• Journal of Physiology & Pathology in Korean Medicine
• /
• v.25 no.1
• /
• pp.29-36
• /
• 2011

Nardostachyts chinensis (N. chinensis) belonging to the family Valerianaceae has been used to elicit stomachic and sedative effects. The MAPKs are serine/threonine kinases involved in the regulation of various cellular responses, such as cell proliferation, differentiation and apoptosis. The PKC also plays a key role in regulating the response of hematopoietic cells to both physiological and pathological inducers of proliferation and differentiation. This study investigated the signaling pathways on the U937 cell differentiation induced by N. chinensis. N. chinensis induced the differentiation of U937 cells, as shown by increased of differentiation surface antigen CD11b. Activation of ERK increased time-dependently in differentiation of U937 cells induced by N. chinensis, but activations of JNK and p38 were unaffected. Inhibitor of ERK (PD98059) significantly reduced CD11b expression induced by N. chinensis in U937 cells. In addition, N. chinensis increased protein level of PKC ${\beta}$I and PKC ${\beta}$II isoforms, but the protein level of PKC ${\alpha}$ and PKC ${\gamma}$was constant. PKC inhibitors (GF 109203X and H-7) inhibited U937 cell differentiation and the ERK activation induced by N. chinensis. These results indicated that PKC and ERK may be involved in U937 cell differentiation induced by N. chinensis.

• Asian Pacific Journal of Cancer Prevention
• /
• v.14 no.2
• /
• pp.739-742
• /
• 2013

Background: This study was to evaluate the survival of patients with pleural and intraperitoneal malignant mesothelioma and to investigate the efficacy of chemotherapy (CT) as well as radiotherapy (RTH) and surgery compared to best supportive care (BSC). Materials and Methods: Forty patients with malignant mesothelioma (38 with pleural and 2 with intraperitoneal) were enrolled. Twenty seven patients underwent (CT) chemotherapy of which 2 also received (RTH) and surgery was only for biopsy in 15/40. Combination chemotherapy included cisplatin-gemcitabine, cisplatin-navelbine and cisplatin (or carboplatin) with premetrexed. Thirteen patients received only best supportive care. Results: A total of 12 (30%) patients were male, and 28 (70%) female. Median age was 54.0 years and the male/female ratio was 1/2.33 (P=0.210). Residential exposure played a major role in two regions, Helwan and Shoubra, in 20% and 15%, respectively. Overall mean survival time was $13.9{\pm}2.29$ months. That for patients who had received best supportive care was $7.57{\pm}1.85$ months, for chemotherapy was $16.5{\pm}3.20$ months, and multimodality treatment regimen $27{\pm}21.0$ months (P=0.028). Kaplan-Meier survival did not significantly vary for sex, residence and the pathological types epithelial, mixed and sarcomatous. The median survival for performance status and treatment modalities was significant (P=0.001 and 0.028). Best supportive care using opioids with a mean dose of 147.1 mg (range 0-1680) of morphine sulphate produced good subjective response and reasonable quality of life but did not affect survival. Conclusions: We conclude that CT prolongs survival compared to BSC in patients with malignant mesothelioma. Moreover, using escalating doses of opioids provides good pain relief and subjective responses.

• BMB Reports
• /
• v.53 no.4
• /
• pp.206-211
• /
• 2020

Vascular smooth muscle cells (VSMCs) are a unique cell type that has unusual plasticity controlled by environmental stimuli. As an abnormal increase of VSMC proliferation is associated with various vascular diseases, tight regulation of VSMC phenotypes is essential for maintaining vascular homeostasis. Hypoxia is one environmental stress that stimulates VSMC proliferation. Emerging evidence has indicated that microRNAs (miRNAs) are critical regulators in the hypoxic responses of VSMCs. Therefore, we previously investigated miRNAs modulated by hypoxia in VSMCs and found that miR-1260b is one of the most upregulated miRNAs under hypoxia. However, the mechanism that underlies the regulation of VSMCs via miR-1260b in response to hypoxia has not been explored. Here we demonstrated that hypoxia-induced miR-1260b promotes VSMC proliferation. We also identified growth differentiation factor 11 (GDF11), a member of the TGF-β superfamily, as a novel target of miR-1260b. miR-1260b directly targets the 3'UTR of GDF11. Downregulation of GDF11 inhibited Smad signaling and consequently enhanced the proliferation of VSMCs. Our findings suggest that miR-1260b-mediated GDF11-Smad-dependent signaling is an essential regulatory mechanism in the proliferation of VSMCs, and this axis is modulated by hypoxia to promote abnormal VSMC proliferation. Therefore, our study unveils a novel function of miR-1260b in the pathological proliferation of VSMCs under hypoxia.

