• Food Science and Preservation
• /
• v.31 no.3
• /
• pp.462-473
• /
• 2024

The anti-inflammatory effect of beluga lentil extract (BLE) and its underlying mechanisms were investigated in lipopolysaccharide (LPS)-treated RAW 264.7 cells. Treatment with BLE significantly decreased nitric oxide (NO) production and protein and mRNA expressions of inducible NO synthase (iNOS) in LPS-treated RAW 264.7 cells. Down-regulation of this inflammatory gene expression was not associated with NF-κB/MAPK signaling pathways, and further mechanistic studies demonstrated that BLE decreased LPS-induced iNOS expression through upregulation of the nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated heme oxygenase-1 (HO-1) expression. These results suggest that beluga lentil represent a potential source of natural anti-inflammatory agents, and further studies will be necessary to determine its anti-inflammatory effects in vivo.

• International Journal of Oncology
• /
• v.57 no.4
• /
• pp.1027-1038
• /
• 2020

Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies and is a leading cause of cancer-related mortality worldwide. Histone deacetylases (HDACs) are a class of enzymes responsible for the epigenetic regulation of gene expression. Some HDAC inhibitors have been shown to be efficient agents for cancer treatment. The aim of the present study was to discover a novel, potent HDAC inhibitor and demonstrate its anticancer effect and molecular mechanisms in CRC cells. A novel fluorinated aminophenyl-benzamide-based compound, CBUD-1001, was designed to specifically target HDAC1, and it was then synthesized and evaluated. CBUD-1001 exerted a potent inhibitory effect on HDAC enzyme activity and exhibited anticancer potency against CRC cell lines. Molecular docking analysis rationalized the high potency of CBUD-1001 by validating its conformation in the HDAC active site. Further investigation using CRC cells demonstrated that CBUD-1001 inhibited HDAC activity by hyper-acetylating histones H3 and H4, and it exerted an apoptotic effect by activating a mitochondrial-dependent pathway. Of note, it was found that CBUD-1001 attenuates the cell motility of CRC cells by downregulating the EMT signaling pathway. Thus, CBUD-1001 may prove to be a promising novel drug candidate for CRC therapy.

• Oncology Letters
• /
• v.17 no.4
• /
• pp.3981-3989
• /
• 2019

Tamoxifen (TAM) is the most widely used treatment for estrogen receptor-positive breast cancer patients. Unfortunately, the majority of these patients exhibit TAM resistance following treatment. We previously reported that proliferation and migration were greater in TAM-resistant MCF-7 (TAMR-MCF-7) cells than in parental MCF-7 cells. Janus kinases (JAKs) are cytosolic tyrosine kinases that transduce signals from plasma membrane cytokines and growth factor receptors. JAK2 selectively phosphorylates signal transducer and activator of transcription (STAT)-3, and the JAK2-STAT3 signaling pathway is known as a crucial signaling pathway for the regulation of cancer progression and metastasis. In the present study, basal phosphorylation of STAT3 was revealed to be greater in TAMR-MCF-7 cells than in control MCF-7 cells. Ruxolitinib, a potent JAK2 inhibitor, was demonstrated to attenuate STAT3 phosphorylation and the proliferation of TAMR-MCF-7 cells. Ruxolitinib also suppressed the enhanced cell migration of TAMR-MCF-7 cells through the inhibition of epithelial mesenchymal transition. Vascular endothelial growth factor (VEGF), a representative target gene of the JAK2-STAT3 pathway, functions as a key regulator of invasion and angiogenesis. Ruxolitinib significantly inhibited VEGF mRNA expression and transcriptional activity. The present study also performed a chick embryo chorioallantoic membrane assay to assess tumor growth and angiogenesis in TAMR-MCF-7 cells. Ruxolitinib reduced tumor weight and the number of blood vessels produced by TAMR-MCF-7 cells in a concentration-dependent manner. These results indicated that JAK2 could be a new therapeutic target for TAM-resistant breast cancer.

