeabilization (MOMP). In contrast, treatment of MCF-7 cells with CTL activated PINK1/Parkin-dependent mitophagy to remove damaged mitochondria, which prevented the elevation of ROS levels, thereby contributing to their reduced sensitivity to CTL. These results suggest that CTL is a potent anti-cancer agent, and its combination with the inhibition of mitophagy could be an effective method for treating breast cancer cells that are less sensitive to CTL.


Asunto(s)
Antineoplásicos Fitogénicos , Neoplasias de la Mama , Resistencia a Antineoplásicos , Femenino , Humanos , Apoptosis , Neoplasias de la Mama/metabolismo , Mitocondrias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Antineoplásicos Fitogénicos/farmacología
3.
Int J Mol Sci ; 24(8)2023 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-37108692

RESUMEN

Lung cancer is one of the most common malignant tumors and a leading cause of cancer-related death in the worldwide. Various anticancer drugs, such as cisplatin and pemetrexed, have been developed for lung cancer treatment but due their drug resistance and side effects, novel treatments need to be developed. In this study, the efficacy of the natural drug JI017, which is known to have few side effects, was tested in lung cancer cells. JI017 inhibited A549, H460, and H1299 cell proliferation. JI017 induced apoptosis, regulated apoptotic molecules, and inhibited colony formation. Additionally, JI017 increased intracellular ROS generation. JI017 downregulated PI3K, AKT, and mTOR expression. JI017 increased the cytosolic accumulation of LC3. We found that JI017 promoted apoptosis through ROS-induced autophagy. Additionally, the xenograft tumor size was smaller in JI017-treated mice. We found that JI017 treatment increased MDA concentrations, decreased Ki-67 protein levels, and increased cleaved caspase-3 and LC3 levels in vivo. JI017 decreased cell proliferation and increased apoptosis by inducing autophagy signaling in H460 and H1299 lung cancer cells. Targeting JI017 and autophagy signaling could be useful in lung cancer treatment.


Asunto(s)
Neoplasias Pulmonares , Humanos , Animales , Ratones , Especies Reactivas de Oxígeno/metabolismo , Línea Celular Tumoral , Neoplasias Pulmonares/metabolismo , Apoptosis , Autofagia , Proliferación Celular , Proteínas Proto-Oncogénicas c-akt/metabolismo
4.
Arch Psychiatr Nurs ; 45: 1-6, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37544683

RESUMEN

OBJECTIVE: To examine the association between problematic use of social media, online health information-seeking, social isolation, and health-promoting behaviors among Korean undergraduate students. METHODS: In total, 178 undergraduate students participated in this study. A multiple linear regression analysis was performed. RESULTS: Predictors of health-promoting behaviors included overall time spent on social media, problematic social media use, social isolation, and online information-seeking, explaining 33.5 % of the variance in health-promoting behaviors. CONCLUSION: Prolonged social media use and social isolation negatively affected undergraduate students' health-promoting behaviors, while online information-seeking positively affected them. Nurses should assist young adults in improving health-promoting behaviors by preventing problematic social media uses, reducing social isolation, and strengthening their online health information-seeking ability.


Asunto(s)
COVID-19 , Medios de Comunicación Sociales , Adulto Joven , Humanos , Conducta en la Búsqueda de Información , Estudiantes , Aislamiento Social
5.
Molecules ; 27(7)2022 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-35408505