• Biomolecules & Therapeutics
• /
• v.23 no.5
• /
• pp.449-457
• /
• 2015

The present study was aimed to investigate the effects of MB12662, a synthetic dunnione compound, on cisplatin-induced vomiting reflexes and intestinal, renal, immune system, and hematopoietic toxicities in ferrets and mice, respectively. Male ICR mice were orally administered MB12662 (5, 10, 25 or 50 mg/kg) for 10 days, during which intraperitoneally challenged with cisplatin (3.5 mg/kg) from day 4 to 7, and sacrificed on day 10 for the pathological examination. Male ferrets were orally administered MB12662 (25, 50 or 100 mg/kg) for 7 days, subcutaneously challenged with cisplatin (5 mg/kg), and monitored for vomiting reflexes and survival of the animals. Four-day injection of cisplatin (3.5 mg/kg) to mice caused body weight loss and degeneration and atrophy of intestinal villi, reducing villi/crypt ratio to a half level of control animals. Cisplatin also induced renal and hepatic toxicities, and depletion of splenocytes and bone marrow progenitor cells. The systemic toxicities including decreased villi/crypt ratio, immune system atrophy, splenocyte depletion, and decreased cellularity in bone marrow were improved by MB12662. Cisplatin (5 mg/kg) induced retching and emetic responses of ferrets, which were remarkably attenuated by MB12662 in a dose-dependent manner. All the ferrets pretreated with MB12662 survived the challenge of cisplatin, in comparison with 40% mortality in vehicle-treated animals, and blood parameters of nephrotoxicity and hepatotoxicity were markedly recovered. It is expected that MB12662 could be a candidate for the body protection against burden, including emesis, of chemotherapeutic agents.

• Biomolecules & Therapeutics
• /
• v.26 no.2
• /
• pp.175-181
• /
• 2018

Carbon monoxide (CO) is well-known as toxic gas and intrinsic signaling molecule such as neurotransmitter and blood vessel relaxant. Recently, it has been reported that low concentration of CO exerts therapeutic actions under various pathological conditions including liver failure, heart failure, gastric cancer, and cardiac arrest. However, little has been known about the effect of CO in neurodegenerative diseases like Parkinson's disease (PD). To test whether CO could exert a beneficial action during oxidative cell death in PD, we examined the effects of CO on 6-hydroxydopamine (6-OHDA)-induced cell death in C6 glioma cells. Treatment of CO-releasing molecule-2 (CORM-2) significantly attenuated 6-OHDA-induced apoptotic cell death in a dose-dependent manner. CORM-2 treatment decreased Bax/Bcl2 ratio and caspase-3 activity, which had been increased by 6-OHDA. CORM-2 increased phosphorylation of NF-E2-related factor 2 (Nrf2) which is a transcription factor regulating antioxidant proteins. Subsequently, CORM-2 also increased the expression of heme oxygenase-1 and superoxide dismutases (CuZnSOD and MnSOD), which were antioxidant enzymes regulated by Nrf2. These results suggest that CO released by CORM-2 treatment may have protective effects against oxidative cell death in PD through the potentiation of cellular adaptive survival responses via activation of Nrf2 and upregulation of heme oxygenase-1, leading to increasing antioxidant defense capacity.