• Oncology Letters
• /
• v.17 no.3
• /
• pp.3589-3598
• /
• 2019

Colorectal cancer (CRC) is a complex disease involving numerous genetic abnormalities. One of the major characteristics of CRC is enhanced Wnt signaling caused by loss-of-function mutations in the adenomatous polyposis coli (APC) gene. Previously, it has been demonstrated that the majority of malignant phenotypes following APC deletion in adult murine small intestines could be rescued when Myc, a downstream target of the Wnt pathway, was deleted. This indicated that Myc is a critical regulator of CRC development following APC loss. Previous studies reported that cyclic adenosine 3',5'-monophosphate (cAMP) can influence the AKT/mammalian target of rapamycin (mTOR) survival pathway in cancer and Myc is a critical downstream molecule of AKT/mTOR signaling. Phosphodiesterase 4D (PDE4D), a member of the cAMP-specific PDE4 family, has been associated with drug resistance in CRC. However, the association between PDE4D and Myc remains unclear. To investigate the potential role of PDE4D in Myc regulation in CRC, the present study evaluated the expression levels of PDE4 subtypes in DLD-1 CRC cells. Additionally, the effects of PDE4 inhibitors on Myc expression and oncogenic properties were analyzed by western blot analysis, reverse transcription-quantitative polymerase chain reaction, colony formation and soft agar assays. It was demonstrated that cAMP/PDE4D signals serve a critical role in regulating Myc expression in DLD-1 CRC cells. Furthermore, PDE4D was identified to be a main hydrolyzer of cAMP and suppression of PDE4D using selective inhibitors of PDE4 increased intracellular cAMP levels, which resulted in a marked decrease in the oncogenic properties of DLD-1 cells, including colony formation, cell proliferation and anchorage-independent growth. Notably, the current data imply that cAMP represses Myc expression via the downregulation of AKT/mTOR signaling, which was abolished by high PDE4D activities in DLD-1 cells. Additionally, a natural polyphenol resveratrol in combination with forskolin elevated the concentration of cAMP and enhanced the expression of Myc and the malignant phenotype of DLD-1 cells, reproducing the effect of known chemical inhibitors of PDE4. In conclusion, the present study identified that cAMP/PDE4D signaling is a critical regulator of Myc expression in DLD-1 and possibly other CRC cells.

• Journal of Ginseng Research
• /
• v.48 no.5
• /
• pp.511-519
• /
• 2024

Background: The cycle of seasonal dormancy of perennating buds is an essential adaptation of perennial plants to unfavorable winter conditions. Plant hormones are key regulators of this critical biological process, which is intricately connected with diverse internal and external factors. Recently, global warming has increased the frequency of aberrant temperature events that negatively affect the dormancy cycle of perennials. Although many studies have been conducted on the perennating organs of Panax ginseng, the molecular aspects of bud dormancy in this species remain largely unknown. Methods: In this study, the molecular physiological responses of three P. ginseng cultivars with different dormancy break phenotypes in the spring were dissected using comparative genome-wide RNA-seq and network analyses. These analyses identified a key role for abscisic acid (ABA) activity in the regulation of bud dormancy. Gene set enrichment analysis revealed that a transcriptional network comprising stress-related hormone responses made a major contribution to the maintenance of dormancy. Results: Increased expression levels of cold response and photosynthesis-related genes were associated with the transition from dormancy to active growth in perennating buds. Finally, the expression patterns of genes encoding ABA transporters, receptors (PYRs/PYLs), PROTEIN PHOSPHATASE 2Cs (PP2Cs), and DELLAs were highly correlated with different dormancy states in three P. ginseng cultivars. Conclusion: This study provides evidence that ABA and stress signaling outputs are intricately connected with a key signaling network to regulate bud dormancy under seasonal conditions in the perennial plant P. ginseng.

