Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the effects of bucillamine and N-acetyl-L-cysteine (NAC) on cytokine production and CIA. Bucillamine and NAC inhibited NF-kappaB activation and tumour necrosis factor-alpha (TNF-alpha) mRNA expression in human monocytic leukaemia cell line THP-1, and cytokine production from monocyte cell lines at concentrations >10-3 M. They also inhibited cytokine production and CIA in mice at a dose of 500 mg/kg. These results suggest that NF-kappaB inhibitors such as bucillamine and NAC may inhibit cytokine-related diseases, including arthritis.
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PMID:Effects of bucillamine and N-acetyl-L-cysteine on cytokine production and collagen-induced arthritis (CIA). 993 17

In the era of personalized medical practice, understanding the genetic basis of patient-specific adverse drug reaction (ADR) is a major challenge. Clozapine provides effective treatments for schizophrenia but its usage is limited because of life-threatening agranulocytosis. A recent high impact study showed the necessity of moving clozapine to a first line drug, thus identifying the biomarkers for drug-induced agranulocytosis has become important. Here we report a methodology termed as antithesis chemical-protein interactome (CPI), which utilizes the docking method to mimic the differences in the drug-protein interactions across a panel of human proteins. Using this method, we identified HSPA1A, a known susceptibility gene for CIA, to be the off-target of clozapine. Furthermore, the mRNA expression of HSPA1A-related genes (off-target associated systems) was also found to be differentially expressed in clozapine treated leukemia cell line. Apart from identifying the CIA causal genes we identified several novel candidate genes which could be responsible for agranulocytosis. Proteins related to reactive oxygen clearance system, such as oxidoreductases and glutathione metabolite enzymes, were significantly enriched in the antithesis CPI. This methodology conducted a multi-dimensional analysis of drugs' perturbation to the biological system, investigating both the off-targets and the associated off-systems to explore the molecular basis of an adverse event or the new uses for old drugs.
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PMID:Exploring off-targets and off-systems for adverse drug reactions via chemical-protein interactome--clozapine-induced agranulocytosis as a case study. 2148 81

Leukemic stem cells (LSCs) are a very rare cell population that result in the development of acute myeloid leukemia (AML). The selective targeting of drivers in LSCs with small molecule inhibitors holds promise for treatment of AML. Recently, we reported the identification of inhibitors of the histone lysine demethylase JMJD1C that preferentially kill MLL rearranged acute leukemia cells. Here, we report the identification of JMJD1C Jumomji domain Modulator 7 (JDM-7). Surface plasmon resonance (SPR) analysis showed that JDM-7 binds to JMJD1C and its family homolog JMJD1B. JDM-7 did not significantly suppress cell proliferation in liquid cell culture at higher doses, but led to a significant decrease in semi-solid colony formation experiments at lower concentrations. Moreover, low doses of JDM-7 did not suppress the proliferation of erythroid progenitor cells. We identified that JDM-7 downregulates the LSC self-renewal gene HOXA9 in leukemia cells. We further found that the structure of JDM-7 is similar to that of Tadalafil, an FDA approved drug. Molecular docking and surface plasmon resonance (SPR) analysis showed that Tadalafil binds to JMJD1C. Moreover, like JDM-7, Tadalafil suppressed colony formation of leukemia cells in semi-solid cell culture at a concentration that did not affect primary umbilical cord blood cells. In summary, we have identified JDM-7 and Tadalafil as potential JMJD1C modulators that selectively inhibit the growth of LSCs.
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PMID:Modulators of histone demethylase JMJD1C selectively target leukemic stem cells. 3328 99