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Prospective Targets for Colon Cancer Prevention: from Basic Research, Epidemiology and Clinical Trial

  • Shingo Miyamoto;Masaru Terasaki;Rikako Ishigamori;Gen Fujii;Michihiro Mutoh
    • Journal of Digestive Cancer Research
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    • v.4 no.2
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    • pp.64-76
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    • 2016
  • The step-wise process of colorectal carcinogenesis from aberrant crypt foci, adenoma to adenocarcinoma, is relatively suitable for chemopreventive intervention. Accumulated evidences have revealed that maintaining an undifferentiated state (stemness), inflammation, and oxidative stress play important roles in this colon carcinogenesis process. However, appropriate molecular targets that are applicable to chemopreventive intervention regarding those three factors are still unclear. In this review, we summarized appropriate molecular targets by identification and validation of the prospective targets from a comprehensive overview of data that showed colon cancer preventive effects in clinical trials, epidemiological studies and basic research. We first selected a study that used aspirin, statins and metformin from FDA approved drugs, and epigallocatechin-gallate and curcumin from natural compounds as potential chemopreventive agents against colon cancer because these agents are considered to be promising chemopreventive agents. Experimental and observational data revealed that there are common target molecules in these potential chemopreventive agents: T-cell factor/lymphoid enhancer factor (TCF/LEF), nuclear factor-&B (NF-κB) and nuclear factor-erythroid 2-related factor 2(NRF2). Moreover, these targets, TCF/LEF, NF-κB and NRF2, have been also indicated to suppress maintenance of the undifferentiated state, inflammation and oxidative stress, respectively. In the near future, novel promising candidate agents for colon cancer chemoprevention could be identified by integral evaluation of their effects on these three transcriptional activities.

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Raw Inonotus obliquus polysaccharide counteracts Alzheimer's disease in a transgenic mouse model by activating the ubiquitin-proteosome system

  • Shumin Wang;Kaiye Dong;Ji Zhang;Chaochao Chen;Hongyan Shuai;Xin Yu
    • Nutrition Research and Practice
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    • v.17 no.6
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    • pp.1128-1142
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    • 2023
  • BACKGROUND/OBJECTIVES: Inonotus obliquus has been used as antidiabetic herb around the world, especially in the Russian and Scandinavian countries. Diabetes is widely believed to be a key factor in Alzheimer's disease (AD), which is widely considered to be type III diabetes. To investigate whether I. obliquus can also ameliorate AD, it would be interesting to identify new clues for AD treatment. We tested the anti-AD effects of raw Inonotus obliquus polysaccharide (IOP) in a mouse model of AD (3×Tg-AD transgenic mice). MATERIALS/METHODS: SPF-grade 3×Tg-AD mice were randomly divided into three groups (Control, Metformin, and raw IOP groups, n = 5 per group). β-Amyloid deposition in the brain was analyzed using immunohistochemistry for AD characterization. Gene and protein expression of pertinent factors of the ubiquitin-proteasome system (UPS) was determined using real-time quantitative polymerase chain reaction and Western blotting. RESULTS: Raw IOP significantly reduced the accumulation of amyloid aggregates and facilitated UPS activity, resulting in a significant reduction in AD-related symptoms in an AD mouse model. The presence of raw IOP significantly enhanced the expression of ubiquitin, E1, and Parkin (E3) at both the mRNA and protein levels in the mouse hippocampus. The mRNA level of ubiquitin carboxyl-terminal hydrolase isozyme L1, a key factor involved in UPS activation, also increased by approximately 50%. CONCLUSIONS: Raw IOP could contribute to AD amelioration via the UPS pathway, which could be considered as a new potential strategy for AD treatment, although we could not exclude other mechanisms involved in counteracting AD processing.