• Research in Plant Disease
• /
• v.30 no.3
• /
• pp.268-277
• /
• 2024

Erwinia pyrifoliae is a gram-negative bacterial pathogen that commonly causes black shoot blight in pear and apple tree. Although the pathogenicity of this bacterial species is very similar to E. amylovora, there is no specific explanation of its pathogenic genes and mechanisms. In this study, our investigation into E. pyrifoliae pathogenicity involved generating seven YKB12327 mutant strains using Tn5 transposon mutagenesis. Observations revealed weakened growth rate and loss of pathogenicity in these mutants. Whole-genome sequencing and alignment analysis identified transposon insertions within the coding sequences of five strains and in the intergenic region of two strains. Annotation analysis elucidated genes directly or indirectly associated with pathogenicity. Notably, mutant strain MT16 displayed a transposon insertion mutation in the cyclic-di-GMP phosphodiesterase (pdeF) gene, a key player in bacterial signaling, governing microbial behavior and adaptation to environmental changes. Our findings provide insights into the genetic regulation of E. pyrifoliae pathogenicity, suggesting potential avenues for further research aimed at understanding and controlling this bacterial pathogen by targeting pdeF to mitigate apple black shoot blight disease.

• Journal of Life Science
• /
• v.19 no.12
• /
• pp.1802-1807
• /
• 2009

Platycodin D, a major component of Platycodi radix, is known to have various activities including anti-inflammatory, anti-hyperlipidemic, anti-tumor activities and others. Recently, it was reported that platycodin D inhibits fat accumulation and adipogenesis. The aim of this study was to investigate whether various adipogenic regulators are modulated by platycodin D treatment during the adipogenesis of 3T3-L1 cells. mRNA levels of terminal markers of adipogenesis such as ADIPOQ (adiponectin) and GLUT (glucose transporter) 4, which were quantified by real time PCR, were decreased by platycodin D treatment. mRNA expression of PPAR (peroxisome proliferator-activated receptor) $\gamma$ and C/EBP (CCAAT/enhaner binding protein) $\alpha$, which are central transcription factors of adipogenesis, were also decreased by platycodin D treatment. To elucidate the detailed molecular mechanism of platycodin D-induced inhibition of adipogenesis, we analyzed mRNA expression of upstream regulators of PPAR$\gamma$ and C/EPB$\alpha$. mRNA levels of the pro-adipogenic regulators, KROX20 and KLF (Kruppel-like factor) 15 were markedly down-regulated by platycodin D treatment. On the other hand, mRNA expression of CHOP (C/EBP homologous protein), an anti-adipogenic regulator, was significantly up-regulated by platycodin D treatment. mRNA levels of other pro-adipogenic regulators, C/EBP$\beta$ and C/EPB$\delta$, were not affected by platycodin D treatment, and another anti-adipogenic regulator, C/EBP$\gamma$ was also not affected by platycodin D treatment. Taken together, these results suggest that platycodin D-induced inhibition of adipogenesis is mediated by gene interactions including the down-regulation of pro-adipogenic regulators, KROX20 and KLF15, and the up-regulation of an anti-adipogenic regulator, CHOP.

• Tuberculosis and Respiratory Diseases
• /
• v.50 no.1
• /
• pp.12-28
• /
• 2001

