After entering the body, aflatoxin B1 is metabolized in the liver by microsomal monooxygenases to the less toxic reactive intermediates aflatoxin M1 and aflatoxin Q1. After aflatoxin B1 is epoxidated to aflatoxin B1 2,3-oxide, it is detoxified by glutathione S-transferases. (L1877, L1956, A2972)
Aflatoxin B1 requires epoxidation to aflatoxin B1 2,3-oxide for activation, which is performed by cytochome P-450 enzymes CYP1A2 and CYP3A4. It produces DNA damage, gene mutation and chromosomal anomalies. Aflatoxins produce singlet oxygen upon their exposure to UV (365-nm) light. Singlet oxygen in turn activates them to mutagens and DNA binding species. Aflatoxin metabolites can intercalate into DNA and alkylate the bases through their epoxide moiety, binding particularity to N7-guanine bases. In addition to randomly mutating DNA, this is thought to cause mutations in the p53 gene, an important gene in preventing cell cycle progression when there are DNA mutations, or signaling apoptosis. Mycotoxins are often able to enter the liver and kidney by human organic anion transporters (hOATs) and human organic cation transporters (hOCTs). They can also inhibit uptake of anions and cations by these transporters, interefering with the secretion of endogenous metabolites, drugs, and xenobiotics including themselves. This results in increased cellular accumulation of toxic compounds causing nephro- and hepatotoxicity. (L1877, A2859, A2972, A3014)
The main target organ in mammals is the liver so aflatoxicosis is primarily a hepatic disease. Protracted exposure to aflatoxins may cause liver damage and necrosis, cholestasis, and hepatomas. Moreover, protracted exposure to aflatoxins has been associated with hepatocellular carcinoma, acute hepatitis, Reye's syndrome, bile duct cell proliferation, periportal fibrosis, hemorrhages, mucous membrane jaundice, fatty liver changes, cirrhosis in malnourished children, and kwashiorkor. However, aflatoxins accumulate in the presence of liver disease, and the association with hepatic cancer is confounded by the occurrence of hepatitis-B. Thus, it is not clear in these various instances whether aflatoxin is a primary cause of the disease, is an innocent bystander which accumulates secondary to the disease process, or is a contributing cause in conjunction with other factors. It is also mutagenic and teratogenic. Inhaled aflatoxins may produce pulmonary adenomatosis. Aflatoxins modify the immune system by affecting antibody formation, complement, cell-mediated immunity, and phagocytosis. (A704, L1956)
来源:Toxin and Toxin Target Database (T3DB)
毒理性
暴露途径
口服、皮肤、吸入和 parenteral（被污染的药物）。 (A3101)
Oral, dermal, inhalation, and parenteral (contaminated drugs). (A3101)
来源:Toxin and Toxin Target Database (T3DB)
毒理性
症状
根据剂量的不同，可能会出现一系列广泛的症状，包括呕吐、腹痛、出血和肺水肿。
A broad range of symptoms can be found depending upon dosage, including, vomiting, abdominal pain, hemorrhage, and pulmonary edema. (L1879)
Effect of dietary restriction on glutathione S-transferase activity specific toward aflatoxin B1-8,9-epoxide
摘要：
Dietary restriction (DR) reduced the metabolic activation of aflatoxin B1 (AFB(1)) in rats, This reduction may be attributed to the decrease of cytochrome P-450-mediated AFB(1) epoxidation and/or increase in the detoxification of AFB(1) catalyzed by hepatic glutathione S-transferase (GST) and other phase II detoxification enzymes. In this study the effect of DR on male rat liver cytosolic GST activity toward AFB(1)-8,9-epoxide was studied. The chemically-synthesized AFB(1)-8,9-epoxide was used as the substrate in this assay, and the formation of AFB(1)-GSH conjugate was analyzed by HPLC. Male Fischer 344 rats fed DR diets (60% of the food consumption of ad libitum (AL)-fed rats) showed a 2.4-fold increase in GST activity when AFB(1)-epoxide was used as the substrate. The results from the enzyme kinetic study showed that DR increased V-max of the liver cytosolic GST but not the K-m. Acute DR has little or no impact on GST activity when 1-chloro-2,4-dinitrobenzene and 2,4-dichloronitrobenzene were used as substrates. The mouse liver GST activity toward AFB(1)-epoxide was 3-fold greater than that of phenobarbital-induced rats, 4.5-fold greater than DR rats, and 14.7-fold greater than the GST activity of AL rats, This direct assay of liver GST activity using AFB(1)-epoxide as the substrate is useful for studying AFB(1)-induced biomarkers, such as AFB(1)-GSH conjugation and AFB(1)-DNA adducts.
The present invention encompasses novel triterpene compounds of general formula I
wherein
R3a R3b R11a R11b R31 and R32 are defined as in claim 1, which are suitable for the prevention and/or treatment of diseases mediated by 11β-HSD and the use thereof for preparing a medicament having the above-mentioned properties.
[EN] HETEROCYCLIC LSF INHIBITORS AND THEIR USES<br/>[FR] INHIBITEURS DE LSF HÉTÉROCYCLES ET LEURS UTILISATIONS
申请人：UNIV BOSTON
公开号：WO2021150835A1
公开（公告）日：2021-07-29
The present invention is directed to heterocyclic SV40 Factor (LSF) inhibitors and their uses. In some implementations, the present invention discloses small-molecule compounds of Formula (I). In some implementations, the compounds of Formula (I) are used in methods for inhibiting LSF in a subject. In some implementations, the compounds of Formula (I) are used in methods for treating cancer in a subject.
The present invention encompasses compounds of general formula (I) wherein R11a to R30 and X are defined as in claim 1, which are suitable for the treatment of and/or prevention of chronic inflammatory diseases, autoimmune diseases, skin diseases, bone diseases, metabolic diseases, infectious diseases and cancer.
COMPOUNDS AS MODULATOR OF JAK-STAT PATHWAY, METHODS AND APPLICATIONS THEREOF
申请人：UNIVERSITY OF MYSORE
公开号：US20160214968A1
公开（公告）日：2016-07-28
The present disclosure relates to compound of structural Formula I and a method for preparing said compounds. The disclosure further relates to a method of employing the Formula I compounds for modulation of Janus kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway in cancer cells, and the corresponding use of compound of Formula I as anti-cancer agents.
Disclosed herein are methods, compositions, probes, assays and kits for identifying a lipid binding protein as a drug binding target. Also disclosed herein are methods, compositions, and probes for mapping a ligand binding site on a lipid binding protein, identification of lipid binding proteins, generating drug-lipid binding protein profiles, high throughput drug screening, and identification of drugs as potential lipid binding protein ligands.