RESUMEN

Lung cancer (LC) is the leading global cause of cancer-related death, and metastasis is a great challenge in LC therapy. Additionally, solid cancer, including lung, prostate, and colon cancer, are characterized by hypoxia. A low-oxygen state is facilitated by the oncogene pathway, which correlates with a poor cancer prognosis. Thus, we need to understand the related mechanisms in solid tumors to improve and develop new anticancer strategies. The experiments herein describe an anticancer mechanism in which heat shock protein 90 (HSP90) stabilizes HIF-1α, a master transcription factor of oxygen homeostasis that has been implicated in the survival, proliferation and malignant progression of cancers. We demonstrate the efficacy of 6-gingerol and the molecular mechanism by which 6-gingerol inhibits LC metastasis in different oxygen environments. Our results showed that cell proliferation was inhibited after 6-gingerol treatment. Additionally, HIF-1α, a transcriptional regulator, was found to be recruited to the hypoxia response element (HRE) of target genes to induce the transcription of a series of target genes, including MMP-9, vimentin and snail. Interestingly, we found that 6-gingerol treatment suppressed activation of the transcription factor HIF-1α by downregulating HSP90 under both normoxic and hypoxic conditions. Furthermore, an experiment in an in vivo xenograft model revealed decreased tumor growth after 6-gingerol treatment. Both in vitro and in vivo analyses showed the inhibition of metastasis through HIF-1α/HSP90 after 6-gingerol treatment. In summary, our study demonstrates that 6-gingerol suppresses proliferation and blocks the nuclear translocation of HIF-1α and activation of the EMT pathway. These data suggest that 6-gingerol is a candidate antimetastatic treatment for LC.


Asunto(s)
Catecoles , Muerte Celular , Subunidad alfa del Factor 1 Inducible por Hipoxia , Neoplasias Pulmonares , Animales , Catecoles/farmacología , Hipoxia de la Célula , Línea Celular Tumoral , Alcoholes Grasos , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Oxígeno
6.
J Lipid Res ; 62: 100152, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34808194

RESUMEN

Testosterone is a hormone essential for male reproductive function. It is produced primarily by Leydig cells in the testicle through activation of steroidogenic acute regulatory protein and a series of steroidogenic enzymes, including a cytochrome P450 side-chain cleavage enzyme (cytochome P450 family 11 subfamily A member 1), 17α-hydroxylase (cytochrome P450 family 17 subfamily A member 1), and 3ß-hydroxysteroid dehydrogenase. These steroidogenic enzymes are mainly regulated at the transcriptional level, and their expression is increased by the nuclear receptor 4A1. However, the effect on Leydig cell function of a small molecule-activating ligand, amodiaquine (AQ), is unknown. We found that AQ effectively and significantly increased testosterone production in TM3 and primary Leydig cells through enhanced expression of steroidogenic acute regulatory protein, cytochome P450 family 11 subfamily A member 1, cytochrome P450 family 17 subfamily A member 1, and 3ß-hydroxysteroid dehydrogenase. Concurrently, AQ dose-dependently increased the expression of 3-hydroxy-3-methylglutaryl-CoA reductase, a key enzyme in the cholesterol synthesis pathway, through induction of the transcriptional and DNA-binding activities of nuclear receptor 4A1, contributing to increased cholesterol synthesis in Leydig cells. Furthermore, AQ increased the expression of fatty acid synthase and diacylglycerol acyltransferase and potentiated de novo synthesis of fatty acids and triglycerides (TGs). Lipidomics profiling further confirmed a significant elevation of intracellular lipid and TG levels by AQ in Leydig cells. These results demonstrated that AQ effectively promotes testosterone production and de novo synthesis of cholesterol and TG in Leydig cells, indicating that AQ may be beneficial for treating patients with Leydig cell dysfunction and subsequent testosterone deficiency.


Asunto(s)
Amodiaquina/farmacología , Colesterol/biosíntesis , Células Intersticiales del Testículo/efectos de los fármacos , Testosterona/biosíntesis , Triglicéridos/biosíntesis , Animales , Células Intersticiales del Testículo/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL
7.
FASEB J ; 34(4): 5332-5347, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32067268

