• Journal of Korean Neurosurgical Society
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• v.65 no.5
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• pp.665-679
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• 2022

Objective : Patients with mild ischemic stroke experience various sequela and residual symptoms, such as anxious behavior and deficits in movement. Few approaches have been proved to be effective and safe therapeutic approaches for patients with mild ischemic stroke by acute stroke. Sildenafil (SIL), a phosphodiesterase-5 inhibitor (PDE5i), is a known remedy for neurodegenerative disorders and vascular dementia through its angiogenesis and neurogenesis effects. In this study, we investigated the efficacy of PDE5i in the emotional and behavioral abnormalities in rats with mild ischemic stroke. Methods : We divided the rats into four groups as follows (n=20, respectively) : group 1, naïve; group 2, middle cerebral artery occlusion (MCAo30); group 3, MCAo30+SIL-pre; and group 4, MCAo30+SIL-post. In the case of drug administration groups, single dose of PDE5i (sildenafil citrate, 20 mg/kg) was given at 30-minute before and after reperfusion of MCAo in rats. After surgery, we investigated and confirmed the therapeutic effect of sildenafil on histology, immunofluorescence, behavioral assays and neural oscillations. Results : Sildenafil alleviated a neuronal loss and reduced the infarction volume. And results of behavior task and immunofluorescence shown possibility that anti-inflammation process and improve motor deficits sildenafil treatment after mild ischemic stroke. Furthermore, sildenafil treatment attenuated the alteration of theta-frequency rhythm in the CA1 region of the hippocampus, a known neural oscillatory marker for anxiety disorder in rodents, induced by mild ischemic stroke. Conclusion : PDE5i as effective therapeutic agents for anxiety and movement disorders and provide robust preclinical evidence to support the development and use of PDE5i for the treatment of mild ischemic stroke residual disorders.

• Korean Journal of Clinical Laboratory Science
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• v.54 no.4
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• pp.249-255
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• 2022

Alzheimer's disease (AD) represents a major public health concern and has been identified as a research priority. Clinical research evidence supports that the core cerebrospinal fluid (CSF) biomarkers for AD, including amyloid-β (Aβ42), total tau (T-tau), and phosphorylated tau (P-tau), reflect key elements of AD pathophysiology. Nevertheless, advances in the clinical identification of new indicators will be critical not only for the discovery of sensitive, specific, and reliable biomarkers of preclinical AD pathology, but also for the development of tests that facilitate the early detection and differential diagnosis of dementia and disease progression monitoring. The early detection of AD in its presymptomatic stages would represent a great opportunity for earlier therapeutic intervention. The chance of successful treatment would be increased since interventions would be performed before extensive synaptic damage and neuronal loss would have occurred. In this study, the importance of developing an early diagnostic method using cognitive decline biomarkers that can discriminate between normal, mild cognitive impairment (MCI), and AD preclinical stages has been emphasized.

• Molecules and Cells
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• v.45 no.3
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• pp.134-147
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• 2022

The anti-oxidant enzyme heme oxygenase-1 (HO-1) is known to exert anti-inflammatory effects. From a library of pyrazolo[3,4-d]pyrimidines, we identified a novel compound KKC080096 that upregulated HO-1 at the mRNA and protein levels in microglial BV-2 cells. KKC080096 exhibited anti-inflammatory effects via suppressing nitric oxide, interleukin1β (IL-1β), and iNOS production in lipopolysaccharide (LPS)-challenged cells. It inhibited the phosphorylation of IKK and MAP kinases (p38, JNK, ERK), which trigger inflammatory signaling, and whose activities are inhibited by HO-1. Further, KKC080096 upregulated anti-inflammatory marker (Arg1, YM1, CD206, IL-10, transforming growth factor-β [TGF-β]) expression. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinetreated mice, KKC080096 lowered microglial activation, protected the nigral dopaminergic neurons, and nigral damage-associated motor deficits. Next, we elucidated the mechanisms by which KKC080096 upregulated HO-1. KKC080096 induced the phosphorylation of AMPK and its known upstream kinases LKB1 and CaMKKbeta, and pharmacological inhibition of AMPK activity reduced the effects of KKC080096 on HO-1 expression and LPS-induced NO generation, suggesting that KKC080096-induced HO-1 upregulation involves LKB1/AMPK and CaMKKbeta/AMPK pathway activation. Further, KKC080096 caused an increase in cellular Nrf2 level, bound to Keap1 (Nrf2 inhibitor protein) with high affinity, and blocked Keap1-Nrf2 interaction. This Nrf2 activation resulted in concurrent induction of HO-1 and other Nrf2-targeted antioxidant enzymes in BV-2 and in dopaminergic CATH.a cells. These results indicate that KKC080096 is a potential therapeutic for oxidative stress-and inflammation-related neurodegenerative disorders such as Parkinson's disease.

