Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 230
Filter
Add more filters

Publication year range
1.
Contact Dermatitis ; 87(1): 81-88, 2022 Jul.
Article in English | MEDLINE | ID: mdl-35293005

ABSTRACT

BACKGROUND: The practical importance of two recently described epoxy hardener allergens-1,3-benzenedimethanamine, N-(2-phenylethyl) derivatives (1,3-BDMA-D) and hydrogenated formaldehyde benzenamine polymer (FBAP)-as occupational allergens remains to be defined. OBJECTIVES: To describe patients diagnosed at the Finnish Institute of Occupational Health (FIOH) with positive reactions to 1,3-BDMA-D or FBAP. METHODS: We searched FIOH's patch-test files from January 2017 to December 2020 for patients examined due to suspected occupational contact allergy to epoxy compounds. We analyzed the patch-test results and sources of exposure to various epoxy hardeners and focused on occupations, symptoms, and the sources of exposure to 1,3-BDMA-D and FBAP. RESULTS: During the study period, 102 patients were examined at FIOH for suspected occupational contact allergy to epoxy compounds. Of these, 19 (19%) were diagnosed with contact allergy to 1,3-BDMA-D (n = 10) or FBAP (n = 12). The largest occupational group was sewage pipe reliners (n = 8). Seven different hardener products contained FBAP, whereas 1,3-BDMA-D was present in only one hardener used by spray painters. CONCLUSIONS: A substantial number of patients with suspected occupational epoxy resin system allergy tested positive to in-house test substances of 1,3-BDMA-D and/or FBAP.


Subject(s)
Dermatitis, Allergic Contact , Dermatitis, Occupational , Allergens/adverse effects , Dermatitis, Allergic Contact/diagnosis , Dermatitis, Allergic Contact/etiology , Dermatitis, Occupational/diagnosis , Dermatitis, Occupational/etiology , Epoxy Compounds/adverse effects , Epoxy Resins/adverse effects , Formaldehyde/adverse effects , Humans , Patch Tests , Polymers
2.
Carcinogenesis ; 42(5): 694-704, 2021 05 28.
Article in English | MEDLINE | ID: mdl-33693566

ABSTRACT

1,3-Butadiene (BD) is a known human carcinogen used in the synthetic polymer industry and also found in cigarette smoke, automobile exhaust and wood burning smoke. BD is metabolically activated by cytochrome P450 monooxygenases (CYP) 2E1 and 2A6 to 3,4-epoxy-1-butene (EB), which can be detoxified by GST-catalyzed glutathione conjugation or hydrolysis. We have previously observed ethnic differences in urinary levels of EB-mercapturic acids in white, Japanese American and Native Hawaiian smokers. In the present study, similar analyses were extended to urinary BD-DNA adducts. BD-induced N7-(1-hydroxy-3-buten-2-yl) guanine (EB-GII) adducts were quantified in urine samples obtained from smokers and non-smokers belonging to three racial/ethnic groups: white, Japanese American and Native Hawaiian. After adjusting for sex, age, nicotine equivalents, body mass index and batch, we found that Japanese American smokers excreted significantly higher amounts of urinary EB-GII than whites [1.45 (95% confidence interval: 1.12-1.87) versus 0.68 (95% confidence interval: 0.52-0.85) fmol/ml urine, P = 4 × 10-5]. Levels of urinary EB-GII in Native Hawaiian smokers were not different from those in whites [0.67 (95% confidence interval: 0.51-0.84) fmol/ml urine, P = 0.938]. There were no racial/ethnic differences in urinary EB-GII adduct levels in non-smokers. Racial/ethnic differences in urinary EB-GII adduct levels in smokers could not be explained by GSTT1 gene deletion or CYP2A6 enzymatic activity. Urinary EB-GII adduct levels in smokers were significantly associated with concentrations of BD metabolite dihyroxybutyl mercapturic acid. Overall, our results reveal that urinary EB-GII adducts in smokers differ across racial/ethnic groups. Future studies are required to understand genetic and epigenetic factors that may be responsible for these differences.


Subject(s)
Butadienes/toxicity , Cytochrome P-450 CYP2A6/genetics , Cytochrome P-450 CYP2E1/genetics , DNA Adducts/drug effects , Acetylcysteine/urine , Adult , Aged , Asian/genetics , Carcinogens/metabolism , Carcinogens/toxicity , DNA Adducts/genetics , DNA Adducts/urine , Epoxy Compounds/adverse effects , Epoxy Compounds/urine , Ethnicity/genetics , Female , Glutathione Transferase/genetics , Humans , Male , Middle Aged , Native Hawaiian or Other Pacific Islander/genetics , Smoke/adverse effects , Smokers , Spectrometry, Mass, Electrospray Ionization , Tobacco Products/adverse effects , Vehicle Emissions/toxicity , White People/genetics
3.
Cell Mol Biol (Noisy-le-grand) ; 67(2): 109-113, 2021 Aug 31.
Article in English | MEDLINE | ID: mdl-34817331