RESUMEN

Transcriptional coactivator with PDZ-binding motif (TAZ) plays crucial role in maintaining testicular structure and function via regulation of senescence of spermatogenic cells. However, it remains unclear whether TAZ is involved in testosterone biosynthesis in testicular Leydig cells. We found that TAZ deficiency caused aberrant Leydig cell expansion and increased lipid droplet formation, which was significantly associated with increased lipogenic enzyme expression. Additionally, the expression of key steroidogenic enzymes, including steroidogenic acute regulatory protein, cytochrome P450 (CYP) 11A1, CYP17A1, and 3ß-hydroxysteroid dehydrogenase, was greatly increased in TAZ-deficient testes and primary Leydig cells. Interestingly, the transcriptional activity of nuclear receptor 4 A1 (NR4A1) was dramatically suppressed by TAZ; however, the protein expression and the subcellular localization of NR4A1 were not affected by TAZ. TAZ directly associated with the N-terminal region of NR4A1 and substantially suppressed its DNA-binding and transcriptional activities. Stable expression of TAZ in the mouse Leydig TM3 cell line decreased the expression of key steroidogenic enzymes, whereas knockdown of endogenous TAZ in TM3 cells increased transcripts of steroidogenic genes induced by NR4A1. Consistently, testosterone production was enhanced within TAZ-deficient Leydig cells. However, TAZ deficiency resulted in decreased testosterone secretion caused by dysfunctional mitochondria and lysosomes. Therefore, TAZ plays essential role in NR4A1-induced steroidogenic enzyme expression and testosterone production in Leydig cells.


Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/antagonistas & inhibidores , Células Intersticiales del Testículo/metabolismo , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Fosfoproteínas/antagonistas & inhibidores , Esteroide 17-alfa-Hidroxilasa/antagonistas & inhibidores , Testosterona/metabolismo , Transactivadores/fisiología , 17-Hidroxiesteroide Deshidrogenasas/genética , 17-Hidroxiesteroide Deshidrogenasas/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Esteroide 17-alfa-Hidroxilasa/genética , Esteroide 17-alfa-Hidroxilasa/metabolismo
8.
Int J Mol Sci ; 22(16)2021 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-34445110

RESUMEN

Epidermal growth factor receptor (EGFR) is overexpressed in lung cancer patients. Despite treatment with various EGFR tyrosine kinase inhibitors, recurrence and metastasis of lung cancer are inevitable. Docetaxel (DTX) is an effective conventional drug that is used to treat various cancers. Several researchers have studied the use of traditional herbal medicine in combination with docetaxel, to improve lung cancer treatment. SH003, a novel herbal mixture, exerts anticancer effects in different cancer cell types. Here, we aimed to investigate the apoptotic and anticancer effects of SH003 in combination with DTX, in human non-small-cell lung cancer (NSCLC). SH003, with DTX, induced apoptotic cell death, with increased expression of cleaved caspases and cleaved poly (ADP-ribose) polymerase in NSCLC cells. Moreover, SH003 and DTX induced the apoptosis of H460 cells via the suppression of the EGFR and signal transducer and activator of transcription 3 (STAT3) signaling pathways. In H460 tumor xenograft models, the administration of SH003 or docetaxel alone diminished tumor growth, and their combination effectively killed cancer cells, with increased expression of apoptotic markers and decreased expression of p-EGFR and p-STAT3. Collectively, the combination of SH003 and DTX may be a novel anticancer strategy to overcome the challenges that are associated with conventional lung cancer therapy.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Docetaxel/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Extractos Vegetales/farmacología , Transducción de Señal/efectos de los fármacos , Células A549 , Angelica , Inhibidores de la Angiogénesis/farmacología , Animales , Apoptosis/efectos de los fármacos , Planta del Astrágalo , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Ratones , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Factor de Transcripción STAT3/metabolismo , Trichosanthes , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
9.
Mar Drugs ; 15(3)2017 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-28245605

RESUMEN

Tuberatolide B (TTB, C27H34O4) is a diastereomeric meroterpenoid isolated from the Korean marine algae Sargassum macrocarpum. However, the anticancer effects of TTB remain unknown. In this study, we demonstrate that TTB inhibits tumor growth in breast, lung, colon, prostate, and cervical cancer cells. To examine the mechanism by which TTB suppresses cell growth, we determined the effect of TTB on apoptosis, ROS generation, DNA damage, and signal transduction. TTB induced ROS production in MDA-MB-231, A549, and HCT116 cells. Moreover, TTB enhanced DNA damage by inducing γH2AX foci formation and the phosphorylation of DNA damage-related proteins such as Chk2 and H2AX. Furthermore, TTB selectively inhibited STAT3 activation, which resulted in a reduction in cyclin D1, MMP-9, survivin, VEGF, and IL-6. In addition, TTB-induced ROS generation caused STAT3 inhibition, DNA damage, and apoptotic cell death. Therefore, TTB suppresses cancer progression by promoting ROS-mediated inhibition of STAT3 signaling, suggesting that TTB is useful for the treatment of cancer.