• The Journal of the Society of Stroke on Korean Medicine
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• v.6 no.1
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• pp.25-32
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• 2005

Background and purpose: Arterial stiffness is an important, independent determinant of cardiovascular risk. Pulse wave velocity (PWV) has been used as a valuable index of arterial stiffness and as a surrogate marker for atherosclerosis. The Framingham risk score was developed using categorized risk factors to predict the 10 year absolute risk of developing coronary heart disease (CHD). This algorithm is established using recommended guidelines for blood pressure, total cholesterol, and high density lipoprotein cholesterol in addition to age, smoking history and history of diabetes. Tongxinluo(TXL) has been shown to have anti hyperlipidemic activity and anti atherogenic effects. To determine its efficacy and safety, we examined whether TXL improves PWV, ABI, Framingham score, blood pressure, and lipid profile in high risk group of cardiovascular diseases. Subjects and methods: 49 subjects with the high risk of cardiovascular diseases were recruited. Subjects were administered TXL with the dose of 1110mg three times a day for 8 weeks. baPWV, ABI, Framingham risk score, Blood pressure and serum lipid profile were assessed at baseline and after 4 and 8weeks. Results: Total cholesterol, LDL cholesterol, triglyceride, total lipid and phospolipid significantly decreased after 4 weeks of medication. Total cholesterol, total lipid and phospolipid significantly decreased after 8 weeks of medication. There were no significant changes in Framingham risk scores, ABI, PWV and blood pressure. On safety assessment, there were no adverse effects, hepatic or renal toxicity. Conclusion: We suggest that TXL is a safe and useful herbal medicine for hyperlipidemia and as for anti-atherognic effects, further research would be necessary.

• IMMUNE NETWORK
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• v.23 no.4
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• pp.35.1-35.16
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• 2023

Defining the molecular dynamics associated with T cell differentiation enhances our understanding of T cell biology and opens up new possibilities for clinical implications. In this study, we investigated the dynamics of CD5 expression in CD8⁺ T cell differentiation and explored its potential clinical uses. Using PBMCs from 29 healthy donors, we observed a stepwise decrease in CD5 expression as CD8⁺ T cells progressed through the differentiation stages. Interestingly, we found that CD5 expression was initially upregulated in response to T cell receptor stimulation, but diminished as the cells underwent proliferation, potentially explaining the differentiation-associated CD5 downregulation. Based on the proliferation-dependent downregulation of CD5, we hypothesized that relative CD5 expression could serve as a marker to distinguish the heterogeneous CD8⁺ T cell population based on their proliferation history. In support of this, we demonstrated that effector memory CD8⁺ T cells with higher CD5 expression exhibited phenotypic and functional characteristics resembling less differentiated cells compared to those with lower CD5 expression. Furthermore, in the retrospective analysis of PBMCs from 30 non-small cell lung cancer patients, we found that patients with higher CD5 expression in effector memory T cells displayed CD8⁺ T cells with a phenotype closer to the less differentiated cells, leading to favorable clinical outcomes in response to immune checkpoint inhibitor (ICI) therapy. These findings highlight the dynamics of CD5 expression as an indicator of CD8⁺ T cell differentiation status, and have implications for the development of predictive biomarker for ICI therapy.