• Korean Journal of Veterinary Service
• /
• v.25 no.1
• /
• pp.45-52
• /
• 2002

The acute phase serum protein response is a well-known general indicator of inflammation, trauma or other pathological conditions and its relevance for the monitoring of the health status of domestic animals is being increasingly realized. The changes in serum protein composition which occur after tissue damage represent a part of the systemic response of the injured animals which is mediated by pro-inflammatory cytokines such as TNF-$\alpha$, IL-6 and IL-1. These responses play a vital role in containing the tissue damage and enhancing the processes of repair and resolution. From a clinical perspective, the assay of acute phase proteins can provide a method for detecting inflammation. In animals, the most sensitive acute phase proteins are haptoglogin, serum amyloid A and at-acid glycoprotein in response to inflammatory condition. The aim of this study was to assess the diagnostic value of the concentrations of serum amyloid A(SAA) and haptoglobin(HP) in serum of pigs infected with Aujeszky's disease virus(ADV). Fifty pigs infected with ADV and 5 normal pigs were used in this experiment. The mean serum concentration of Shh of pigs infected with ADV was 96.8 $\pm$ 7.1 $\mu\textrm{g}$/㎖(range, 36.0∼187.5 $\mu\textrm{g}$/㎖) and that of normal pigs was 42.9$\pm$3.3 $\mu\textrm{g}$/㎖(range, 17.3∼127.8 $\mu\textrm{g}$/㎖). The mean serum concentration of HP of pigs infected with ADV was 1,164.4 $\pm$ 96.9 $\mu\textrm{g}$/㎖ (range, 790.2∼l,769.2 $\mu\textrm{g}$/㎖) and that of normal pigs was 675.4 $\pm$ 56.3 $\mu\textrm{g}$/㎖ (range, 650.0-690.4 $\mu\textrm{g}$/㎖). The mean concentrations of SAA and HP in serum of pigs infected with ADV compared with those of normal pigs showed approximately a two-fold. It was concluded that the concentrations of Shh and HP in serum may proved to be diagnostic marker of Aujeszky's disease.

• Biomolecules & Therapeutics
• /
• v.29 no.2
• /
• pp.127-134
• /
• 2021

Neuroinflammation―a common pathological feature of neurodegenerative disorders such as Alzheimer's disease―is mediated by microglial activation. Thus, inhibiting microglial activation is vital for treating various neurological disorders. 7,3',4'-Trihydroxyisoflavone (THIF)―a secondary metabolite of the soybean compound daidzein―possesses antioxidant and anticancer properties. However, the effects of 7,3',4'-THIF on microglial activation have not been explored. In this study, antineuroinflammatory effects of 7,3',4'-THIF in lipopolysaccharide (LPS)-stimulated BV2 microglial cells were examined. 7,3',4'-THIF significantly suppressed the production of the proinflammatory mediators nitric oxide (NO), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) as well as of the proinflammatory cytokine interleukin-6 (IL-6) in LPS-stimulated BV2 microglial cells. Moreover, 7,3',4'-THIF markedly inhibited reactive oxygen species (ROS) generation. Western blotting revealed that 7,3',4'-THIF diminished LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), glycogen synthase kinase-3β (GSK-3β), and nuclear factor kappa B (NF-κB). Overall, 7,3',4'-THIF exerts antineuroinflammatory effects against LPS-induced microglial activation by suppressing mitogen-activated protein kinase (MAPK) and NF-κB signaling, ultimately reducing proinflammatory responses. Therefore, these antineuroinflammatory effects of 7,3',4'-THIF suggest its potential as a therapeutic agent for neurodegenerative disorders.