ABSTRACT

To investigate the first-line treatment of recurrent Nasopharyngeal Carcinoma treprimcab combined with chemotherapy. From January 2019 to January 2020, 48 patients with recurrent nasopharyngeal Carcinoma (RNPC) were treated in our hospital. According to the method of the random number, 24 patients were divided into the combined group and the Control Group. The patients in the combined group were given the Combined Treatment of triptolide and chemotherapy. While the Control Group only received chemotherapy. The therapeutic effects and adverse reactions of the two groups were compared, the levels of Carcinoembryonic Antigen (CEA) and carbohydrate Antigen 19-9 (CA19-9) were measured before and after treatment. The total effective rate of the combined group was 79.17% higher than that of the control group (62.50%). The total effective rate of the two groups was statistically significant (P & Lt; 0.05). The incidence of grade i/ii adverse reaction in the control group was lower than that in the combined group, such as nausea and vomiting, oral mucositis, Leukopenia, liver and kidney function damage, central granulocyte count reduction, anaemia adverse reaction. The incidence of grade iii/iv Adr in the control group was higher than that in the combined group. The incidence of grade i/ii Adr in the thrombocytopenia group was higher than that in the combined group, and the incidence of grade iii/iv Adr in the control group was lower than that in the combined group. The side effects of nausea and vomiting and oral mucositis in the control group and the combined group were statistically significant (P & Lt; 0.05). There was no significant difference between the control group and the combined group in the incidence of Leukopenia, liver and kidney injury, neutrophil, anaemia and Thrombocytopenia (P & GT; 0.05). The level of CD4 + / CD8 + in control group and combined group before treatment was higher than that after treatment (P & Lt; 0.05). The quality of life of the combined group was 91.67% higher than that of the control group (70.83%). The quality of life of the control group was significantly higher than that of the combined group (P & Lt; 0.05). The levels of CEA and CA19-9 in the two groups after treatment were lower than those before treatment, and the levels of CEA and CA19-9 in the combined group were lower than those in the control group (P & Lt; 0.05). The first-line treatment of recurrent nasopharyngeal Carcinoma with triprimmab combined with chemotherapy has a good clinical effect and has a broad clinical research prospect.


Subject(s)
Antigens, Tumor-Associated, Carbohydrate/metabolism , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/metabolism , Carcinoembryonic Antigen/metabolism , Nasopharyngeal Carcinoma/drug therapy , Nasopharyngeal Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Diterpenes/administration & dosage , Diterpenes/adverse effects , Epoxy Compounds/administration & dosage , Epoxy Compounds/adverse effects , Female , Humans , Male , Middle Aged , Mucositis/chemically induced , Nasopharyngeal Carcinoma/metabolism , Nasopharyngeal Carcinoma/pathology , Nasopharyngeal Neoplasms/metabolism , Nasopharyngeal Neoplasms/pathology , Nausea/chemically induced , Neoplasm Recurrence, Local , Phenanthrenes/administration & dosage , Phenanthrenes/adverse effects , Treatment Outcome , Vomiting/chemically induced , Young Adult
4.
Contact Dermatitis ; 82(6): 343-349, 2020 Jun.
Article in English | MEDLINE | ID: mdl-32144776

ABSTRACT

BACKGROUND: Detailed epidemiological studies on occupational skin diseases (OSDs) are scarce. OBJECTIVES: To analyze risk occupations for OSDs in the Finnish Register of Occupational Diseases (FROD). METHODS: We retrieved numbers of OSD cases (excluding skin infections) for different occupations from the FROD in 2005-2016. In the FROD, Finnish ISCO-08-based classification of occupations was used since 2011, and the preceding ISCO-88-based version until 2010. We combined cases from the earlier and the later period using conversion tables provided by Statistics Finland. We included occupations with at least five cases and analyzed them in detail. We calculated incidence rates for OSDs and separately for allergic contact dermatitis (ACD) in different risk occupations using national labor force statistics. We also studied causes of ACD in these occupations. RESULTS: Risk occupations with the largest number of OSD cases included farmers, hairdressers, assistant nurses, cooks, cleaners, machinists, and nurses. Occupations with the highest incidences of OSDs comprised spray painters (23.8/10 000 person years), bakers (20.4), and dental technicians (19.0). Epoxy compounds and acrylates were prominent causes of ACD in occupations with the highest incidences of ACD. CONCLUSIONS: Uniform use of International Standard Classification of Occupations (ISCO) would facilitate comparisons of OSD figures in different countries.


