• Title/Summary/Keyword: Preclinical research

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Glucose-dependent insulinotropic polypeptide (GIP) alleviates ferroptosis in aging-induced brain damage through the Epac/Rap1 signaling pathway

  • Jiwon Ko;Soyoung Jang;Soyeon Jang;Song Park;Junkoo Yi;Dong Kyu Choi;Seonggon Kim;Myoung Ok Kim;Su-Geun Lim;Zae Young Ryoo
    • BMB Reports
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    • v.57 no.9
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    • pp.417-423
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    • 2024
  • Glucose-dependent insulinotropic polypeptide (GIP), a 42-amino-acid hormone, exerts multifaceted effects in physiology, most notably in metabolism, obesity, and inflammation. Its significance extends to neuroprotection, promoting neuronal proliferation, maintaining physiological homeostasis, and inhibiting cell death, all of which play a crucial role in the context of neurodegenerative diseases. Through intricate signaling pathways involving its cognate receptor (GIPR), a member of the G protein-coupled receptors, GIP maintains cellular homeostasis and regulates a defense system against ferroptosis, an essential process in aging. Our study, utilizing GIP-overexpressing mice and in vitro cell model, elucidates the pivotal role of GIP in preserving neuronal integrity and combating age-related damage, primarily through the Epac/Rap1 pathway. These findings shed light on the potential of GIP as a therapeutic target for the pathogenesis of ferroptosis in neurodegenerative diseases and aging.

Reactive Oxygen Species (ROS) Generation Contributes to the Synergistic Anticancer Effect of Astragalus Membranaceus and Adenophora Triphylla Var. Japonica in H1299 Human Lung Carcinoma Cells (H1299 인체폐암세포주에서 활성산소종 생성에 의한 황기와 사삼의 항암 시너지 작용)

  • Min, Tae Rin;Park, Hyun Ji;Park, Shin Hyung
    • Journal of Physiology & Pathology in Korean Medicine
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    • v.32 no.3
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    • pp.157-164
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    • 2018
  • This study was designed to investigate the mechanism of the synergistic anticancer effect of Astragalus membranaceus (AM) and Adenophora triphylla var. japonica (AT) in H1299 human lung carcinoma cells. A combined treatment of ethanol extract of AM (EAM) and AT (EAT) explosively increased the reactive oxygen species (ROS) generation in H1299 cells compared to the single treatment of each of them. Co-treatment of N-acetyl-L-cysteine (NAC) with EAM and EAT markedly enhanced the cell viability and suppressed apoptosis in H1299 cells, suggesting that ROS generation contributed to the anticancer effect of EAM and EAT. Interestingly, the combined treatment of EAM and EAT down-regulated p-AKT in H1299 cells, which was abrogated by NAC treatment. These results clearly indicated that ROS generation mediated the inactivation of AKT. Co-treatment of LY294002 with EAM and EAT significantly reduced the cell viability at a concentration which EAM and EAT didn't show any cytotoxicity. In addition, the recovery of cell viability by co-treatment of NAC with EAM and EAT was quite reversed by LY294002 treatment, which confirmed that the inactivation of AKT played a pivotal role in ROS-mediated apoptosis. Taken together, our results demonstrated that the synergistic anticancer effect of EAM and EAT was mediated by ROS generation and inactivation of AKT. We provide a valuable preclinical data for the development of more effective combination of AM and AT to treat lung cancer.

A case of transitional carcinoma in the nasal cavity of a dog (개의 비강 내 이행암종 증례)

  • Kang, Hwa-Jung;Kang, Sang-Chul;Jung, Ji-Youl;Jo, Suk-Hee;Roh, In-Soon;Lee, Joo-Myung;Cheong, Jongtae;Kim, Jung-Hun;An, Min-Chan;Bae, Jong-Hee;Kim, Jae-Hoon
    • Korean Journal of Veterinary Research
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    • v.48 no.3
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    • pp.305-310
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    • 2008
  • A 10-year-old female Yorkshire terrier with the clinical signs of nasal swelling, epistaxis and nasal discharge was presented to the Veterinary Teaching Hospital in the Cheju National University. Abnormal nasal mass was detected in physical examination and radiographic findings. After surgical excision, the sample of nasal mass was referred to Pathology Department of Veterinary Medicine. Grossly, the mass was soft, friable, and $2.5{\times}4cm$ cm in size. Histopathologically, the mass was composed of mediumsized non-keratinizing columnar to polyhedral cells arranged in anastomosing ribbon and large nest. It has complex in-folding of thick epithelial layers separated by fibrovascular septa. Tumor cells showed characteristic palisading arrangement of columnar cells, and perpendicularly distributed to the basement membrane. The cells had pale basophilic cytoplasm, oval nucleus and one or more nucleoli, and indistinct cellular border. Many tumor cell emboli were presented in lymphatics. Immunohistochemistry revealed that tumor cells were cytokeratin (CK) 19 and CK clone MNF116 positive and but CK7 and CK high molecular weight negative. Based on the gross, histopathologic, and immunohistochemical findings, the mass was diagnosed as transitional carcinoma in nasal cavity. In our best knowledge, this is the first report of transitional carcinoma originated from transitional zone of canine nasal cavity in Korea.