Background and Object : Immunostimulatory CpG-oligodeoxynucleotides (ISS CpG-ODN) up-regulate the $T_{H1}$-type immune response and down-regulate the $T_{H2}$-type response. This study was performed to investigate the immune response changes resulting from ISS CpG-ODN on bronchial hyperresponsiveness, eosinophilic inflammation and mucus hypersecretion in rat asthma. Materials and Methods : 10 normal controls(NC) and 26 asthmatic rats, which were generated by ovalbumin(OVA) sensitization and challenge, were studied. The asthmatic rats were randomized into 11 asthma controls(AC) and 15 in the asthma-CpG treatment group(CpG). The CpG group was administered ISS CpG-ODN intramuscularly and the AC group was administered a placebo(0.9% NaCl) on day 15 and 20. After CpG-ODN or placebo administration, we measured the IFN-${\gamma}$($T_{H1}$-type cytokine) and IL-4($T_{H2}$-type cytokine) levels in the bronchoalveolar lavage fluid(BALF), the specific airway resistance(sRaw), eosinophilic fraction in BALF, eosinophilic infiltration, goblet cell dysplasia and MUC5AC gene expression in the lung tissue. Results : In the BALF of the CpG group, the IFN-${\gamma}$ concentration was significantly high and the IL-4 concentration was significantly low when compared with the AC group. Both the sRaw and eosinophilic fraction, and infiltration into the BALF and lung tissue significantly lower in the CpG group when compared with the AC group. However, little difference in goblet cell dysplasia and MUC5AC gene expression was observed between the CpG group and the AC group. Conclusion : ISS CpG-ODN decreases bronchial hyperresponsiveness and eosinophilic inflammation in the rat asthma model through the up-regulation of the $T_{H1}$-type immune response with the down-regulation of the $T_{H2}$-type response. However, the effect of these immune response changes on mucus hypersecretion was is not remarkable in this study.

• Tuberculosis and Respiratory Diseases
• /
• v.49 no.6
• /
• pp.703-714
• /
• 2000

Background : Surfactant protein A (SP-A) is important in the regulation of surfactant secretion, synthesis and recycling. SP-A has important roles in regulating surfactant metabolism as well as in determining surfactant's physical properties. Since systemic sepsis is one of the common causes of acute respiratory distress syndrome (ARDS) and abnormalities in surfactant function have been described in ARDS, the authors investigated the effects of endotoxemia on the accumulation of mRNA encoding SP-A and SP-A protein content. Methods : Adult rats were given various doses of intraperitoneal endotoxin from Salmonella enteritidis and sacrificed at different times. SP-A mRNA was measured by filter hybridization method. Lung SP-A protein content was determined by double sandwich ELISA assay using a polyclonal antiserum raised in rabbits against purified rat SP-A. Results : 1) The accumulation of SP-A mRNA in the endotoxin treated group 24 hours after 2mg/kg and 5mg/kg endotoxin treatments was significantly increased 50.9% and 27.3%, respectively, compared to the control group (P<0.001, P<0.025). 2) The accumulation of SP-A mRNA 24 hours in the 5mg/kg endotoxin treated group was significantly increased by 26.5% compared to the control group (P<0.01). 3) Total amount of lung SP-A was not altered at 24 hours by various doses of treatment. Total lung SP-A content 144 hours after endotoxin administration was significantly decreased by 51.4% compared to the control group (P<0.01). Conclusions : The specific regulation of SP-A by various time course in vivo is evident. The late decline in SP-A protein content was unexpected and suggests that SP-A may be differentially regulated during lung inflammation. The functional significance of these alterations remains to be clarified.

• Tuberculosis and Respiratory Diseases
• /
• v.55 no.3
• /
• pp.257-266
• /
• 2003

Background : The surfactant protein A(SP-A) is important in the regulation of surfactant secretion, synthesis and recycling. Since the acute respiratory distress syndrome(ARDS) is usually viewed as the functional and morphological expression of a similar underlying lung injury casued by a variety of insults and since abnormalities in surfactant function have been described in ARDS, the authors investigated the different effects of endotoxin and thiourea on the accumulation of mRNA encoding SP-A. Methods : Sprague-Dawley rats were given 5 mg/kg intraperitoneal endotoxin from Salmonella enteritidis and 3.5 mg/kg intraperitoneal thiourea and sacrified at different time periods. Results : 1) SP-A mRNA was significantly increased 67.0% in 6 hours and 73.4% in 24 hours after 5 mg/kg endotoxin treatment respectively(P<0.005, P<0.005). 2) SP-A mRNA significantly decreased 32.9% in 24 hours after 3.5 mg/kg thiourea treatment(P<0.05). Conclusions : These results indicate that the differential regulation of surfactant protein A in vivo is evident and suggest that surfactant protein A might be differentially regulated during different kind of insults of lung injury at different time periods without altering lung wet to dry ratios.