Subject(s)
Dermatitis, Allergic Contact/epidemiology , Dermatitis, Allergic Contact/etiology , Dermatitis, Occupational/epidemiology , Dermatitis, Occupational/etiology , Occupations/statistics & numerical data , Acrylates/adverse effects , Barbering/statistics & numerical data , Construction Industry/statistics & numerical data , Cooking/statistics & numerical data , Dental Technicians/statistics & numerical data , Dermatitis, Irritant/epidemiology , Epoxy Compounds/adverse effects , Farmers/statistics & numerical data , Finland/epidemiology , Household Work/statistics & numerical data , Humans , Incidence , Manufacturing Industry/statistics & numerical data , Nurses/statistics & numerical data , Registries
5.
Contact Dermatitis ; 82(6): 337-342, 2020 Jun.
Article in English | MEDLINE | ID: mdl-32037572

ABSTRACT

BACKGROUND: Skin diseases are among the most common occupational diseases, but detailed analyses on their epidemiology, diagnoses, and causes are relatively scarce. OBJECTIVES: To analyze data on skin disease in the Finnish Register of Occupational Diseases (FROD) for (1) different diagnoses and (2) main causes of allergic contact dermatitis (ACD). METHODS: We retrieved data on recognized cases with occupational skin disease (OSD) in the FROD from a 12-year-period 2005-2016 and used national official labor force data of the year 2012. RESULTS: We analyzed a total of 5265 cases, of which 42% had irritant contact dermatitis (ICD), 35% ACD, 11% contact urticaria/protein contact dermatitis (CU/PCD), and 9% skin infections. The incidence rate of OSD in the total labor force was 18.8 cases/100 000 person years. Skin infections concerned mainly scabies in health care personnel. Twenty-nine per cent of the ACD cases were caused by plastics/resins-related allergens, mainly epoxy chemicals. Other important causes for ACD were rubber, preservatives, metals, acrylates, and hairdressing chemicals. Cases of occupational ACD due to isothiazolinones reached a peak in 2014. CONCLUSION: Our analysis confirms that epoxy products are gaining importance as causes of OSD and the isothiazolinone contact allergy epidemic has started to wane.


Subject(s)
Dermatitis, Allergic Contact/epidemiology , Dermatitis, Allergic Contact/etiology , Dermatitis, Irritant/epidemiology , Dermatitis, Occupational/epidemiology , Dermatitis, Occupational/etiology , Acrylates/adverse effects , Adult , Dermatitis, Irritant/etiology , Epoxy Compounds/adverse effects , Epoxy Resins/adverse effects , Female , Finland/epidemiology , Hair Preparations/adverse effects , Humans , Incidence , Isocyanates/adverse effects , Male , Metals/adverse effects , Middle Aged , Preservatives, Pharmaceutical/adverse effects , Registries , Rubber/adverse effects , Skin Diseases, Infectious/epidemiology , Thiazoles/adverse effects , Urticaria/epidemiology
6.
Biomed Chromatogr ; 34(8): e4864, 2020 Aug.
Article in English | MEDLINE | ID: mdl-32330997

ABSTRACT

Triptolide (TP), one of the main bioactive diterpenes of the herbal medicine Tripterygium wilfordii Hook F, is used for the treatment of autoimmune diseases in the clinic and is accompanied by severe hepatotoxicity. CYP3A4 has been reported to be responsible for TP metabolism, but the mechanism remains unclear. The present study applied a UPLC-QTOF-MS-based metabolomics analysis to characterize the effect of CYP3A4 on TP-induced hepatotoxicity. The metabolites carnitines, lysophosphatidylcholines (LPCs) and a serious of amino acids were found to be closely related to liver damage indexes in TP-treated female mice. Metabolomics analysis further revealed that the CYP3A4 inducer dexamethasone improved the level of LPCs and amino acids, and defended against oxidative stress. On the contrary, pretreatment with the CYP3A4 inhibitor ketoconazole increased liver damage with most metabolites being markedly altered, especially carnitines. Among these metabolites, except for LPC18:2, LPC20:1 and arginine, dexamethasone and ketoconazole both affected oxidative stress induced by TP. The current study provides new mechanistic insights into the metabolic alterations, leading to understanding of the role of CYP3A4 in hepatotoxicity induced by TP.