• BMB Reports
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• v.56 no.12
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• pp.663-668
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• 2023

C-reactive protein (CRP) is an inflammatory marker and risk factor for atherosclerosis and cardiovascular diseases. However, the mechanism through which CRP induces myocardial damage remains unclear. This study aimed to determine how CRP damages cardiomyocytes via the change of mitochondrial dynamics and whether survivin, an anti-apoptotic protein, exerts a cardioprotective effect in this process. We treated H9c2 cardiomyocytes with CRP and found increased intracellular ROS production and shortened mitochondrial length. CRP treatment phosphorylated ERK1/2 and promoted increased expression, phosphorylation, and translocation of DRP1, a mitochondrial fission-related protein, from the cytoplasm to the mitochondria. The expression of mitophagy proteins PINK1 and PARK2 was also increased by CRP. YAP, a transcriptional regulator of PINK1 and PARK2, was also increased by CRP. Knockdown of YAP prevented CRP-induced increases in DRP1, PINK1, and PARK2. Furthermore, CRP-induced changes in the expression of DRP1 and increases in YAP, PINK1, and PARK2 were inhibited by ERK1/2 inhibition, suggesting that ERK1/2 signaling is involved in CRP-induced mitochondrial fission. We treated H9c2 cardiomyocytes with a recombinant TAT-survivin protein before CRP treatment, which reduced CRP-induced ROS accumulation and reduced mitochondrial fission. CRP-induced activation of ERK1/2 and increases in the expression and activity of YAP and its downstream mitochondrial proteins were inhibited by TAT-survivin. This study shows that mitochondrial fission occurs during CRP-induced cardiomyocyte damage and that the ERK1/2-YAP axis is involved in this process, and identifies that survivin alters these mechanisms to prevent CRP-induced mitochondrial damage.

• Korean Journal of Radiology
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• v.24 no.5
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• pp.384-394
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• 2023

Objective: Mammographic density is an independent risk factor for breast cancer that can change after neoadjuvant chemotherapy (NCT). This study aimed to evaluate percent changes in volumetric breast density (ΔVbd%) before and after NCT measured automatically and determine its value as a predictive marker of pathological response to NCT. Materials and Methods: A total of 357 patients with breast cancer treated between January 2014 and December 2016 were included. An automated volumetric breast density (Vbd) measurement method was used to calculate Vbd on mammography before and after NCT. Patients were divided into three groups according to ΔVbd%, calculated as follows: Vbd (post-NCT - pre-NCT)/pre-NCT Vbd × 100 (%). The stable, decreased, and increased groups were defined as -20% ≤ ΔVbd% ≤ 20%, ΔVbd% < -20%, and ΔVbd% > 20%, respectively. Pathological complete response (pCR) was considered to be achieved after NCT if there was no evidence of invasive carcinoma in the breast or metastatic tumors in the axillary and regional lymph nodes on surgical pathology. The association between ΔVbd% grouping and pCR was analyzed using univariable and multivariable logistic regression analyses. Results: The interval between the pre-NCT and post-NCT mammograms ranged from 79 to 250 days (median, 170 days). In the multivariable analysis, ΔVbd% grouping (odds ratio for pCR of 0.420 [95% confidence interval, 0.195-0.905; P = 0.027] for the decreased group compared with the stable group), N stage at diagnosis, histologic grade, and breast cancer subtype were significantly associated with pCR. This tendency was more evident in the luminal B-like and triple-negative subtypes. Conclusion: ΔVbd% was associated with pCR in breast cancer after NCT, with the decreased group showing a lower rate of pCR than the stable group. Automated measurement of ΔVbd% may help predict the NCT response and prognosis in breast cancer.