• Journal of Gastric Cancer
• /
• v.21 no.2
• /
• pp.155-168
• /
• 2021

Purpose: Previous studies have demonstrated the usefulness of the controlling nutritional status (CONUT) score in nutritional assessment and survival prediction of patients with various malignancies. However, its value in advanced gastric cancer (GC) treated with neoadjuvant chemotherapy and curative gastrectomy remains unclear. Materials and Methods: The CONUT score at different time points (pretreatment, preoperative, and postoperative) of 272 patients with advanced GC were retrospectively calculated from August 2004 to October 2015. The χ² test or Mann-Whitney U test was used to estimate the relationships between the CONUT score and clinical characteristics as well as short-term outcomes, while the Cox proportional hazard model was used to estimate long-term outcomes. Survival curves were estimated by using the Kaplan-Meier method and log-rank test. Results: The proportion of moderate or severe malnutrition among all patients was not significantly changed from pretreatment (13.5%) to pre-operation (11.7%) but increased dramatically postoperatively (47.5%). The pretreatment CONUT-high score (≥4) was significantly associated with older age (P=0.010), deeper tumor invasion (P=0.025), and lower pathological complete response rate (CONUT-high vs. CONUT-low: 1.2% vs. 6.6%, P=0.107). Pretreatment CONUT-high score patients had worse progression-free survival (P=0.032) and overall survival (OS) (P=0.026). Adjusted for pathologic node status, the pretreatment CONUT-high score was strongly associated with worse OS in pathologic node-positive patients (P=0.039). Conclusions: The pretreatment CONUT score might be a straightforward index for immune-nutritional status assessment, while being a reliable prognostic indicator in patients with advanced GC receiving neoadjuvant chemotherapy and curative gastrectomy. Moreover, lower pretreatment CONUT scores might indicate better chemotherapy responses.

• Urogenital Tract Infection
• /
• v.13 no.3
• /
• pp.51-57
• /
• 2018

Purpose: The effects of Lactobacillus fermentation extract (LFE) on cystitis induced by Escherichia coli lipopolysaccharide (LPS) in the mouse bladder were investigated by pathological analyses and measurement of the levels of tumor necrosis factor-alpha ($TNF-{\alpha}$) and interleukin-18 (IL-18). Materials and Methods: LFE was administered orally ($5{\mu}g/L$) to mice for 10 days after which the study group (n=12) received transurethral injection of $5{\mu}g/L$ LPS. The bladder tissue was then harvested after 24 hours and subjected to hematoxylin and eosin staining. A semi-quantitative score was used to evaluate inflammation (bladder inflammation index, BII). $TNF-{\alpha}$ immunohistochemical staining and multiplex cytokine assays were also performed. $TNF-{\alpha}$ and IL-18 levels were determined. The results were compared with those of the control group (n=12). Results: The BII in the control and study groups was $2.7{\pm}0.5$ and $1.1{\pm}0.7$, respectively, with the control group scores differing significantly from the study group scores (p<0.001). $TNF-{\alpha}$ immunohistochemical staining results were similar. The $TNF-{\alpha}$ levels determined by the multiplex cytokine assay were $2.82{\pm}1.35pg/mg$ and $1.55{\pm}0.56pg/mg$ for the control and study groups, respectively, and the difference between these groups was statistically significant (p=0.007). Conclusions: Oral administration of LFE appears to have a preventive effect against the inflammatory responses and $TNF-{\alpha}$ expression induced by transurethral instillation of LPS in the mouse bladder. Further studies are required to determine the clinical application of this finding.

• Molecules and Cells
• /
• v.44 no.5
• /
• pp.281-291
• /
• 2021

Tissue-resident macrophages play an important role in maintaining tissue homeostasis and innate immune defense against invading microbial pathogens. Brain-resident macrophages can be classified into microglia in the brain parenchyma and non-parenchymal brain macrophages, also known as central nervous system-associated or border-associated macrophages, in the brain-circulation interface. Microglia and non-parenchymal brain macrophages, including meningeal, perivascular, and choroid plexus macrophages, are mostly produced during embryonic development, and maintained their population by self-renewal. Microglia have gained much attention for their dual roles in the maintenance of brain homeostasis and the induction of neuroinflammation. In particular, diverse phenotypes of microglia have been increasingly identified under pathological conditions. Single-cell phenotypic analysis revealed that microglia are highly heterogenous and plastic, thus it is difficult to define the status of microglia as M1/M2 or resting/activated state due to complex nature of microglia. Meanwhile, physiological function of non-parenchymal brain macrophages remain to be fully demonstrated. In this review, we have summarized the origin and signatures of brain-resident macrophages and discussed the unique features of microglia, particularly, their phenotypic polarization, diversity of subtypes, and inflammasome responses related to neurodegenerative diseases.