Subject(s)
Chemical and Drug Induced Liver Injury , Cytochrome P-450 CYP3A , Diterpenes/adverse effects , Metabolomics/methods , Phenanthrenes/adverse effects , Animals , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/pathology , Chromatography, High Pressure Liquid/methods , Cytochrome P-450 CYP3A/drug effects , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 CYP3A Inhibitors/pharmacology , Dexamethasone/pharmacology , Epoxy Compounds/adverse effects , Female , Ketoconazole/pharmacology , Liver/metabolism , Liver/pathology , Mass Spectrometry/methods , Metabolome/drug effects , Mice , Mice, Inbred C57BL
7.
Contact Dermatitis ; 80(1): 18-25, 2019 Jan.
Article in English | MEDLINE | ID: mdl-30259537

ABSTRACT

BACKGROUND: Epoxy resin systems (ERSs) are among the leading causes of occupational allergic contact dermatitis. OBJECTIVES: To identify riskful exposures and sources of skin exposure, and to quantify skin exposure to diglycidyl ether of bisphenol A (DGEBA) epoxy monomer, in construction coating work. METHODS: Skin exposure to epoxy chemicals was studied in 5 coating companies through (a) interviews and visual observation, (b) quantifying DGEBA on 12 workers' skin by tape-stripping, (c) measuring DGEBA on 23 surfaces by wipe-sampling, and (d) quantifying DGEBA in new sewage pipe. Acetone extracts of the tapes, wipes and sawdust from a newly hardened sewage pipe were analysed by gas chromatography/mass spectrometry. RESULTS: Identified riskful exposures were, for example, mixing ERSs, handling coating pots, and working above shoulder level. Epoxy stains on, for example, tools, equipment and clothing were seen in all workplaces. Protective gloves were of varying quality, and were not always suitable for chemicals. The amount of DGEBA on the workers' skin varied considerably. All screened tool handles were contaminated. Two-day-old epoxy sewage pipe contained 3.2% DGEBA. CONCLUSIONS: Construction coating entails skin contact with ERSs directly and via contaminated surfaces, personal protective equipment, and recently hardened epoxy materials. Observation is a useful method for assessing skin exposure in coating work.


Subject(s)
Benzhydryl Compounds/adverse effects , Construction Industry , Dermatitis, Allergic Contact/etiology , Dermatitis, Occupational/etiology , Epoxy Compounds/adverse effects , Occupational Exposure , Construction Materials , Gloves, Protective , Health Knowledge, Attitudes, Practice , Humans , Observation , Skin
10.
Occup Med (Lond) ; 69(7): 511-514, 2019 Dec 07.
Article in English | MEDLINE | ID: mdl-31394570

ABSTRACT

BACKGROUND: A delayed asthma reaction occurring several hours after exposure is difficult to diagnose. AIMS: To confirm a delayed asthma reaction in five workers following epoxy exposure. CASE REPORT: Working conditions with exposure to epoxy encountered at the workplace were reproduced in a challenge chamber. Specific inhalation challenge (SIC) with epoxy was compared to a control challenge. All five cases had delayed a asthma response 6-15 h after epoxy exposure. CONCLUSIONS: Our study confirms that SIC is a useful tool in diagnosing delayed asthma response.


Subject(s)
Asthma, Occupational/diagnosis , Epoxy Compounds/adverse effects , Inhalation Exposure , Adult , Forced Expiratory Volume , Humans , Male , Middle Aged , Occupational Exposure/adverse effects
11.
Carcinogenesis ; 39(5): 661-668, 2018 05 03.
Article in English | MEDLINE | ID: mdl-29538615

ABSTRACT

Although benzene has long been recognized as a cause of human leukemia, the mechanism by which this simple molecule causes cancer has been problematic. A complicating factor is benzene metabolism, which produces many reactive intermediates, some specific to benzene and others derived from redox processes. Using archived serum from 20 nonsmoking Chinese workers, 10 with and 10 without occupational exposure to benzene (exposed: 3.2-88.9 ppm, controls: 0.002-0.020 ppm), we employed an adductomic pipeline to characterize protein modifications at Cys34 of human serum albumin, a nucleophilic hotspot in extracellular fluids. Of the 47 measured human serum albumin modifications, 39 were present at higher concentrations in benzene-exposed workers than in controls and many of the exposed-control differences were statistically significant. Correlation analysis identified three prominent clusters of adducts, namely putative modifications by benzene oxide and a benzene diolepoxide that grouped with other measures of benzene exposure, adducts of reactive oxygen and carbonyl species, and Cys34 disulfides of small thiols that are formed following oxidation of Cys34. Benzene diolepoxides are potent mutagens and carcinogens that have received little attention as potential causes of human leukemia. Reactive oxygen and carbonyl species-generated by redox processes involving polyphenolic benzene metabolites and by Cyp2E1 regulation following benzene exposure-can modify DNA and proteins in ways that contribute to cancer. The fact that these diverse human serum albumin modifications differed between benzene-exposed and control workers suggests that benzene can increase leukemia risks via multiple pathways involving a constellation of reactive molecules.


