The design, synthesis and bioevaluation of a series of novel L-tyrosine derivatives as peroxisome proliferator-activated receptor (PPAR) agonists are reported. Four intermediates and twenty L-tyrosine derivatives containing phenoxyacetyl moiety TM1 were synthesized starting from L-tyrosine via four step reactions including the esterification of carboxyl group, phenoxyacetylation of a-amino group, bromoalkylation of phenolic hydroxyl group and then nucleophilic substitution reaction with various heterocyclic amines in 21%-75% overall yield. Subsequently TM1 were hydrolyzed to give sixteen corresponding target compounds TM2 in 77%-99% yield. The chemical structures of the thirty-nine new compounds were identified using 1H NMR, 13C NMR techniques and thirty-five were confirmed by HR-MS techniques. Screening results in vitro showed that the PPAR relative activation activities of the target molecules are weak overall, while compound TM2i reaches 50.01%, which hints that the molecular structures of these obtained compounds need to be modified further.
Hep G2 Cells ; Humans ; Hypoglycemic Agents ; chemical synthesis ; chemistry ; pharmacology ; Molecular Structure ; Peroxisome Proliferator-Activated Receptors ; agonists ; metabolism ; Phenoxyacetates ; chemical synthesis ; chemistry ; pharmacology ; Structure-Activity Relationship ; Tyrosine ; analogs & derivatives ; chemical synthesis ; chemistry ; pharmacology

Merkel cell carcinoma is a rare aggressive primary skin cancer which mostly occurs in the elderly on sun-exposed skin. It usually presents as a solitary dome-shaped red or purple nodule on the head, neck and extremities. The mortality rate is higher than the rate for malignant melanoma because its local recurrence is common. Agent Orange, an herbicide widely used as a defoliant in the Vietnam War, contains dioxin contaminants and can cause several dermatoses and skin cancers. We report a case of multiple Merkel cell carcinoma in a 65-year-old male with lesions on the head and neck, who had been exposed to Agent Orange during Vietnam War.
2,4,5-Trichlorophenoxyacetic Acid ; 2,4-Dichlorophenoxyacetic Acid ; Aged ; Carcinoma, Merkel Cell ; Citrus sinensis ; Extremities ; Head ; Humans ; Male ; Melanoma ; Neck ; Recurrence ; Skin ; Skin Diseases ; Skin Neoplasms ; Tetrachlorodibenzodioxin ; Veterans ; Vietnam

A defoliant is a toxic chemical agent used to remove leaves. Defoliants are classified into 6 types (purple, pink, green, blue, white and orange). From 1962 to 1971, due to removing leaves and securing their ability to see, the U.S. Army Chemical Corps veterans handled and sprayed defoliant in Vietnam. This resulted in exposure to Agent Orange and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin). This agent induces many medical problems in humans. Since 1992 in Korea, exposure to defoliants have given rise to several problems. However, there were few reactions due to the lack of data, social apathy, and international relationships. In this article, we review characteristics and diseases related to defoliants.
2,4,5-Trichlorophenoxyacetic Acid ; 2,4-Dichlorophenoxyacetic Acid ; Apathy ; Citrus sinensis ; European Continental Ancestry Group ; Humans ; Korea ; Skin ; Skin Diseases ; Tetrachlorodibenzodioxin ; Veterans ; Vietnam

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), one of the components of Agent Orange, has been reported to be a deadly poison despite its presence at extremely small doses. TCDD is reported to cause various kinds of cancers and other harmful effects on humans. However, a correlation between exposure to TCDD and acute coronary syndrome (ACS) is not yet proven. Thus, we examined the correlation between exposure to TCDD and ACS through an analysis of coronary angiograms from veterans of the Vietnam War. Two hundred fifty-one consecutive men undergoing coronary angiograms owing to ACS between April 2004 and May 2009 at Gwangju Veterans Hospital were analyzed. Included subjects were between 50 and 70 years of age. The patients were divided into two groups: 121 patients who had been exposed to TCDD (Group I) and 130 patients who had not been exposed to TCDD (Group II). Clinical and coronary angiographic findings were evaluated. Baseline clinical characteristics, inflammatory markers, and echocardiographic parameters were not significantly different between the two groups. The incidence of hypertension (71.1% vs. 60.0%, p=0.039) and hyperlipidemia (27.3% vs. 16.9%, p=0.038) was higher in Group I than in Group II. Total occlusion, stent length, stent use, and coronary lesion characteristics were not significantly different between the two groups. The rate of major adverse cardiovascular events (MACE) had no relationship with exposure to TCDD. Exposure to TCDD might not affect severity or the rate of MACE in persons with ACS.
2,4,5-Trichlorophenoxyacetic Acid ; 2,4-Dichlorophenoxyacetic Acid ; Acute Coronary Syndrome ; Angiography ; Citrus sinensis ; Hospitals, Veterans ; Humans ; Hyperlipidemias ; Hypertension ; Incidence ; Male ; Stents ; Tetrachlorodibenzodioxin ; Veterans ; Vietnam