Asunto(s)
Antineoplásicos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Terpenos/farmacología , Células A549 , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ciclina D1/metabolismo , Daño del ADN/efectos de los fármacos , Progresión de la Enfermedad , Células HCT116 , Células HeLa , Humanos , Proteínas Inhibidoras de la Apoptosis/metabolismo , Interleucina-6/metabolismo , Células MCF-7 , Metaloproteinasa 9 de la Matriz/metabolismo , Fosforilación/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/metabolismo
10.
BMC Complement Altern Med ; 16(1): 507, 2016 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-27927199

RESUMEN

BACKGROUND: Herbal medicines have been used in cancer treatment, with many exhibiting favorable side effect and toxicity profiles compared with conventional chemotherapeutic agents. SH003 is a novel extract from Astragalus membranaceus, Angelica gigas, and Trichosanthes Kirilowii Maximowicz combined at a 1:1:1 ratio that impairs the growth of breast cancer cells. This study investigates anti-cancer effects of SH003 in prostate cancer cells. METHODS: SH003 extract in 30% ethanol was used to treat the prostate cancer cell lines DU145, LNCaP, and PC-3. Cell viability was determined by MTT and BrdU incorporation assays. Next, apoptotic cell death was determined by Annexin V and 7-AAD double staining methods. Western blotting was conducted to measure protein expression levels of components of cell death and signaling pathways. Intracellular reactive oxygen species (ROS) levels were measured using H2DCF-DA. Plasmid-mediated ERK2 overexpression in DU145 cells was used to examine the effect of rescuing ERK2 function. Results were analyzed using the Student's t-test and P-values < 0.05 were considered to indicate statistically-significant differences. RESULTS: Our data demonstrate that SH003 induced apoptosis in DU145 prostate cancer cells by inhibiting ERK signaling. SH003 induced apoptosis of prostate cancer cells in dose-dependent manner, which was independent of androgen dependency. SH003 also increased intracellular ROS levels but this is not associated with its pro-apoptotic effects. SH003 inhibited phosphorylation of Ras/Raf1/MEK/ERK/p90RSK in androgen-independent DU145 cells, but not androgen-dependent LNCaP and PC-3 cells. Moreover, ERK2 overexpression rescued SH003-induced apoptosis in DU145 cells. CONCLUSIONS: SH003 induces apoptotic cell death of DU145 prostate cancer cells by inhibiting ERK2-mediated signaling.


Asunto(s)
Apoptosis/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Extractos Vegetales/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Angelica , Planta del Astrágalo , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Masculino , Extractos Vegetales/farmacología , Trichosanthes
11.
Sci Total Environ ; 919: 170704, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38346654

RESUMEN

South Korea recently shifted its assessment indicator for organic matter in terrestrial environments from chemical oxygen demand (COD) to total organic carbon (TOC) due to the increase in refractory organic carbon levels. However, in the marine environment, where the inflow of refractory organic matter is also on the rise, COD is still used in some instances to assess organic pollution in contaminated areas. Our findings reveal that the main source of dissolved organic carbon (DOC) is terrestrial-derived refractory organic carbon, which enters through nearby wastewater treatment plant (WWPT) outlets. The low oxidation efficiency of COD to TOC (approximately 4 %) prevents it from being an accurate measure of terrestrial-derived refractory DOC. Contrasting results were observed when comparing the organic pollution index (OPI), which we calculated using TOC, with the currently employed water quality index (WQI) for ocean water quality evaluation, particularly in areas influenced by WWPTs. This discrepancy arises because the WQI primarily evaluates autochthonous organic carbon through chlorophyll measurements, whereas the OPI incorporates both autochthonous and allochthonous organic carbon through TOC measurements. Our findings demonstrate that TOC can effectively replace COD as an organic pollution indicator in marine environments.