Resveratrol Exerts Differential Effects in Vitro and in Vivo against Ovarian Cancer Cells

  • Stakleff, Kimberly Sloan;Sloan, Tricia;Blanco, Denise;Marcanthony, Sharon;Booth, Tristan D.;Bishayee, Anupam
    • Asian Pacific Journal of Cancer Prevention
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    • v.13 no.4
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    • pp.1333-1340
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    • 2012
  • Epithelial ovarian cancer represents the most lethal gynecological cancer, and the high mortality rate makes this malignancy a major health concern. Poor prognosis results from an inability to detect ovarian cancers at an early, curable stage, as well as from the lack of an effective therapy. Thus, effective and novel strategies for prevention and treatment with non-toxic agents merit serious consideration. Resveratrol, obtained from grapes, berries, peanuts and red wine, has been shown to have a potent growth-inhibitory effect against various human cancer cells as well as in in vivo preclinical cancer models. The objective here was to evaluate potential antitumor effects of resveratrol in both in vitro and in vivo NuTu-19 ovarian cancer models. In vitro an invasion assay was performed. After 48 h, the numbers of viable cells that invaded the extracellular matrix layer were reduced by 94% with resveratrol in comparison to control. For the in vivo anti-tumor assessment, 10 rats were injected with NuTu-19 cells into the ovarian bursa. Thereafter, half were provided with a diet mixed with a dose of 100 mg resveratrol/kg body weight/day for 28 days. Following sacrifice, anticancer effects were assessed by histological evaluation of ovarian as well as surrounding tissues, and immunohistochemical detection of cell proliferation and apoptosis, but there were no observable differences between the control and resveratrol-treated groups for any of the biological endpoints. While resveratrol is effective in suppressing the in vitro cellular invasion of NuTu-19 ovarian cancer cells, these effects do not appear to impact on in vivo NuTu-19 ovarian cancers in rats.

Direct Costs of Cervical Cancer Management in Morocco

  • Berraho, Mohamed;Najdi, Adil;Mathoulin-Pelissier, Simone;Salamon, Roger;Nejjari, Chakib
    • Asian Pacific Journal of Cancer Prevention
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    • v.13 no.7
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    • pp.3159-3163
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    • 2012
  • Background: For cervical cancer the epidemiological profile is poorly known in Morocco and no data is available concerning the direct medical costs. The purpose of this work is to estimate the direct cost of medical management of invasive cervical cancer during the first year after diagnosis in Morocco. Methods: The estimation of direct costs of medical management of invasive cervical cancer during the first year after diagnosis in Morocco is based on the estimation of individual cost in each stage which covers diagnosis, treatment and follow-up during first year. The cost was estimated per patient and whole cycle-set using the costs for each drug and procedure as indicated by the Moroccan National Agency for Health Insurance. Extrapolation of the results to the whole country was used to calculate the total annual cost of cervical cancer treatments in Morocco. Results: Overall approximately 1,978 new cases of cervical cancer occur each year in Morocco. The majority (82.96%) of these cases were diagnosed at a late stage (stageII or more). The cost of one case of cervical cancer depends on stage of diagnosis, the lowest cost is $382 for stageCis followed by the cost of stageIA1 for young women (< 40 years) which is $2,952. The highest cost is for stageIV, which is $7,827. The total cost of cervical cancer care for one year after diagnosis is estimated at $13,589,360. The share allocated to treatment is the most important part of the global care budget with an annual sum of $13,027,609 whereas other cost components are represented as follows: $435,694 for annual follow-up activity and $126,057 for diagnosis and preclinical staging. Conclusion: This study provides health decision-makers with a first estimate of costs and the opportunity to achieve the optimal use of available data to estimate the needs of health facilities in Morocco.