Subject(s)
Benzene/adverse effects , Carcinogenesis/chemically induced , Leukemia/chemically induced , Adult , Benzene Derivatives/adverse effects , Carcinogens/toxicity , Cyclohexanes/adverse effects , Epoxy Compounds/adverse effects , Female , Humans , Leukemia/blood , Leukemia/metabolism , Male , Mutagens/adverse effects , Occupational Exposure/adverse effects , Risk , Serum Albumin/metabolism
12.
Mol Pharm ; 15(2): 560-570, 2018 02 05.
Article in English | MEDLINE | ID: mdl-29307194

ABSTRACT

Triptolide (TP) has been used as one of the most common systemic treatments for various diseases since the 1960s. However, TP displays diverse side effects on various organs, which limits its clinical application. To overcome this issue, numerous C-14-hydroxyl group derivatives of TP have been synthesized. In this research, the C-14-hydroxyl group of TP is modified by a cell-penetrating peptide polyarginine (R7). The derivative TP-disulfide-CR7 (TP-S-S-CR7) containing a disulfide linkage between TP and R7 possesses less toxicity at various concentrations on the immortal human keratinocyte (HaCaT) cell line by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay compared with free TP. Treating HaCaT cells with TP (100 nM) could increase intracellular ROS (reactive oxygen species) and decrease the activity of SOD (superoxide dismutase). Meanwhile, treating HaCaT cells with equimolar concentration of TP-S-S-CR7 did not cause both of the above TP-induced alterations. In addition, TP-S-S-CR7 did not show significant dermal toxicity on guinea pigs and could efficiently overcome the barrier of corneum and then reach epidermis and dermis within 2 h of transdermal administration. In addition, there was a relatively lower concentration of TP in blood indicating less toxicity on organs. Such results suggest that topical therapy using polyarginine is possible by the transdermal delivery of TP.


Subject(s)
Cell-Penetrating Peptides/chemistry , Diterpenes/administration & dosage , Drug Delivery Systems/methods , Phenanthrenes/administration & dosage , Skin/metabolism , Administration, Cutaneous , Animals , Cell Line , Cell Survival/drug effects , Diterpenes/adverse effects , Diterpenes/blood , Diterpenes/chemistry , Drug Stability , Epoxy Compounds/administration & dosage , Epoxy Compounds/adverse effects , Epoxy Compounds/blood , Epoxy Compounds/chemistry , Guinea Pigs , Humans , Keratinocytes , Male , Mice , Phenanthrenes/adverse effects , Phenanthrenes/blood , Phenanthrenes/chemistry , Rats , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolism , Skin/drug effects , Superoxide Dismutase/metabolism , Toxicity Tests
13.
Acta Pharmacol Sin ; 39(12): 1847-1854, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30013034

ABSTRACT

Triptolide (TP) is the main active ingredient of Tripterygium wilfordii Hook.f, which has attracted great interest due to its promising efficacy for autoimmune diseases and tumors. However, severe adverse reactions, especially hepatotoxicity, have restricted its approval in the market. In the present study we explored the role of hepatic natural killer T (NKT) cells in the pathogenesis of TP-induced liver injury in mice. TP (600 µg/kg/day, i.g.) was administered to female mice for 1, 3, or 5 days. We found that administration of TP dose-dependently induced hepatotoxicity, evidenced by the body weight reduction, elevated serum ALT and AST levels, as well as significant histopathological changes in the livers. However, the mice were resistant to the development of TP-induced liver injury when their NKT cells were depleted by injection of anti-NK1.1 mAb (200 µg, i.p.) on days -2 and -1 before TP administration. We further revealed that TP administration activated NKT cells, dominantly releasing Th1 cytokine IFN-γ, recruiting neutrophils and macrophages, and leading to liver damage. After anti-NK1.1 injection, however, the mice mainly secreted Th2 cytokine IL-4 in the livers and exhibited a significantly lower percentage of hepatic infiltrating neutrophils and macrophages upon TP challenge. The activation of NKT cells was associated with the upregulation of Toll-like receptor (TLR) signaling pathway. Collectively, these results demonstrate a novel role of NKT cells contributing to the mechanisms of TP-induced liver injury. More importantly, the regulation of NKT cells may promote effective measures that control drug-induced liver injury.


Subject(s)
Chemical and Drug Induced Liver Injury/physiopathology , Diterpenes/adverse effects , Liver/metabolism , Natural Killer T-Cells/metabolism , Phenanthrenes/adverse effects , Animals , Epoxy Compounds/adverse effects , Female , Interferon-gamma/metabolism , Interleukin-4/metabolism , Leukocytes/metabolism , Mice, Inbred C57BL , Signal Transduction/drug effects
14.
Acta Pharmacol Sin ; 39(2): 311-327, 2018 Feb.
Article in English | MEDLINE | ID: mdl-28905938