• Korean Journal of Radiology
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• v.23 no.7
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• pp.742-751
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• 2022

Objective: To assess focal mineral deposition in the globus pallidus (GP) by CT and quantitative susceptibility mapping (QSM) of MRI scans and evaluate its clinical significance, particularly cerebrovascular degeneration. Materials and Methods: This study included 105 patients (66.1 ± 13.7 years; 40 male and 65 female) who underwent both CT and MRI with available QSM data between January 2017 and December 2019. The presence of focal mineral deposition in the GP on QSM (GP_QSM) and CT (GP_CT) was assessed visually using a three-point scale. Cerebrovascular risk factors and small vessel disease (SVD) imaging markers were also assessed. The clinical and radiological findings were compared between the different grades of GP_QSM and GP_CT. The relationship between GP grades and cerebrovascular risk factors and SVD imaging markers was assessed using univariable and multivariable linear regression analyses. Results: GP_CT and GP_QSM were significantly associated (p < 0.001) but were not identical. Higher GP_CT and GP_QSM grades showed smaller gray matter (p = 0.030 and p = 0.025, respectively) and white matter (p = 0.013 and p = 0.019, respectively) volumes, as well as larger GP volumes (p < 0.001 for both). Among SVD markers, white matter hyperintensity was significantly associated with GP_CT (p = 0.006) and brain atrophy was significantly associated with GP_QSM (p = 0.032) in at univariable analysis. In multivariable analysis, the normalized volume of the GP was independently positively associated with GP_CT (p < 0.001) and GP_QSM (p = 0.002), while the normalized volume of the GM was independently negatively associated with GP_CT (p = 0.040) and GP_QSM (p = 0.035). Conclusion: Focal mineral deposition in the GP on CT and QSM might be a potential imaging marker of cerebral vascular degeneration. Both were associated with increased GP volume.

• Journal of Plant Biotechnology
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• v.50
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• pp.34-44
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• 2023

The tetraploid Solanum hjertingii, a wild tuber-bearing species from Mexico is a relative of potato, S. tuberosum. The species has been identified as a potential source of resistance to blackening for potato breeding. It does not exhibit enzymatic browning nor blackspot which are physiological disorders. However, due to their sexual incompatibility, somatic hybridization between S. hjertingii and S. tuberosum must be used to introduce various traits from this wild species into potato. After somatic hybridization, molecular markers are essential for selecting fusion products. In this study, the chloroplast genome of S. hjertingii was sequenced by next-generation sequencing technology and compared with those of other Solanum species to develop specific markers for S. hjertingii. The chloroplast genome has a total sequence length of 155,545 bp, and its size, gene content, order and orientation are similar to those of the other Solanum species. Phylogenic analysis including 15 other Solanaceae species grouped S. hjertingii with S. demissum, S. hougasii, and S. stoloniferum. After detailed comparisons of the chloroplast genome sequence with eight other Solanum species, we identified one InDel and seven SNPs specific to S. hjertingii. Based on these, five PCR-based markers were developed for discriminating S. hjertingii from other Solanum species. The results obtained in this study will aid in exploring the evolutionary aspects of Solanum species and accelerating breeding using S. hjertingii.

• Journal of Plant Biotechnology
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• v.50
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• pp.45-55
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• 2023

The diploid Solanum cardiophyllum, a wild tuberbearing species from Mexico is one of the relatives to potato, S. tuberosum. It has been identified as a source of resistance to crucial pathogens and insects such as Phytophthora infestans, Potato virus Y, Colorado potato beetle, etc. and is widely used for potato breeding. However, the sexual hybridization between S. cardiophyllum and S. tuberosum is limited due to their incompatibility. Therefore, somatic hybridization can introduce beneficial traits from this wild species into the potato. After somatic hybridization, selecting fusion products using molecular markers is essential. In the current study, the chloroplast genome of S. cardiophyllum was sequenced by next-generation sequencing technology and compared with those of other Solanum species to develop S. cardiophyllum-specific markers. The total length of the S. cardiophyllum chloroplast genome was 155,570 bp and its size, gene content, order and orientation were similar to those of the other Solanum species. Phylogenic analysis with 32 other Solanaceae species revealed that S. cardiophyllum was expectedly grouped with other Solanum species and most closely located with S. bulbocastanum. Through detailed comparisons of the chloroplast genome sequences of eight Solanum species, we identified 13 SNPs specific to S. cardiophyllum. Further, four SNP-specific PCR markers were developed for discriminating S. cardiophyllum from other Solanum species. The results obtained in this study would help to explore the evolutionary aspects of Solanum species and accelerate breeding using S. cardiophyllum.