Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chloroquine and related anti-malarial drugs appear to promote apoptosis in T-cells by suppressing NF-kappa-B, which enhances the expression of anti-apoptotic proteins (e.g., Bcl-2). Thus, chloroquine has found applications in autoimmune diseases where it apparently facilitates apoptosis of abnormally persistent T-cell clones. The mode of action of chloroquine in prevention of malaria is not known, but it may be to minimize replication of the parasite in the liver cells, which occurs before invasion of the erythrocytes, by facilitating premature apoptosis of the infected host cells. After introduction of chloroquine in the 1950s world-wide for prophylactic use, chloroquine-resistant malaria emerged. Here it is hypothesized that concurrent with emergence of chloroquine-resistant malaria (presumably with enhanced anti-apoptotic capabilities), other intracellular parasites have evolved to enhance their ability to prevent apoptosis in host cells. Two examples of viral diseases that have emerged from areas of high incidence of chloroquine-resistant malaria are AIDS from HIV and SARS from coronavirus. The hypothesis holds that prophylactic exposure to pro-apoptotic chloroquine drugs caused natural selection for strains of viruses and other parasites that have enhanced anti-apoptotic abilities. When transmitted to host organisms that are not under the influence of the pro-apoptotic drug, the new "anti-apoptotic" strains may cause unexpected diseases. In the case of SARS, the coronavirus appears to have accessed a new niche where it proves to be lethal to its host. In the case of AIDS, the HIV (which has had a long-term symbiotic relationship with primates) has run amuck because the infected cells are now substantially more tolerant to the toxins (i.e., resistant to apoptosis) that they secrete than the uninfected bystander cells, which are not unusually resistant to apoptosis. A corollary to the hypothesis is that if the level of resistance to apoptosis in the infected cells were no higher than the level of resistance in the bystander cells, then the infected cells would preferentially kill themselves through apoptosis. It appears that in the case of HIV, the increased resistance to apoptosis is provided by expression of Bcl-2 and suppression of p53. Hence, drugs that suppresses Bcl-2 or restore p53 function might be effective in restoring the parity of resistance to apoptosis between infected and uninfected cells. Currently, an antisense drug targeting Bcl-2 (G3139/Genasense(TM), Genta, Inc.) is in late-stage cancer trials and may be on the market for those indications in months. It would be interesting to try these drugs against various intracellular parasites including HIV. This approach to prevent or eliminate active infections might be particularly attractive against a range of parasites (virus, bacteria, protozoa, fungus) when safe and effective vaccines are not available.
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PMID:Hypothesis links emergence of chloroquine-resistant malaria and other intracellular pathogens and suggests a new strategy for treatment of diseases caused by intracellular parasites. 1497 2

Hepatic dysfunction is a common clinical complication in malaria, although its pathogenesis remains largely unknown. Using a variety of in vivo and ex vivo approaches, we have shown for the first time that malarial infection induces hepatic apoptosis through augmentation of oxidative stress. Apoptosis in hepatocyte has been confirmed by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin-nick-end labeling assay (TUNEL) and caspase-3 activation. Gene expression analysis using RT-PCR indicates the significant down-regulation of Bcl-2 and up-regulation of Bax expression in liver of malaria infected mice suggesting the involvement of mitochondrial pathway of apoptosis. The levels of Fas expression and caspase-8 activity in infected liver were same as that of uninfected control mice indicating death receptor (Fas) pathway did not contribute to liver apoptosis during malarial infection. Moreover, evidence has been presented by confocal microscopy to show the translocation of Bax from cytosol to mitochondria in apoptotic hepatocyte, resulting in opening of permeability transition pores, which in turn decreases mitochondrial membrane potential and induces cytochrome c release into cytosol. Malarial infection induces the generation of hydroxyl radical (*OH) in liver, which may be responsible for the induction of oxidative stress and apoptosis as administration of *OH specific antioxidant as well as spin trap, alpha-phenyl-tert-butyl-nitrone in malaria-infected mice significantly inhibits the development of oxidative stress as well as induction of apoptosis. Thus, results suggest the implication of oxidative stress induced-mitochondrial pathway of apoptosis in the pathophysiology of hepatic dysfunction in malaria.
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PMID:Apoptosis in liver during malaria: role of oxidative stress and implication of mitochondrial pathway. 1660 2