ABSTRACT

Triptolide (TP), an oxygenated diterpene, has a variety of beneficial pharmacodynamic activities but its clinical applications are restricted due to severe testicular injury. This study aimed to delineate the molecular mechanisms of TP-induced testicular injury in vitro and in vivo. TP (5-50000 nmol/L) dose-dependently decreased the viability of TM4 Sertoli cells with an IC50 value of 669.5-269.45 nmol/L at 24 h. TP (125, 250, and 500 nmol/L) dose-dependently increased the accumulation of ROS, the phosphorylation of JNK, mitochondrial dysfunction and activation of the intrinsic apoptosis pathway in TM4 cells. These processes were attenuated by co-treatment with the antioxidant N-acetyl cysteine (NAC, 1 mmol/L). Furthermore, TP treatment inhibited the translocation of Nrf2 from cytoplasm into the nucleus as well as the expression of downstream genes NAD(P)H quinone oxidoreductase1 (NQO1), catalase (CAT) and hemeoxygenase 1 (HO-1), thus abrogating Nrf2-mediated defense mechanisms against oxidative stress. Moreover, siRNA knockdown of Nrf2 significantly potentiated TP-induced apoptosis of TM4 cells. The above results from in vitro experiments were further validated in male mice after oral administration of TP (30, 60, and 120 mg·kg-1·d-1, for 14 d), as evidenced by the detected indexes, including dose-dependently decreased SDH activity, increased MDA concentration, altered testicle histomorphology, elevated caspase-3 activation, apoptosis induction, increased phosphorylation of JNK, and decreased gene expression of NQO1, CAT and HO-1 as well as nuclear protein expression of Nrf2 in testicular tissue. Our results demonstrate that TP activates apoptosis of Sertoli cells and injury of the testis via the ROS/JNK-mediated mitochondrial-dependent apoptosis pathway and down-regulates Nrf2 activation.


Subject(s)
Apoptosis/drug effects , Diterpenes/adverse effects , Phenanthrenes/adverse effects , Sertoli Cells/drug effects , Testis/drug effects , Animals , Caspase 3/metabolism , Cytochromes c/metabolism , Epoxy Compounds/adverse effects , JNK Mitogen-Activated Protein Kinases/metabolism , Male , Membrane Potential, Mitochondrial/drug effects , Mice, Inbred ICR , NF-E2-Related Factor 2/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Reactive Oxygen Species/metabolism , Sertoli Cells/pathology , Signal Transduction/drug effects , Testis/pathology , bcl-2-Associated X Protein/metabolism
15.
Int J Mol Sci ; 19(2)2018 Jan 26.
Article in English | MEDLINE | ID: mdl-29373547

ABSTRACT

Triptolide (TP), a major extract of the herb Tripterygium wilfordii Hook F (TWHF), has been shown to exert potent pharmacological effects, especially an immunosuppressive effect in the treatment of rheumatoid arthritis (RA). However, its multiorgan toxicity prevents it from being widely used in clinical practice. Recently, several attempts are being performed to reduce TP toxicity. In this review, recent progress in the use of TP for RA, including its pharmacological effects and toxicity, is summarized. Meanwhile, strategies relying on chemical structural modifications, innovative delivery systems, and drug combinations to alleviate the disadvantages of TP are also reviewed. Furthermore, we also discuss the challenges and perspectives in their clinical translation.


Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Diterpenes/therapeutic use , Phenanthrenes/therapeutic use , Animals , Antirheumatic Agents/administration & dosage , Antirheumatic Agents/adverse effects , Diterpenes/administration & dosage , Diterpenes/adverse effects , Drug Evaluation, Preclinical , Epoxy Compounds/administration & dosage , Epoxy Compounds/adverse effects , Epoxy Compounds/therapeutic use , Humans , Phenanthrenes/administration & dosage , Phenanthrenes/adverse effects
16.
Rev Gaucha Enferm ; 39: e20180095, 2018 Nov 29.
Article in Portuguese, English | MEDLINE | ID: mdl-30517435

ABSTRACT

OBJECTIVE: To identify the adverse reactions associated with the infusion of hematopoietic stem cells on day zero of hematopoietic stem cell transplantation. METHODOLOGY: Integrative literature review, without temporal cut, with search in the following databases: PubMed, CINAHL, SCOPUS, BVS, SciELO, Web of Science and CAPES; the final sample consisted of 18 scientific articles, published between 1998 and 2017, based on the inclusion and exclusion criteria. RESULTS: Mild and moderate adverse reactions were the most frequent in studies that used the classification by severity, and nausea and emesis had the highest incidence; the most affected organ systems were the cardiovascular, respiratory and gastrointestinal. CONCLUSION: The main adverse reactions identified in the studies were nausea and emesis. Those classified as mild and moderate were the most frequent in the studies that used the severity classification; and the cardiovascular, respiratory and gastrointestinal systems were the most affected in those that used the classification by organic systems.