Bleeding Efficiency and Meat Oxidative Stability and Microbiological Quality of New Zealand White Rabbits Subjected to Halal Slaughter without Stunning and Gas Stun-killing

  • Nakyinsige, K.;Fatimah, A.B.;Aghwan, Z.A.;Zulkifli, I.;Goh, Y.M.;Sazili, A.Q.
    • Asian-Australasian Journal of Animal Sciences
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    • v.27 no.3
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    • pp.406-413
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    • 2014
  • A study was conducted to compare the effect of halal slaughter without stunning and gas stun killing followed by bleeding on residual blood content and storage stability of rabbit meat. Eighty male New Zealand white rabbits were divided into two groups of 40 animals each and subjected to either halal slaughter without stunning (HS) or gas stun-kill (GK). The volume of blood lost during exsanguination was measured. Residual blood was further quantified by determination of haemoglobin content in Longissimus lumborum (LL) muscle. Storage stability of the meat was evaluated by microbiological analysis and measuring lipid oxidation in terms of thiobarbituric acid reactive substances (TBARS). HS resulted in significantly higher blood loss than GK. HS had significantly lower residual haemoglobin in LL muscle compared to GK. Slaughter method had no effect on rabbit meat lipid oxidation at 0, 1, and 3 d postmortem. However, at 5 and 8 days of storage at $4^{\circ}C$, significant differences (p<0.05) were found, with meat from the GK group exhibiting significantly higher levels of MDA than that from HS. At day 3, greater growth of Pseudomonas aeroginosa and E. coli were observed in the GK group (p<0.05) with B. thermosphacta and total aerobic counts remained unaffected by slaughter method. At days 5 and 7 postmortem, bacterial counts for all tested microbes were affected by slaughter method, with GK exhibiting significantly higher growth than HS. It can be concluded that slaughter method can affect keeping quality of rabbit meat, and HS may be a favourable option compared to GK due to high bleed out.

Pharmacokinetic Characterization of KR-67500, a Novel 11β-HSD1 Inhibitor (새로운 11β-HSD1 저해제인 KR-67500의 약물동태)

  • Im, So Hee;Ahn, Jin Hee;Kim, Ki Young;Bae, Myung Ae;Kim, Sang Kyum;Ahn, Sung-Hoon
    • YAKHAK HOEJI
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    • v.59 no.2
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    • pp.59-65
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    • 2015
  • KR-67500, trans-4-(2-(4-methyl-1,1-dioxido-6-(2,4,6-trichlorophenyl)-1,2,6-thiadiazinan-2-yl)acetamido)adamantane-1-carboxamide, is a novel $11{\beta}$-HSD1 inhibitor with its therapeutic effects of its anti-diabetic, anti-adipogenic and anti-osteoporotic activity. This study was performed to evaluate in vitro and in vivo pharmacokinetic properties of KR-67500 as a new drug candidate. KR-67500 was stable and highly bound to proteins in rat plasma. The microsomal stabilities of KR-67500 in human and rat liver were high. The inhibitory effect of KR-67500 for five cytochrome P450 enzymes was low. Preclinical pharmacokinetic studies have been carried out with intravenous or oral administrations of KR-67500 (10 mg/kg) to male rats and monkey. KR-67500 showed low clearance (0.68 l/h/kg) and high oral bioavailability (102%) in male rats. These results suggest that KR-67500 has good drug-like pharmacokinetic properties with a low first-pass effect and high bioavailability for an oral therapeutic agent of diabetes and osteoporosis.

Precise System Models using Crystal Penetration Error Compensation for Iterative Image Reconstruction of Preclinical Quad-Head PET