The Analysis of Registration Status of Herbal Medicine and Medication Interventional Clinical Trials for Simple Obesity in Children and Adolescents -Focused on WHO ICTRP- (소아청소년 단순 비만에 대한 한약 및 약물 중재 임상시험 등록 현황 분석 - WHO ICTRP를 중심으로 -)

  • Jeong Yoon Kyoung;Choi Seo Yeon;Bang Miran;Lee Boram;Chang Gyu Tae
    • The Journal of Pediatrics of Korean Medicine
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    • v.38 no.1
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    • pp.55-77
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    • 2024
  • Objectives This study aimed to analyze the registration status and characteristics of clinical trials on herbal medicine (HM) and medication interventions for simple obesity in children and adolescents. Methods All interventional clinical trials registered in the International Clinical Trials Registry Platform of the World Health Organization until December 12, 2024, were collected. The study design, interventions, inclusion and exclusion criteria, and outcome measures were extracted. Results A total of 24 clinical trials (23 medications and 1 HM) were analyzed. The most common study designs were single-center, randomized controlled, parallel, and phase 2. Placebo controls were used in 87.5% of the studies, blinding was used in 79.1%, and quadruple blinding was the most common. Informed consent was obtained from 70.8% of the participants. Among the oral medications (66.6%), metformin was the most common (25%). Among the non-oral medications (29.1%), exenatide (Bydureon) was the most common intervention (42.8%). Body mass index was the most commonly reported primary outcome measure (79.1%), with most assessments performed at 6 months. Conclusions Based on the characteristics of the medication interventional clinical trial design analyzed in this study, additional high-quality multicenter traditional Korean medicine trials need to be designed in the future.

Management of Adverse Reactions to Iodinated Contrast Media for Computed Tomography in Korean Referral Hospitals: A Survey Investigation

  • Seungchul Han;Soon Ho Yoon;Whal Lee;Young-Hun Choi;Dong Yoon Kang;Hye-Ryun Kang
    • Korean Journal of Radiology
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    • v.20 no.1
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    • pp.148-157
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    • 2019
  • Objective: To evaluate the current status of managing adverse reactions to iodinated contrast media (ICM) for computed tomography in referral hospitals in South Korea compared with hospitals in other countries. Materials and Methods: This survey investigation involved 59 Korean and 15 overseas hospitals using guideline-based questionnaires consisting of 24 items in 7 main categories related to managing adverse reactions to ICM. Results: Informed written consent with risk factor evaluation was appropriately performed in most of the Korean hospitals. There was considerable variability in assessing renal function across the hospitals; serum creatinine level was used as a reference in 76.4% of Korean hospitals. The Korean hospitals preferred a more stringent approach to determining normal renal function (p = 0.01), withholding metformin (p = 0.01), and fasting before ICM exposure (p < 0.001) compared with overseas hospitals. All the Korean hospitals had an emergency protocol and in-hospital system for adverse reactions to ICM. The Korean (87.7%) and overseas hospitals (100%) were similarly equipped with epinephrine (p = 0.332), but only 38.6% of Korean hospitals were equipped with a bronchodilator (p = 0.004). For patients with a previous hypersensitivity reaction to ICM, 62.3% of Korean hospitals pre-medicated with anti-histamine and corticosteroid according to the severity of the previous reaction, and changed the culprit ICM in 52.8%, while skin test was performed in 17%. Conclusion: In general, Korean referral hospitals were well-prepared regarding informed consent, protocol, and an in-hospital system for managing adverse reactions to ICM. Nevertheless, there was considerable variability in details and management, thus requiring standardization by reflecting current guidelines.