12.
Environ Pollut ; 361: 124786, 2024 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-39173862

RESUMEN

Over the past 50 years, fossil fuel consumption has increased dramatically, rising approximately eight-fold since 1950 and doubling since 1980. This surge has led to increased emissions of brown carbon (BrC) into the atmosphere, which are subsequently deposited onto oceans and land through dry or wet deposition processes. However, the source-specific fluxes of atmospheric organic carbon (OC) and BrC into the ocean are not adequately represented in the global carbon cycle. For the first time, we calculated BrC concentration using the optical intensity of organic matter and determined the global wet depositional flux of fossil fuel-derived BrC. Using the ratio of humic-like substances to OC fluxes, we estimated the global wet deposition of fossil fuel-derived BrC to be 2.0 ± 0.6 Tg C yr-1. Of this amount, the flux into oceans (0.7 ± 0.2 Tg C yr-1) represents 1.6% of the production rate of refractory dissolved organic carbon (RDOC) in the ocean (43 Tg yr-1). Notably, an increase in the proportion of fossil fuel-derived BrC in atmospheric OC may change the composition of OC in precipitation, resulting in a more refractory composition, which deviates from previously established paradigms. Our findings indicate that the flux of fossil fuel-derived RDOC from the atmosphere into the ocean, which is inadequately represented in current global DOC cycling models, may play a significant role in oceanic carbon cycles. These findings necessitate reconsidering our understanding of oceanic carbon cycling and highlight the need to improve existing models to better account for these newly identified processes and their potential impacts on global carbon dynamics.

13.
BMC Complement Med Ther ; 24(1): 70, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-38303001

RESUMEN

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the leading causes of human death worldwide. Herbal prescription SH003 has been developed to treat several cancers including NSCLC. Due to the multi-component nature of SH003 with multiple targets and pathways, a network pharmacology study was conducted to analyze its active compounds, potential targets, and pathways for the treatment of NSCLC. METHODS: We systematically identified oral active compounds within SH003, employing ADME criteria-based screening from TM-MC, OASIS, and TCMSP databases. Concurrently, SH003-related and NSCLC-associated targets were amalgamated from various databases. Overlapping targets were deemed anti-NSCLC entities of SH003. Protein-protein interaction networks were constructed using the STRING database, allowing the identification of pivotal proteins through node centrality measures. Empirical validation was pursued through LC-MS analysis of active compounds. Additionally, in vitro experiments, such as MTT cell viability assays and western blot analyses, were conducted to corroborate network pharmacology findings. RESULTS: We discerned 20 oral active compounds within SH003 and identified 239 core targets shared between SH003 and NSCLC-related genes. Network analyses spotlighted 79 hub genes, including TP53, JUN, AKT1, STAT3, and MAPK3, crucial in NSCLC treatment. GO and KEGG analyses underscored SH003's multifaceted anti-NSCLC effects from a genetic perspective. Experimental validations verified SH003's impact on NSCLC cell viability and the downregulation of hub genes. LC-MS analysis confirmed the presence of four active compounds, namely hispidulin, luteolin, baicalein, and chrysoeriol, among the eight compounds with a median of > 10 degrees in the herb-compounds-targets network in SH003. Previously unidentified targets like CASP9, MAPK9, and MCL1 were unveiled, supported by existing NSCLC literature, enhancing the pivotal role of empirical validation in network pharmacology. CONCLUSION: Our study pioneers the harmonization of theoretical predictions with practical validations. Empirical validation illuminates specific SH003 compounds within NSCLC, simultaneously uncovering novel targets for NSCLC treatment. This integrated strategy, accentuating empirical validation, establishes a paradigm for in-depth herbal medicine exploration. Furthermore, our network pharmacology study unveils fresh insights into SH003's multifaceted molecular mechanisms combating NSCLC. Through this approach, we delineate active compounds of SH003 and target pathways, reshaping our understanding of its therapeutic mechanisms in NSCLC treatment.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Farmacología en Red , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de la Angiogénesis , Western Blotting
14.
Anticancer Res ; 44(5): 1905-1913, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38677764