  • Lee, Sooyoung;Bae, Seungbin;Lee, Hakjae;Kim, Kwangdon;Lee, Kisung;Kim, Kyeong-Min;Bae, Jaekeon
    • Journal of the Korean Physical Society
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    • v.73 no.11
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    • pp.1764-1773
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    • 2018
  • A-PET is a quad-head PET scanner developed for use in small-animal imaging. The dimensions of its volumetric field of view (FOV) are $46.1{\times}46.1{\times}46.1mm^3$ and the gap between the detector modules has been minimized in order to provide a highly sensitive system. However, such a small FOV together with the quad-head geometry causes image quality degradation. The main factor related to image degradation for the quad-head PET is the mispositioning of events caused by the penetration effect in the detector. In this paper, we propose a precise method for modelling the system at the high spatial resolution of the A-PET using a LOR (line of response) based ML-EM (maximum likelihood expectation maximization) that allows for penetration effects. The proposed system model provides the detection probability of every possible ray-path via crystal sampling methods. For the ray-path sampling, the sub-LORs are defined by connecting the sampling points of the crystal pair. We incorporate the detection probability of each sub-LOR into the model by calculating the penetration effect. For comparison, we used a standard LOR-based model and a Monte Carlo-based modeling approach, and evaluated the reconstructed images using both the National Electrical Manufacturers Association NU 4-2008 standards and the Geant4 Application for Tomographic Emission simulation toolkit (GATE). An average full width at half maximum (FWHM) at different locations of 1.77 mm and 1.79 mm are obtained using the proposed system model and standard LOR system model, which does not include penetration effects, respectively. The standard deviation of the uniform region in the NEMA image quality phantom is 2.14% for the proposed method and 14.3% for the LOR system model, indicating that the proposed model out-performs the standard LOR-based model.

Immediate implant placement in conjunction with guided bone regeneration and/or connective tissue grafts: an experimental study in canines

  • Lim, Hyun-Chang;Paeng, Kyeong-Won;Kim, Myong Ji;Jung, Ronald E.;Hammerle, Christoph HF.;Jung, Ui-Won;Thoma, Daniel S.
    • Journal of Periodontal and Implant Science
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    • v.52 no.2
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    • pp.170-180
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    • 2022
  • Purpose: This study was conducted to assess the effect of hard and/or soft tissue grafting on immediate implants in a preclinical model. Methods: In 5 mongrel dogs, the distal roots of P2 and P3 were extracted from the maxilla (4 sites in each animal), and immediate implant placement was performed. Each site was randomly assigned to 1 of the following 4 groups: i) gap filling with guided bone regeneration (the GBR group), ii) subepithelial connective tissue grafting (the SCTG group), iii) GBR and SCTG (the GBR/SCTG group), and iv) no further treatment (control). Non-submerged healing was provided for 4 months. Histological and histomorphometric analyses were performed. Results: Peri-implant tissue height and thickness favored the SCTG group (height of periimplant mucosa: 1.14 mm; tissue thickness at the implant shoulder and ±1 mm from the shoulder: 1.14 mm, 0.78 mm, and 1.57 mm, respectively; median value) over the other groups. Bone grafting was not effective at the level of the implant shoulder and on the coronal level of the shoulder. In addition, simultaneous soft and hard tissue augmentation (the GBR/SCTG group) led to a less favorable tissue contour compared to GBR or SCTG alone (height of periimplant mucosa: 3.06 mm; thickness of peri-implant mucosa at the implant shoulder and ±1 mm from the shoulder: 0.72 mm, 0.3 mm, and 1.09 mm, respectively). Conclusion: SCTG tended to have positive effects on the thickness and height of the periimplant mucosa in immediate implant placement. However, simultaneous soft and hard tissue augmentation might not allow a satisfactory tissue contour in cases where the relationship between implant position and neighboring bone housing is unfavorable.

Overviews on the Clinical Use of Stem Cells in Orthopaedics (근골격계에서 줄기세포를 이용한 재생치료의 개관)

  • Im, Gun-Il
    • Journal of the Korean Orthopaedic Association
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    • v.54 no.6
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    • pp.475-477
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    • 2019
  • Stem cell research arose from the need to explore new therapeutic possibilities for intractable and lethal diseases. Although musculoskeletal disorders are basically nonlethal, their high prevalence and the relative ease of performing clinical trials have facilitated the clinical application of stem cells in this field. On the other hand, despite the plethora of in vitro and preclinical studies in stem cell research for regenerative medicine in the musculoskeletal system, few reliable clinical studies have been published. Stem cell therapy can be applied locally for bone, cartilage, and tendon regeneration. The candidate disease modalities in bone regeneration include large bone defects, nonunion of fractures, and osteonecrosis. Focal osteochondral defect and osteoarthritis are the current targets for cartilage regeneration. For tendon regeneration, bone-tendon junction problems, such as rotator cuff tears are hot topics in clinical research. To date, the literature supporting stem cell-based therapies comprises mostly case reports or case series.