BACKGROUND: Self-inflicted dermatosis is a kind of self-inflicted skin disease. Most Vietnam veterans from Korea have visited the Veterans Hospitals for dermatological examination to determine the relationship between their skin diseases and Agent Orange. We were suspicious of the possibility that several Vietnam veterans intentionally produced their own skin lesions. OBJECTIVE: We conducted this study to determine the clinical characteristics of self-inflicted dermatoses of Korean Vietnam veterans. METHODS: From January, 1999 to December, 2007, a total 24 Vietnam veterans who were diagnosed as having self-inflicted dermatoses during their dermatological examinations at our hospital were included in this study. We investigated their clinical presentation, the laboratory examinations, the pathologic examinations, the medical records and the associated diseases. RESULTS: Itching was the most common subjective complaint and the duration of the itching was as follows; 20 to 30 yrs (50.0%), 1 to 10 yrs (25.0%), 10 to 20 yrs (20.8%) etc. The skin lesions were all multiple, and the involved area was as follows; upper extremities (83.3%), trunk (75.0%), lower extremities (70.8%) etc. There were two categories of clinical skin presentation. The first was the cases with lesion that were thought to be made by physical trauma such as stinging or excoriation, and the second more common cases had lesions that were thought to be made by chemical agents (70.8%). These cases resembled allergic or toxic irritant dermatitis and the lesions were composed of vesicles, erosions, ulcers and crusts that were within an arm's reach. Only 4 cases admitted to intentionally inflicting their skin lesions because of intense itching, and the others denied that they made the skin lesions by themselves. Skin biopsies were carried out in 19 of the total 24 cases, and the most common finding was spongiotic dermatitis (57.8%). CONCLUSION: This study showed the distribution and characteristics of self-inflicted dermatoses, and the study provides fundamental data for dermatologists to assess patients with self-inflicted dermatoses.
2,4,5-Trichlorophenoxyacetic Acid ; 2,4-Dichlorophenoxyacetic Acid ; Biopsy ; Bites and Stings ; Citrus sinensis ; Dermatitis ; Dermatitis, Irritant ; Hospitals, Veterans ; Humans ; Intention ; Korea ; Lower Extremity ; Medical Records ; Pruritus ; Skin ; Skin Diseases ; Tetrachlorodibenzodioxin ; Ulcer ; Upper Extremity ; Veterans ; Vietnam

Sphingosylphosphorylcholine (SPC) is significantly increased in the malicious ascites of tumor patients and induces perinuclear reorganization of keratin 8 (K8) filaments in PANC-1 cells. The reorganization contributes to the viscoelasticity of metastatic cancer cells resulting in increased migration. Recently, we reported that transglutaminase-2 (Tgase-2) is involved in SPC-induced K8 phosphorylation and reorganization. However, effects of Tgase-2 inhibitors on SPC-induced K8 phosphorylation and reorganization were not clearly studied. We found that ethacrynic acid (ECA) concentration-dependently inhibited Tgase-2. Therefore, we examined the effects of ECA on SPC-induced K8 phosphorylation and reorganization. ECA concentration-dependently suppressed the SPC-induced phosphorylation and perinuclear reorganization of K8. ECA also suppressed the SPC-induced migration and invasion. SPC induced JNK activation through Tgase-2 expression and ECA suppressed the activation and expression of JNK in PANC-1 cells. These results suggested that ECA might be useful to control Tgase-2 dependent metastasis of cancer cells such as pancreatic cancer and lung cancers.
Ascites ; Ethacrynic Acid* ; Humans ; Keratin-8* ; Lung Neoplasms ; Neoplasm Metastasis ; Pancreatic Neoplasms ; Phosphorylation*