Chloroquine (CLQ) and Pyrimethamine (PYR) are used for the treatment of malaria and some autoimmune diseases; although their mechanism of action is only partially understood, their therapeutic effectiveness in the second case has been attributed to their ability to increase apoptosis of T lymphocytes. In view of the potential for immunomodulation during malaria chemotherapy, we investigated the effects of CLQ and PYR treatment on lymphocyte apoptosis and cytokine expression during infection with blood-stage Plasmodium. This work shows that infection of BALB/c mice with Plasmodium yoelii 17XL (Py17XL) reduced apoptosis in spleen cells but when infected mice were treated with CLQ, apoptosis of B and T lymphocytes increased significantly via a Fas-mRNA expression independent mechanism associated with downregulation of Bcl-2 expression, whereas treatment with PYR increased apoptosis to a lesser extent and only in B lymphocytes. CLQ treatment of Py17XL infected mice upregulated tumour necrosis factor-alpha mRNA expression, while PYR treatment increased interferon-gamma mRNA expression. In infected mice, treatment with CLQ downregulated expression of the anti-inflammatory cytokines, interleukin-10 and transforming growth factor-beta (TGF-beta), while PYR treatment upregulated TGF-beta. Thus, in addition to their anti-malarial effects, both drugs modulate the immune response in malaria by increasing apoptosis and modulating the mRNA expression of cytokines involved in parasite elimination and regulation of inflammatory responses.
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PMID:Immunomodulatory role of chloroquine and pyrimethamine in Plasmodium yoelii 17XL infected mice. 1721 67

Chloroquine (CQ) is used to treat malaria and a variety of inflammatory diseases including systemic lupus erythematosus and rheumatoid arthritis. However, CQ is known to cause cytotoxicity of which mechanism is still uncertain. This study investigated the molecular mechanism responsible for the cell death in CQ-treated A172 human glioblastoma cells. CQ-induced apoptotic cell death of the cells in a time- and concentration-dependent manner. CQ also increased the production of nitric oxide in the cells. However, the pretreatment with aminoguanidine (AG) and N-Omega-nitro-l-arginine methyl ester (NAME), nitric oxide synthase inhibitors, did not block the CQ-induced cell death. In contrast to NO level increase, the level of intracellular reactive oxygen species (ROS) and their extracellular release were transiently and mildly increased by CQ. In addition, CQ depleted cellular GSH content, which was accompanied with time-dependent increase in GSH peroxidase without any significant change in GSH reductase activity. Glutathione (GSH) S-transferase activity was only transiently increased at 15 min treatment with CQ. Furthermore, the CQ-induced cell death was significantly suppressed when intracellular GSH decrease was prevented by the pretreatment with N-acetylcysteine (NAC) or glutathione ethylester (GSH-EE). At the same time, the pretreatment of the cells with NAC and GSH-EE significantly blocked the CQ-induced NO increase, representing that CQ-induced NO increase was resulted from the depletion of GSH. CQ also induced time-dependent increase in Bax level and caspase-3 activity with no change in Bcl-2 level. Overall, these results suggest that CQ-induced NO increase and cell death are dependent on GSH depletion, the cellular redox changes.
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PMID:Chloroquine-induced nitric oxide increase and cell death is dependent on cellular GSH depletion in A172 human glioblastoma cells. 1835 72

Cerebral malaria is responsible for a high proportion of mortality in human Plasmodium falciparum infection. Previous studies have reported the presence of apoptosis in endothelial cells, astrocytes, neurons, and glial cells in experimental murine cerebral malaria caused by infection with Plasmodium berghei ANKA. Using this model, we tested two strategies, which have been shown to improve survival in murine models of sepsis: 1) treatment with z-VAD, a pancaspase inhibitor; and 2) overexpression of Bcl-2 using transgenic mice expressing human Bcl-2 (which prevents the release of apoptotic mediators from the mitochondria) from a myeloid cell promoter. Neither of these anti-apoptotic strategies, previously shown to provide therapeutic benefit in sepsis, improved survival in experimental cerebral malaria.
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PMID:Failure of two distinct anti-apoptotic approaches to reduce mortality in experimental cerebral malaria. 1905 86

Regulatory T cells (Treg) play crucial roles in regulating autoimmune responses and immunity to tumors and infectious diseases. However, numerous subpopulations of Treg are now being described and the utility of various Treg markers is being reassessed. Here we report the results of a detailed phenotypic comparison of two supposedly regulatory human T-cell populations, namely CD4+FOXP3+ T cells and CD4+CD25hi T cells. We find that CD4+FOXP3+ cells are extremely heterogeneous with respect to CD25 expression and that FOXP3+ and CD25hi CD4+ T cells differ in their expression of chemokine receptors (CCR), CD95 and Bcl-2, suggestive of distinct migration characteristics and susceptibility to apoptosis. Further, we propose that CD25 expression should be regarded as an activation marker rather than as a defining marker of Treg. Lastly, CD4+FOXP3+ T cells activated in vitro with malaria antigen expressed the highest levels of CCR4 and CD95, and the lowest levels of CCR7, indicating that they are most likely generated from effector memory cells during an immune response and rapidly succumb to apoptosis at the end of the response.
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PMID:Phenotypic analysis of human peripheral blood regulatory T cells (CD4+FOXP3+CD127lo/-) ex vivo and after in vitro restimulation with malaria antigens. 1987 16