Anti-diabetic activities of catalpol in db/db mice

  • Bao, Qinwen;Shen, Xiaozhu;Qian, Li;Gong, Chen;Nie, Maoxiao;Dong, Yan
    • The Korean Journal of Physiology and Pharmacology
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    • v.20 no.2
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    • pp.153-160
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    • 2016
  • The objective was to investigate the hypoglycemic action of catalpol in spontaneous diabetes db/db mice. 40 db/db mice were randomly divided into five groups: model control gourp; db/db plus catalpol 40, 80, 120 mg/kg body wt. groups and db/db plus metformin 250 mg/kg group. Age-matched db/m mice were selected as normal control group. The mice were administered with corresponding drugs or solvent by gavage for 4 weeks. The oral glucose tolerance test was carried out at the end of $3^{rd}$ week. After 4 weeks of treatment, the concentrations of fasting blood glucose (FBG), glycated serum protein (GSP), insulin (INS), triglyceride (TG), total cholesterol (TC) and adiponection (APN) in serum were detected. The protein expressions of phosphorylation-$AMPK{\alpha}$1/2 in liver, phosphorylation-$AMPK{\alpha}$1/2 and glucose transporter-4 (GLUT-4) in skeletal muscle and adipose tissues were detected by western blot. Real time RT-PCR was used to detect the mRNA expressions of acetyl-CoA carboxylase (ACC) and Hydroxymethyl glutaric acid acyl CoA reductase (HMGCR) in liver. Our results showed that catalpol could significantly improve the insulin resistance, decrease the serum concentrations of INS, GSP, TG, and TC. The concentrations of APN in serum, the protein expression of phosphorylation-$AMPK{\alpha}$1/2 in liver, phosphorylation-$AMPK{\alpha}$1/2 and GLUT-4 in peripheral tissue were increased. Catalpol could also down regulate the mRNA expressions of ACC and HMGCR in liver. In conclusion, catalpol ameliorates diabetes in db/db mice. It has benefit effects against lipid/glucose metabolism disorder and insulin resistance. The mechanism may be related to up-regulating the expression of phosphorylation-$AMPK{\alpha}$1/2.

Sitagliptin and Vildagliptin Use Evaluation among Dipeptidyl Peptidase 4 Inhibitors in Adult Koreans with Type 2 Diabetes Mellitus (한국인 제2형 당뇨병 환자에 대한 디펩티딜 펩티다제 4 억제제 중 Sitagliptin과 Vildagliptin의 약물 사용 평가)

  • Park, Hyun-Jung;Lee, Ok-Sang;Lim, Sung-Cil
    • YAKHAK HOEJI
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    • v.56 no.2
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    • pp.136-143
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    • 2012
  • Type 2 Diabetes Mellitus (T2DM) is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and dietary modification. As the condition progresses, medications may be needed such as oral sulfonylurea or others. Recently, dipeptidyl peptidase 4 (DPP- 4) Inhibitor is new drug which can control blood glucose by increasing the active levels of incretin hormone in the body. However, researches have been carried out for mostly Caucasian and Japanese, not for Koreans at all. Therefore, this study was to evaluate the efficacy and safety of DPP-4 inhibitor (Sitagliptin, Vildagliptin) in patients with T2DM in Koreans. This study was carried out retrospectively with reviewing of medical records from the 141 patients who received sitagliptin or vildagliptin over 24 week periods from January 2009, to December 2009. Information including demographics, concomitant medication, disease duration, and exercise was evaluated. $HbA_{1c}$, random blood glucose, post prandial 2 hour glucose, blood pressure, AST, ALT, serum creatinine, total cholesterol, triglyceride levels were also collected at baseline and endpoint (at 24 weeks). In each post-treatment group, $HbA_{1c}$, random blood glucose and post prandial 2 hour glucose levels were decreased significantly from baseline in the sitagliptin group (-0.82%, -28.76 mg/dl, -46.65 mg/dl) and vildagliptin group(-1.22%, -27.96 mg/dl, -67.2 mg/dl). Greater $HbA_{1c}$ mean reductions from baseline to 24 weeks were seen in patients with higher baseline values (>7.0%), with shorter disease durations (${\leq}1$ year) compared with those with lower baseline values (<7.0%), with longer disease durations (>1 year) in both sitagliptin and vildagliptin groups. The incidences of hypoglycemia, headache and upper respiratory infection were 0%, 8.7%, 5.8% in sitagliptin group and 2.8%, 8.3%, 6.9% in vildagliptin group. In conclusion, our results showed DPP-4 inhibitor provided similar efficacy compared with sulfonylurea after 24 weeks of treatment and were safer than sulfonylurea in hypoglycemia for Korean T2DM. Also vildagliptin was associated with significant improvement in $HbA_{1c}$ reduction in Korean patient with subgroup (body mass index<25 $kg/m^2$, metformin dose${\geq}$1000 mg, p<0.05) compared to sitagliptin. Therefore, even though DPP-4 inhibitor use for Korean needs to be studied more consistently in the future, DPP-4 inhibitor is a safe and effective drug for Korean T2DM based on our result.