OBJECTIVES: The aim of this study was to examine the levels of serum 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and evaluate their association with age, body mass index, smoking, military record-based variables, and estimated exposure to Agent Orange in Korean Vietnam veterans. METHODS: Serum levels of TCDD were analyzed in 102 Vietnam veterans. Information on age, body mass index, and smoking status were obtained from a self-reported questionnaire. The perceived exposure was assessed by a 6-item questionnaire. Two proximity-based exposures were constructed by division/brigade level and battalion/company level unit information using the Stellman exposure opportunity index model. RESULTS: The mean and median of serum TCDD levels was 1.2 parts per trillion (ppt) and 0.9 ppt, respectively. Only 2 Vietnam veterans had elevated levels of TCDD (>10 ppt). The levels of TCDD did not tend to increase with the likelihood of exposure to Agent Orange, as estimated from either proximity-based exposure or perceived self-reported exposure. The serum TCDD levels were not significantly different according to military unit, year of first deployment, duration of deployment, military rank, age, body mass index, and smoking status. CONCLUSIONS: The average serum TCDD levels in the Korean Vietnam veterans were lower than those reported for other occupationally or environmentally exposed groups and US Vietnam veterans, and their use as an objective marker of Agent Orange exposure may have some limitations. The unit of deployment, duration of deployment, year of first deployment, military rank, perceived self-reported exposure, and proximity-based exposure to Agent Orange were not associated with TCDD levels in Korean Vietnam veterans. Age, body mass index and smoking also were not associated with TCDD levels.
2,4,5-Trichlorophenoxyacetic Acid/*poisoning ; 2,4-Dichlorophenoxyacetic Acid/*poisoning ; Adult ; Age Factors ; *Body Mass Index ; Defoliants, Chemical/*poisoning ; Humans ; Male ; Middle Aged ; Questionnaires ; Regression Analysis ; Republic of Korea/epidemiology ; Self Report ; Smoking/*blood ; Tetrachlorodibenzodioxin/*blood/poisoning ; Time Factors ; Veterans/*statistics & numerical data ; Vietnam Conflict ; Young Adult

OBJECTIVES: The aim of this study was to evaluate the association between Agent Orange exposure and self-reported diseases in Korean Vietnam veterans. METHODS: A postal survey of 114 562 Vietnam veterans was conducted. The perceived exposure to Agent Orange was assessed by a 6-item questionnaire. Two proximity-based Agent Orange exposure indices were constructed using division/brigade-level and battalion/company-level unit information. Adjusted odds ratios (ORs) for age and other confounders were calculated using a logistic regression model. RESULTS: The prevalence of all self-reported diseases showed monotonically increasing trends as the levels of perceived self-reported exposure increased. The ORs for colon cancer (OR, 1.13), leukemia (OR, 1.56), hypertension (OR, 1.03), peripheral vasculopathy (OR, 1.07), enterocolitis (OR, 1.07), peripheral neuropathy (OR, 1.07), multiple nerve palsy (OR, 1.14), multiple sclerosis (OR, 1.24), skin diseases (OR, 1.05), psychotic diseases (OR, 1.07) and lipidemia (OR, 1.05) were significantly elevated for the high exposure group in the division/brigade-level proximity-based exposure analysis, compared to the low exposure group. The ORs for cerebral infarction (OR, 1.08), chronic bronchitis (OR, 1.05), multiple nerve palsy (OR, 1.07), multiple sclerosis (OR, 1.16), skin diseases (OR, 1.05), and lipidemia (OR, 1.05) were significantly elevated for the high exposure group in the battalion/company-level analysis. CONCLUSIONS: Korean Vietnam veterans with high exposure to Agent Orange experienced a higher prevalence of several self-reported chronic diseases compared to those with low exposure by proximity-based exposure assessment. The strong positive associations between perceived self-reported exposure and all self-reported diseases should be evaluated with discretion because the likelihood of reporting diseases was directly related to the perceived intensity of Agent Orange exposure.
2,4,5-Trichlorophenoxyacetic Acid/*poisoning ; 2,4-Dichlorophenoxyacetic Acid/*poisoning ; Cardiovascular Diseases/epidemiology/etiology ; Defoliants, Chemical/*poisoning ; Endocrine System Diseases/epidemiology/etiology ; Gastrointestinal Diseases/epidemiology/etiology ; Humans ; Logistic Models ; Male ; Middle Aged ; Neoplasms/epidemiology/etiology ; Neuromuscular Diseases/epidemiology/etiology ; Odds Ratio ; Prevalence ; Republic of Korea/epidemiology ; Respiratory Tract Diseases/epidemiology/etiology ; *Self Report ; Tetrachlorodibenzodioxin/*poisoning ; *Veterans ; Vietnam Conflict