Quinacrine has been widely explored in treatment of malaria, giardiasis, and rheumatic diseases. We find that quinacrine stabilizes p53 and induces p53-dependent and independent cell death. Treatment by quinacrine alone at concentrations of 10-20 mM for 1-2 d cannot kill hepatocellular carcinoma cells, such as HepG2, Hep3B, Huh7, which are also resistant to TRAIL. However, quinacrine renders these cells sensitive to treatment by TRAIL. Co-treatment of these cells with quinacrine and TRAIL induces overwhelming cell death within 3-4 h. Levels of DR5, a pro-apoptotic death receptor of TRAIL, are increased upon treatment with quinacrine, while levels of Mcl-1, an anti-apoptotic member of the Bcl-2 family, are decreased. While the synergistic effect of quinacrine with TRAIL appears to be in part independent of p53, knockdown of p53 in HepG2 cells by siRNA results in more cell death after treatment by quinacrine and TRAIL. The mechanism by which quinacrine sensitizes hepatocellular carcinoma cells to TRAIL and chemotherapies, and the potential for clinical application currently are being further explored. Lastly, quinacrine synergizes with chemotherapeutics, such as adriamycin, 5-FU, etoposide, CPT11, sorafenib, and gemcitabine, in killing hepatocellular carcinoma cells in vitro and the drug enhances the activity of sorafenib to delay tumor growth in vivo.
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PMID:Quinacrine sensitizes hepatocellular carcinoma cells to TRAIL and chemotherapeutic agents. 2172 12

Although the anti-malaria drug chloroquine (CQ) has been shown to enhance chemotherapy and radiation sensitivity in clinical trials, the potential mechanisms underlying this enhancement are still unclear. Here, we examined the relevant mechanisms by which the multipotent CQ enhanced the cytotoxicity of topotecan (TPT). The lung cancer cell line A549 was treated with TPT alone or TPT combined with CQ at non-cytotoxic concentrations. Cell viability was assessed using the MTT assay. The percentage of apoptotic cells and the presence of a side population of cells were both determined by flow cytometry. Autophagy and the expression of Bcl-2 family proteins were examined by Western blotting. The accumulation of YFP-LC3 dots and the formation of acidic vesicular organelles were examined by confocal microscopy. CQ sensitized A549 cells to TPT and enhanced TPT-induced apoptosis in a Bcl-2 family protein-independent fashion. CQ inhibited TPT-induced autophagy, which modified the cytotoxicity of TPT. However, CQ failed to modify the transfer of TPT across the cytoplasmic membrane and did not increase lysosomal permeability. This study showed that CQ at non-cytotoxic concentrations potentiated the cytotoxicity of TPT by interfering with autophagy, implying that CQ has significant potential as a chemotherapeutic enhancer.
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PMID:Chloroquine enhances the cytotoxicity of topotecan by inhibiting autophagy in lung cancer cells. 2195 46

Placental malaria is a common clinical complication during pregnancy and is associated with abortion, premature delivery, intrauterine growth retardation and low birth weight. The present study was designed to delineate the underlying mechanism of placental pathology during malarial infection with special reference to oxidative stress and apoptosis. Experimentally, pregnant BALB/c mice were infected with Plasmodium berghei infected red blood cells on gestation day 10. The presence of malarial infection in placenta was confirmed by histopathological studies. It was observation that infected placenta had plugged placental sinusoids with parasitized red blood cells and malarial pigments. Interestingly, we found significant increase in the level of malondialdehyde, the index of oxidative stress and decreased activity of catalase, the antioxidant in infected placenta. Furthermore, in infected placenta the oxidative stress mediated apoptosis was determined by DNA fragmentation assay, ethidium bromide/acridine orange staining and caspase activity. It was observed that oxidative stress begin after second day of malarial infection. Interestingly, it was observed that there was down regulation of anti-apoptotic protein Bcl-2 and up regulation of pro-apoptotic protein Bax in infected placenta, suggesting the involvement of mitochondrial pathway of apoptosis which was further confirmed by activation of caspase 9. However, no change in the expression of Fas gene and caspase 8 activity, indicated the absence of death receptor pathway. Thus, it can be concluded that the placental pathology during malarial infection is mediated by mitochondrial pathway of apoptosis occurring due to augmented lipid peroxidation which may in turn jeopardise the materno-fetal relationship.
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PMID:Role of oxidative stress and apoptosis in the placental pathology of Plasmodium berghei infected mice. 2239 90

The inability to acquire protective immunity against Plasmodia is the chief obstacle to malaria control, and inadequate T-cell responses may facilitate persistent blood-stage infection. Malaria is characterized by a highly inflammatory cytokine milieu, and the lack of effective protection against infection suggests that memory T cells are not adequately formed or maintained. Using a genetically targeted strain of Plasmodium berghei, we observed that the Plasmodium ortholog of macrophage migration inhibitory factor enhanced inflammatory cytokine production and also induced antigen-experienced CD4 T cells to develop into short-lived effector cells rather than memory precursor cells. The short-lived effector CD4 T cells were more susceptible to Bcl-2-associated apoptosis, resulting in decreased CD4 T-cell recall responses against challenge infections. These findings indicate that Plasmodia actively interfere with the development of immunological memory and may account for the evolutionary conservation of parasite macrophage migration inhibitory factor orthologs.
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PMID:A Plasmodium-encoded cytokine suppresses T-cell immunity during malaria. 2277 13


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