35-Year Research History of Cytotoxicity and Cancer: a Quantitative and Qualitative Analysis

  • Farghadani, Reyhaneh;Haerian, Batoul Sadat;Ebrahim, Nader Ale;Muniandy, Sekaran
    • Asian Pacific Journal of Cancer Prevention
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    • v.17 no.7
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    • pp.3139-3145
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    • 2016
  • Cancer is the leading cause of morbidity and mortality worldwide, characterized by irregular cell growth. Cytotoxicity or killing tumor cells that divide rapidly is the basic function of chemotherapeutic drugs. However, these agents can damage normal dividing cells, leading to adverse effects in the body. In view of great advances in cancer therapy, which are increasingly reported each year, we quantitatively and qualitatively evaluated the papers published between 1981 and December 2015, with a closer look at the highly cited papers (HCPs), for a better understanding of literature related to cytotoxicity in cancer therapy. Online documents in the Web of Science (WOS) database were analyzed based on the publication year, the number of times they were cited, research area, source, language, document type, countries, organization-enhanced and funding agencies. A total of 3,473 publications relevant to the target key words were found in the WOS database over 35 years and 86% of them (n=2,993) were published between 2000-2015. These papers had been cited 54,330 times without self-citation from 1981 to 2015. Of the 3,473 publications, 17 (3,557citations) were the most frequently cited ones between 2005 and 2015. The topmost HCP was about generating a comprehensive preclinical database (CCLE) with 825 (23.2%) citations. One third of the remaining HCPs had focused on drug discovery through improving conventional therapeutic agents such as metformin and ginseng. Another 33% of the HCPs concerned engineered nanoparticles (NPs) such as polyamidoamine (PAMAM) dendritic polymers, PTX/SPIO-loaded PLGAs and cell-derived NPs to increase drug effectiveness and decrease drug toxicity in cancer therapy. The remaining HCPs reported novel factors such as miR-205, Nrf2 and p27 suggesting their interference with development of cancer in targeted cancer therapy. In conclusion, analysis of 35-year publications and HCPs on cytotoxicity in cancer in the present report provides opportunities for a better understanding the extent of topics published and may help future research in this area.

Determination of 11 Illicit Compounds in Dietary Supplements Using High-Performance Liquid Chromatography and Liquid Chromatography-Tandem Mass Spectrometry

  • Shin, Dasom;Kang, Hui-Seung;Kim, Hyung-soo;Moon, Guiim
    • Journal of Food Hygiene and Safety
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    • v.35 no.4
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    • pp.326-333
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    • 2020
  • In this work, we developed an analytical method for determining 11 illicit compounds in dietary supplements using high-performance liquid chromatography and liquid chromatography-tandem mass spectrometry. Eleven target compounds, including those meant for weight loss (7-keto-dihydroepiandrosterone, buformin, metformin, phenformin, salbutamol, and tolbutamide), sexual enhancement (dihydroepiandrosterone), and relaxation (asarone, kavain, magnoflorine, and picamilon) were screened and confirmed in dietary supplements. Method validation was performed by evaluating the selectivity, linearity, limit of quantification (LOQ), accuracy, and precision according to the Association of Official Analytical Chemists guidelines. The linearity was > 0.993 for all analytes. The LOQs were ranged in 2.1-9.9 ㎍/mL (HPLC-DAD) and 0.002-0.008 ㎍/mL (LC-MS/MS). The accuracies (expressed as recovery) were 90.0-106% (HPLC-DAD) and 83.0-114% (LC-MS/MS). The precision (expressed as the relative standard deviation) was below 10% using HPLC and LC-MS/MS. The proposed method can be used for the surveillance of illicit compounds in dietary supplements.