OBJECTIVETo explore the quantitative relationship between the reduction of distortion product otoacoustic emission (DPOAE) and the percentage of outer hair cell loss.

METHODSCoadministration of cisplatin (0.2 mg/kg) and ethacrynic acid (40 mg/kg) were used to establish a cochlear lesion model in chinchillas. DPOAE was measured before and 1 week, 2 weeks, and 3 weeks later respectively after cisplatin and ethacrynic acid treatment. Animals were terminated 3 weeks after the treatment. Cochlear surface preparations were performed, and the cochlear hair cells were counted through entire length of the cochlea. The correlation between DPOAE reduction and outer hair cell missing was analyzed using Pearson correlation analysis.

RESULTSCisplatin and ethacrynic acid treatment induced cochlear hair cell lesion that the outer hair cell loss in the cochlea developed in a stereotypic pattern; damage began in the base of the cochlea and progressed towards the apex. Reduction of DPOAE was relatively consistent with outer hair cells loss. On the average, 1% outer hair cells loss may result in 0.24 dB reduction in DPOAE levels. Pearson analysis showed a positive correlation between the reduction in DPOAE and missing of outer hair cells (r = 0.796, P < 0.05).

CONCLUSIONSIt may be helpful to evaluate missing percentage of outer hair cells from reduction in DPOAE levels.

Animals ; Cell Count ; Chinchilla ; Cisplatin ; Disease Models, Animal ; Ethacrynic Acid ; Hair Cells, Auditory, Outer ; cytology ; pathology ; Otoacoustic Emissions, Spontaneous

The aim of this study was to investigate the inhibitory effect and the underlying mechanism of ethacrynic acid (EA) on the contraction in mice. BL-420S force measuring system was used to measure the tension of mouse tracheal rings. The whole cell patch clamp technique was utilized to record the channel currents of airway smooth muscle (ASM) cells. The calcium imaging system was used to determine the intracellular Ca concentration ([Ca]) in ASM cells. The results showed that EA significantly inhibited the high K (80 mmol/L) and acetylcholine (ACh, 100 µmol/L)-induced contraction of mouse tracheal rings in a dose-dependent manner. The maximal relaxation percentages were (97.02 ± 1.56)% and (85.21 ± 0.03)%, and the median effective concentrations were (40.28 ± 2.20) μmol/L and (56.22 ± 7.62) μmol/L, respectively. EA decreased the K and ACh-induced elevation of [Ca] from 0.40 ± 0.04 to 0.16 ± 0.01 and from 0.50 ± 0.01 to 0.39 ± 0.01, respectively. In addition, EA inhibited L-type voltage-dependent calcium channel (LVDCC) and store-operated calcium channel (SOCC) currents in ASM cells, and Ca influx. Moreover, EA decreased the resistance of the respiratory system (Rrs) in vivo in mice. These results indicated that EA inhibits LVDCC and SOCC, which results in termination of Ca influx and decreases of [Ca], leading to relaxation of ASM. Taken together, EA might be a potential bronchodilator.
Animals ; Calcium ; metabolism ; Calcium Channels, L-Type ; Enzyme Inhibitors ; pharmacology ; Ethacrynic Acid ; pharmacology ; Mice ; Muscle Contraction ; drug effects ; Muscle, Smooth ; drug effects ; Respiratory System ; cytology ; drug effects