RESUMEN

BACKGROUND/AIM: BRAF mutations are relatively uncommon in lung cancer. However, the majority of therapies targeting BRAF mutations have been developed exclusively for lung cancer patients with V600E mutations, limiting their effectiveness in treating tumors with the non-V600E BRAF mutations. As a result, there is a need to explore effective therapeutic strategies for patients with lung cancer carrying non-V600 BRAF mutations. Therefore, this study aims to identify a combination treatment approach that effectively targets lung cancer with G469A non-V600 BRAF alteration. MATERIALS AND METHODS: The efficacy of drug treatments was assayed using a patient-derived xenograft (PDX) mouse model. Histological analysis was performed using hematoxylin and eosin and immunohistochemical staining. Cell viability and growth were determined using the WST-8 and colony formation assays. Protein levels and apoptosis were analyzed using western blot and flow cytometry, respectively. RESULTS: We demonstrated that the lung cancer cells harboring the non-V600E G469A mutation were responsive to the combination of SH003 and dabrafenib. By utilizing patient-derived xenograft (PDX) models, we identified that this combined treatment induces apoptosis and exhibits antitumor effects through the reduction of ERK signals. The synergistic effect of the combination treatment on BRAF G469A lung cancer cells was consistent with its effects on PDX models, suggesting that the molecular mechanism of apoptosis involves a decrease in the MEK/ERK signaling pathway. CONCLUSION: The SH003 and dabrafenib combination can be potentially developed as an effective treatment strategy for addressing lung cancer patients with the BRAF G469A mutation.


Asunto(s)
Imidazoles , Neoplasias Pulmonares , Sistema de Señalización de MAP Quinasas , Mutación , Oximas , Proteínas Proto-Oncogénicas B-raf , Ensayos Antitumor por Modelo de Xenoinjerto , Humanos , Proteínas Proto-Oncogénicas B-raf/genética , Imidazoles/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Animales , Oximas/farmacología , Ratones , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Línea Celular Tumoral , Apoptosis/efectos de los fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico
15.
Anticancer Res ; 44(10): 4347-4358, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39348976

RESUMEN

BACKGROUND/AIM: Cancer remains a major global health concern due to its high mortality rates. Advanced diagnostic imaging, such as in vivo near-infrared (NIR) fluorescence imaging, enhances early detection by reducing autofluorescence and enabling deeper tissue penetration, addressing some limitations of conventional methods. Understanding the underlying causes of autofluorescence, even in mouse model fluorescence imaging, is crucial for accurate interpretation. This study investigated the origins of autofluorescence observed in experimental animals under NIR wavelengths, achieving successful fluorescence imaging in a clinically relevant tumor mouse model. MATERIALS AND METHODS: Both fasting and non-fasting groups were evaluated to assess the dietary impact on autofluorescence, with various feeds tested. Subcutaneous and lung tumor models were established in C57BL/6 and BALB/c nude mice using LL/2-iRFP cells. Cryo-sectioning and lung tissue imaging were conducted to confirm tumor presence and assess fluorescence signals. RESULTS: It was found that autofluorescence, notably common in the abdomen, is attributed to dietary factors. By selecting feed that lacks autofluorescence, the impact of dietary fluorescence on imaging was evaluated, leading to the establishment of optimized imaging conditions suited to the presence or absence of autofluorescence. Subsequently, utilizing lung cancer cells expressing near-infrared proteins (LL/2-iRFP), intratracheal, and subcutaneous tumor mouse models were developed, and successful in vivo imaging was achieved using the optimized imaging protocols, effectively bypassing autofluorescence. CONCLUSION: This study emphasizes the importance of understanding and addressing autofluorescence in fluorescence imaging, presenting valuable insights for enhancing the reliability and accuracy of diagnostic imaging techniques in cancer research and clinical practice.