Subject(s)
Hematopoietic Stem Cell Transplantation/adverse effects , Postoperative Complications/etiology , Cardiovascular Diseases/etiology , Cryopreservation , Cryoprotective Agents , Epoxy Compounds/adverse effects , Gastrointestinal Diseases/etiology , Humans , Nausea/etiology , Respiration Disorders/etiology , Time Factors , Vomiting/etiology
17.
Biomacromolecules ; 18(5): 1473-1481, 2017 May 08.
Article in English | MEDLINE | ID: mdl-28391683

ABSTRACT

The development of synthetic and well-defined extracellular matrices that are free of xenogeneic components and are capable of inducing desired cellular responses holds great potential for use in vitro as 3D cell culture environments and in vivo as scaffolds for tissue regeneration. In this study, the impact of free and partially occupied epoxide groups on the viability, activity, and behavior of rat fibroblasts encapsulated in thermoresponsive hydrogels based on poly(N-isopropylacrylamide) (pNiPAAm) was investigated. While fibroblasts encapsulated in neat pNiPAAm remained rounded and showed significant toxicity by 5 days, those encapsulated in the epoxide-modified thermogels demonstrated not only high viability but also an ability to proliferate, attach, produce extracellular matrix (ECM) components, and cluster. The results demonstrated that the presence of free epoxide groups led to the local conjugation of available proteins to produce a modified structure in situ, which supported cell viability, activity, and cluster formation within the hydrogel.


Subject(s)
Epoxy Compounds/chemistry , Fibroblasts/drug effects , Hydrogels/chemistry , Tissue Scaffolds/chemistry , Acrylamides/chemistry , Animals , Cell Line , Cell Movement , Cell Proliferation , Cell Survival , Epoxy Compounds/adverse effects , Extracellular Matrix/drug effects , Fibroblasts/physiology , Hot Temperature , Hydrogels/adverse effects , Protein Binding , Rats , Tissue Scaffolds/adverse effects
18.
Diabetes Obes Metab ; 19(12): 1751-1761, 2017 12.
Article in English | MEDLINE | ID: mdl-28556449

ABSTRACT

AIMS: There are no treatments for the extreme hyperphagia and obesity in Prader-Willi syndrome (PWS). The bestPWS clinical trial assessed the efficacy, safety and tolerability of the methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib. MATERIALS AND METHODS: Participants with PWS (12-65 years old) were randomly assigned (1:1:1) to biweekly placebo, 1.8 mg beloranib or 2.4 mg beloranib injection for 26 weeks at 15 US sites. Co-primary endpoints were the changes in hyperphagia [measured by Hyperphagia Questionnaire for Clinical Trials (HQ-CT); possible score 0-36] and weight by intention-to-treat. ClinicalTrials.gov registration: NCT02179151. RESULTS: One-hundred and seven participants were included in the intention-to-treat analysis: placebo (n = 34); 1.8 mg beloranib (n = 36); or 2.4 mg beloranib (n = 37). Improvement (reduction) in HQ-CT total score was greater in the 1.8 mg (mean difference -6.3, 95% CI -9.6 to -3.0; P = .0003) and 2.4 mg beloranib groups (-7.0, 95% CI -10.5 to -3.6; P = .0001) vs placebo. Compared with placebo, weight change was greater with 1.8 mg (mean difference - 8.2%, 95% CI -10.8 to -5.6; P < .0001) and 2.4 mg beloranib (-9.5%, 95% CI -12.1 to -6.8; P < .0001). Injection site bruising was the most frequent adverse event with beloranib. Dosing was stopped early due to an imbalance in venous thrombotic events in beloranib-treated participants (2 fatal events of pulmonary embolism and 2 events of deep vein thrombosis) compared with placebo. CONCLUSIONS: MetAP2 inhibition with beloranib produced statistically significant and clinically meaningful improvements in hyperphagia-related behaviours and weight loss in participants with PWS. Although investigation of beloranib has ceased, inhibition of MetAP2 is a novel mechanism for treating hyperphagia and obesity.


Subject(s)
Aminopeptidases/antagonists & inhibitors , Appetite Depressants/therapeutic use , Cinnamates/therapeutic use , Cyclohexanes/therapeutic use , Epoxy Compounds/therapeutic use , Glycoproteins/antagonists & inhibitors , Hyperphagia/prevention & control , Obesity/prevention & control , Prader-Willi Syndrome/drug therapy , Protease Inhibitors/therapeutic use , Sesquiterpenes/therapeutic use , Adolescent , Adult , Aminopeptidases/metabolism , Appetite Depressants/administration & dosage , Appetite Depressants/adverse effects , Body Mass Index , Cinnamates/administration & dosage , Cinnamates/adverse effects , Cyclohexanes/administration & dosage , Cyclohexanes/adverse effects , Dose-Response Relationship, Drug , Double-Blind Method , Early Termination of Clinical Trials , Epoxy Compounds/administration & dosage , Epoxy Compounds/adverse effects , Female , Glycoproteins/metabolism , Humans , Hyperphagia/etiology , Hyperphagia/physiopathology , Intention to Treat Analysis , Male , Methionyl Aminopeptidases , Obesity/etiology , Prader-Willi Syndrome/physiopathology , Protease Inhibitors/administration & dosage , Protease Inhibitors/adverse effects , Sesquiterpenes/administration & dosage , Sesquiterpenes/adverse effects , Severity of Illness Index , Venous Thrombosis/chemically induced , Venous Thrombosis/physiopathology , Weight Loss/drug effects , Young Adult
19.
Diabetes Obes Metab ; 19(8): 1165-1170, 2017 08.
Article in English | MEDLINE | ID: mdl-28261955