Effects in Metabolism and Adipocyte Inflammation Induced by the Complex Herbal Medicine composed of Cornus officinalis, Dioscorea rhizoma, Aurantii fructus, Mori folium in Obese Type 2 Diabetes Mouse Model (산수유 산약 지각 상엽으로 구성된 복합처방투여가 고지방, 고탄수화물 식이로 유발된 비만형 당뇨병 동물모델의 대사인자 및 지방세포 염증반응 조절에 미치는 영향)

  • Han, Su-Ryun;Paik, Sun-Ho;Kwon, Oh-Jun;Ahn, Young-Min;Lee, Byung-Cheol;Ahn, Se-Young
    • The Journal of Korean Medicine
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    • v.33 no.3
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    • pp.184-199
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    • 2012
  • Objectives: There is a steady increase in the prevalence of obesity worldwide and obesity is often accompanied by inflammation. Although much emphasis has been placed on the adipose tissue inflammation in obesity, a study with herbal medicine is few. This study aimed to investigate the antidiabetic and anti-inflammatory effect of a complex herbal medicine (CHM) composed of Cornus officinalis, Dioscorea rhizoma, Aurantii fructus, and Mori Foliumon on obese type 2 diabetes mice. Methods: Type 2 diabetes mellitus and obesity were induced by Surwit's high fat, high sucrose diet for 8 weeks. Mice were divided into ND (normal diet, n=10), HFD (high fat and high sucrose diet, n=10), CHM (high fat and high sucrose diet with complex herbal medicine, n=10) and Met (high fat and high sucrose diet with metformin, n=10) groups. The body weight, fructosamine and OGTT (oral glucose tolerance test) were measured. After 8 weeks the blood samples of all mice were taken from the heart, and lipid profiles were measured. Epididymal fat pad, histological size of the adipocyte tissue and liver weights were measured. Inflammatory markers such as leptin and adipocyte tissue macrophage were measured to evaluate the effect of CHM on adipocyte tissue inflammation. Results: Compared with the HFD group, there was an improvement in OGTT and epididymal fat decreased in the CHM group. White adipocyte size and adipocyte tissue macrophage decreased in CHM group. Conclusions: These results suggest that CHM has antidiabetic and anti-inflammatory effects in high fat, high sucrose diet induced obese mice.

Effect of the supplementation of Coconopsis lanceolata extract on lipid metabolism amelioration in type 2 diabetes mouse model induced by high fat diet (울릉도 섬더덕 추출물의 급여가 제2형 당뇨 동물의 지질대사 개선에 미치는 영향)

  • Yun, Won-Kap;Bae, Hyun-Ji;Kim, You-Jeong;Kwon, O Jun;Im, Moo Hyeog;Cho, Hyun Duk;Kim, Taewan
    • Food Science and Preservation
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    • v.21 no.1
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    • pp.107-113
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    • 2014
  • The present study was designed to investigate the antihyperlipidemic effect of Coconopsis lanceolata extract in C57BL/6J mice. The mice were divided into four groups: normal diet group (ND), high fat diet group (HFD), positive control group with 0.05% metformin (PC), Coconopsis lanceolata extract group (UCL). After 5 weeks of feeding, average body weight of the UCL group mice was slightly decreased, while that of the HFD group significantly increased) Also, liver and adipose tissue weights in the UCL group significantly increased. The levels of trigliceride (TG) and total in the plasma of UCL-supplemented group were significantly lower than those of high fat diet group. On the other hand, HDL-cholesterol level was increased. Expression level of proteins related with adipogenesis such as SREBP-1c, ACC, and FAS in the liver of the UCL group mice was much lower comparing with the HFD group mice. In conclusion, the results showed that the Coconopsis lanceolata extract possesses significant antihyperlipidemic effects in C57BL/6J mice.