Asunto(s)
Modelos Animales de Enfermedad , Neoplasias Pulmonares , Ratones Desnudos , Imagen Óptica , Animales , Imagen Óptica/métodos , Ratones , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Ratones Endogámicos BALB C , Línea Celular Tumoral , Humanos , Ratones Endogámicos C57BL , Espectroscopía Infrarroja Corta/métodos , Femenino
16.
J Extracell Vesicles ; 13(9): e12508, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39323378

RESUMEN

Extracellular vesicles (EVs) have emerged as a potential delivery vehicle for nucleic-acid-based therapeutics, but challenges related to their large-scale production and cargo-loading efficiency have limited their therapeutic potential. To address these issues, we developed a novel "shock wave extracellular vesicles engineering technology" (SWEET) as a non-genetic, scalable manufacturing strategy that uses shock waves (SWs) to encapsulate siRNAs in EVs. Here, we describe the use of the SWEET platform to load large quantities of KRASG12C-targeting siRNA into small bovine-milk-derived EVs (sBMEVs), with high efficiency. The siRNA-loaded sBMEVs effectively silenced oncogenic KRASG12C expression in cancer cells; they inhibited tumour growth when administered intravenously in a non-small cell lung cancer xenograft mouse model. Our study demonstrates the potential for the SWEET platform to serve as a novel method that allows large-scale production of cargo-loaded EVs for use in a wide range of therapeutic applications.


Asunto(s)
Vesículas Extracelulares , Proteínas Proto-Oncogénicas p21(ras) , ARN Interferente Pequeño , Vesículas Extracelulares/metabolismo , Animales , ARN Interferente Pequeño/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Humanos , Ratones , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Mutación , Bovinos
17.
Int Immunopharmacol ; 137: 112470, 2024 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-38908085

RESUMEN

BACKGROUND: The surplus cytokines remaining after use in the early stages of the inflammatory response stimulate immune cells even after the response is over, causing a secondary inflammatory response and ultimately damaging the host, which is called a cytokine storm. Inhibiting heat shock protein 90 (Hsp90), which has recently been shown to play an important role in regulating inflammation in various cell types, may help control excessive inflammatory responses and cytokine storms. METHODS: We discovered an anti-inflammatory compound by measuring the inhibitory effect of CD86 expression on spleen DCs (sDCs) using the chemical compounds library of Hsp90 inhibitors. Subsequently, to select the hit compound, the production of cytokines and expression of surface molecules were measured on the bone marrow-derived DCs (BMDCs) and peritoneal macrophages. Then, we analyzed the response of antigen-specific Th1 cells. Finally, we confirmed the effect of the compound using acute lung injury (ALI) and delayed-type hypersensitivity (DTH) models. RESULTS: We identified Be01 as the hit compound, which reduced CD86 expression the most in sDCs. Treatment with Be01 decreased the production of pro-inflammatory cytokines (IL-6, TNF-α, and IL-1ß) in BMDC and peritoneal macrophages stimulated by LPS. Under the DTH model, Be01 treatment reduced ear swelling and pro-inflammatory cytokines in the spleen. Similarly, Be01 treatment in the ALI model decreased neutrophil infiltration and lower levels of secreted cytokines (IL-6, TNF-α). CONCLUSIONS: Reduction of CD80 and CD86 expression on DCs by Be01 indicates reduced secondary inflammatory response by Th1 cells, and reduced release of pro-inflammatory cytokines by peritoneal macrophages may initially control the cytokine storm.