ABSTRACT

AIMS: Hypothalamic injury-associated obesity (HIAO) results from damage to the hypothalamus that often occurs with surgical removal/radiation therapy of tumours in the hypothalamic region, such as craniopharyngioma. There is currently no rigorously studied pharmaceutical treatment for the intractable weight gain and cardiometabolic consequences that occur in patients with HIAO. We aimed to assess efficacy, safety and tolerability of beloranib treatment for 4 to 8 weeks in patients with HIAO. MATERIALS AND METHODS: This Phase 2a, double-blind, placebo-controlled study included 14 patients with HIAO, randomized to receive beloranib 1.8 mg or placebo subcutaneously twice weekly for 4 weeks with an optional 4-week open-label extension in which all patients received beloranib. The primary endpoint was change in weight from baseline to Week 4. RESULTS: Participants were 64% female, with a mean (SD) age of 32 (9) years, BMI of 43 (7) kg/m2 and weight of 126 (22) kg. Compared with placebo (N = 4), beloranib 1.8 mg (N = 8) resulted in a mean (95% CI) difference in weight of -3.2 (-5.4, -0.9) kg after 4 weeks. Weight loss continued through the 8 weeks in patients randomized to beloranib (mean -6.2 [-8.2, -4.1] kg). Beloranib treatment was associated with improvements in high-sensitivity CRP. Adverse events were mild to moderate. No patients who received beloranib discontinued treatment. CONCLUSION: Beloranib treatment resulted in progressive weight loss in patients with HIAO that was comparable to that observed with beloranib in patients with exogenous obesity. These findings indicate a novel mechanism for treating obesity in patients with HIAO.


Subject(s)
Aminopeptidases/antagonists & inhibitors , Appetite Depressants/therapeutic use , Cardiovascular Diseases/prevention & control , Cinnamates/therapeutic use , Cyclohexanes/therapeutic use , Epoxy Compounds/therapeutic use , Glycoproteins/antagonists & inhibitors , Hypothalamus/injuries , Metabolic Syndrome/prevention & control , Obesity, Morbid/drug therapy , Sesquiterpenes/therapeutic use , Adult , Aminopeptidases/metabolism , Appetite Depressants/administration & dosage , Appetite Depressants/adverse effects , Biomarkers/blood , Body Mass Index , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/etiology , Cinnamates/administration & dosage , Cinnamates/adverse effects , Cohort Studies , Cyclohexanes/administration & dosage , Cyclohexanes/adverse effects , Double-Blind Method , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/therapeutic use , Epoxy Compounds/administration & dosage , Epoxy Compounds/adverse effects , Female , Follow-Up Studies , Glycoproteins/metabolism , Humans , Injections, Subcutaneous , Male , Metabolic Syndrome/epidemiology , Metabolic Syndrome/etiology , Methionyl Aminopeptidases , Obesity, Morbid/blood , Obesity, Morbid/etiology , Obesity, Morbid/physiopathology , Proof of Concept Study , Risk , Sesquiterpenes/administration & dosage , Sesquiterpenes/adverse effects , Weight Loss/drug effects , Young Adult
20.
Occup Med (Lond) ; 67(9): 722-724, 2017 12 30.
Article in English | MEDLINE | ID: mdl-29040709

ABSTRACT

We describe a 43-year-old epoxy floor layer who developed work-related asthma while exposed to an epoxy hardener based on isophorone diamine (IPDA). Challenge exposures to the curing of the epoxy resin system and subsequently to the polyfunctional amine hardener containing IPDA both elicited delayed asthmatic reactions. This report further indicates that exposure to epoxy hardeners containing polyfunctional amines should be considered as a potential cause of occupational asthma. Appropriate work hygiene measures should be implemented to minimize airborne exposure to these volatile compounds.


Subject(s)
Asthma, Occupational/etiology , Epoxy Compounds/adverse effects , Adult , Asthma, Occupational/physiopathology , Dermatitis, Occupational/etiology , Dermatitis, Occupational/physiopathology , Humans , Male , Occupational Exposure/adverse effects
SELECTION OF CITATIONS
SEARCH DETAIL