Asunto(s)
Antiinflamatorios , Citocinas , Células Dendríticas , Proteínas HSP90 de Choque Térmico , Macrófagos Peritoneales , Ratones Endogámicos C57BL , Animales , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP90 de Choque Térmico/metabolismo , Citocinas/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Ratones , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/inmunología , Macrófagos Peritoneales/metabolismo , Hipersensibilidad Tardía/tratamiento farmacológico , Hipersensibilidad Tardía/inmunología , Antígeno B7-2/metabolismo , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/inmunología , Células Cultivadas , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/inmunología , Células TH1/inmunología , Células TH1/efectos de los fármacos , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Femenino , Modelos Animales de Enfermedad , Bazo/inmunología , Bazo/efectos de los fármacos
18.
Anim Cells Syst (Seoul) ; 28(1): 340-352, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39011371

RESUMEN

Preventing disease and maintaining the health of the elderly are crucial goals for an aging population, with obesity and immune function restoration being of paramount importance. Obesity, particularly visceral obesity characterized by excessive fat accumulation around the abdominal organs, is linked to chronic conditions such as diabetes, hypertension, cardiovascular diseases, and immune dysfunction. Globally, obesity is considered a disease, prompting significant research interest in its treatment. Therefore, it is essential to explore potential therapeutic and preventive strategies to address obesity and the decline in immune function brought about by aging. Tenebrio molitor larvae (TML), commonly known as 'mealworms,' are rich in unsaturated fatty acids, including oleic and linoleic acids, and essential amino acids, such as isoleucine and tyrosine. In this study, we aimed to investigate the effects of the consumption of TML oil and mealworm fermented extract (MWF-1) on obesity and immunological changes in aged obese mice. Our data showed reduced body fat in 23-week-old C57BL/6 mice fed processed TML products for 6 weeks. Additionally, the characteristically high levels of serum triglycerides decreased by treating with TML oil. The immune responsiveness results confirmed an increase in B cells by treating with MWF-1, while cytokine levels (interferon-gamma, tumor necrosis factor-alpha, interleukin-2, and -6) were restored to levels similar to young mice. These results suggest that TML oil and MWF-1 are promising dietary supplements for addressing obesity and restoring immune function.

19.
Biomater Res ; 28: 0026, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38665698

RESUMEN

Despite notable advancements in cancer therapeutics, metastasis remains a primary obstacle impeding a successful prognosis. Our prior study has identified heme oxygenase 2 (HO2) as a promising therapeutic biomarker for the aggressive subsets within tumor. This study aims to systematically evaluate HO2 as a therapeutic target of cancer, with a specific emphasis on its efficacy in addressing cancer metastasis. Through targeted inhibition of HO2 by TiNIR (tumor-initiating cell probe with near infrared), we observed a marked increase in reactive oxygen species. This, in turn, orchestrated the modulation of AKT and cJUN activation, culminating in a substantial attenuation of both proliferation and migration within a metastatic cancer cell model. Furthermore, in a mouse model, clear inhibition of cancer metastasis was unequivocally demonstrated with an HO2 inhibitor administration. These findings underscore the therapeutic promise of targeting HO2 as a strategic intervention to impede cancer metastasis, enhancing the effectiveness of cancer treatments.

20.
Mar Pollut Bull ; 186: 114446, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36502775

RESUMEN

To determine the driving mechanisms between submarine groundwater discharge (SGD) and massive blooms of the green alga Ulva, we examined the magnitude of SGD and SGD-derived nutrient fluxes from November 2019 to July 2020 in Ihotewoo (north) and Bangdu (east) bays, Jeju Island, Korea. The variability of SGD flux at both the sites, where the hydraulic gradient is low, closely followed the daily variability of the tidal range, indicating that SGD flux is primarily driven by tidal pumping. Although the average annual SGD-driven nutrient fluxes were 24-37 % lower in Bangdu Bay than in Ihotewoo Bay, massive Ulva blooms only occurred in Bangdu Bay. A longer residence time (poor water exchange) and continuous SGD input with high dissolved inorganic nitrogen play a significant role in the growth and extentsion of Ulva blooms.


Asunto(s)
Agua Subterránea , Ulva , Monitoreo del Ambiente , Corea (Geográfico) , Bahías , República de Corea
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