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)

Leishmaniasis is a spectrum of diseases ranging in severity from cutaneous (CL), post-kala-azar dermal (PKDL), and diffuse cutaneous (DCL) to mucocutaneous (MCL) and visceral (VL) infections that are endemic in 86 tropical and subtropical countries around the world, accounting for 75,000 deaths per year. Different forms of leishmaniases are generally caused by different distinct species of Leishmania having a digenetic life cycle alternating between an aflagellated amastigote form replicative within the macrophages of the host and a flagellated promastigote form that multiplies within the gut of the sandfly. VL, MCL, PKDL, DCL, and CL forms of the disease can be arranged on a priority basis in accordance with the humoral immune responses of host. Generally, the cell-mediated immunity, particularly the delayed-type hypersensitivity to leishmanial antigens, is associated with CL, MCL, PKDL, and cured VL cases. The serodiagnosis of leishmaniasis appears to be an alternative to parasite detection in biopsy samples either by the staining of amastigotes or by culturing the amastigotes, which transform to a promastigote form and replicate. A battery of immunological procedures have been developed or adapted to demonstrate either humoral or cell-mediated immune responses against Leishmania for diagnosis and epidemiological survey. The sensitivity and specificity of such diagnostic methods depend on the type, source, and purity of antigen employed, as some of the leishmanial antigens have common cross-reactive epitopes shared with other microorganisms, particularly Trypanosoma, Mycobacteria, Plasmodia, and Schistosoma. Serodiagnostic techniques for the detection of antileishmanial antibodies have been employed with about 72 to 100, 23 to 90, 83, and 33 to 100% success in VL, CL, MCL, and PKDL patients, respectively. The Leishmanin skin test (LST) is useful to detect MCL and CL, with about 100 and 84% success, respectively. In PKDL, the gradual fall of antileishmanial antibody titer to some extent and the rise of delayed hypersensitivity to the parasite antigen are the characteristic features associated with the chronicity of the disease. The use of whole promastigote as the source of antigens in the direct agglutination test (DAT) and immunofluorescent test (IFAT) gave cross-reactions with the sera of leprosy, tuberculosis, and African trypanosomiasis patients. Again, the use of cell-free extracts of promastigotes generally gave false positive results with the sera of normal human and Chagas' disease, leprosy, tuberculosis, and malaria patients in enzyme-linked immunosorbent assay (ELISA), dot ELISA, immunodiffusion, immunoelectrophoresis, and counter-current immunoelectrophoresis tests.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Serodiagnosis of leishmaniasis. 763 32

Sensitivities and specificities of IgG subclasses-ELISA and IgG-indirect fluorescent antibody test (IFAT) against Leishmania braziliensis (Lb) and L. amazonensis (La) antigens were determined in 17 patients with mucosal (ML) and 19 with muco-cutaneous (MCL) leishmaniasis. Using IFAT-IgG both antigens gave high sensitivities and were statistically similar, being 89.5% with La and 100% with Lb. Using ELISA, the highest sensitivity was achieved with total IgG for ML (94.7% with both antigens) and MCL (100% with both antigens). Cross-reactivity, observed with Chagas disease and malaria sera reduced the specificity of the IgG-based assays, being 50 to 70% with IFAT and 40 to 70% with ELISA. An increase in specificity was obtained with IgG1-ELISA (90% with Lb and 100% with La). Serum levels of anti-Lb-IgG and IgG3 dropped 90 days after treatment. IgG subclasses antibody detection constitute an valuable alternative to increase the efficiency of sorological diagnostics of ML/MCL.
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PMID:Antibody subclass profile against Leishmania braziliensis and Leishmania amazonensis in the diagnosis and follow-up of mucosal leishmaniasis. 1459 66

Farnesyltransferase inhibitors (FTIs) have mainly been used in cancer therapy. However, more recently, investigations on these inhibitors revealed that FTIs can be used for the treatment of other diseases such as Progeria, P. falciparum resistant malaria, Trypnosomatid, etc. Hence the development of novel FTIs is an important task for the drug discovery program. Initially, numerous peptidomimetic FTIs were developed from the template of CAAX (CVIM was the first pharmacophore model used as a peptidomimetic). Later, many non-peptidomimetic FTIs have been discovered with the structural modification of the peptidomimetics. The structural analysis of those developed FTIs by various researchers suggested that the presence of a heterocycle or a polar group in place of the thiol group is required for interaction with the Zn(2+) ion. The bulky naphthyl, quinolinyl, phenyl, phenothazine, etc in this position provide better hydrophobicity to the molecules which interact with the aromatic amino acid moieties in the hydrophobic pocket. A hydrophilic region with polar groups is necessary for the polar or hydrogen bonding interactions with the amino acids or water molecules in the active site. Many FTIs have been isolated from natural products, which possessed inhibitory activity against farnesyltransferase (FTase). Among them, pepticinnamin E (9R), fusidienol (9T), gliotoxin (9V), cylindrol A (9X), etc possessed potential FTase inhibitory activities and their structural features are comparable to those of the synthetic molecules. The clinical studies progressing on FTIs showed that tipifarnib in combination with bortezomib is used for the treatment of patients with advanced acute leukemias. Successful phase I and II studies are undergoing for tipifarnib alone or in combination with other drugs/radiation for the treatment of multiple myeloma, AML, breast cancer, mantle cell lymphoma, solid tumors, non-small cell lung cancer (NSCLC), pancreatic cancer, glioblastoma, etc. Phase I pharmacokinetic (maximum tolerated dose, toxicity) and pharmacodynamic studies of AZD3409 (an orally active double prodrug) is progressing on patients with solid malignancies taking 500 mg once a day. A phase II study is undergoing on lonafarnib alone and in combination with zoledronic acid and pravastatin for the treatment of Hutchinson-Gilford Progeria syndrome (HGPS) and progeroid laminopathies. Lonafarnib therapy improved cardiovascular status of children with HGPS, by improved peripheral arterial stiffness, bone structure and audiological status in the patients. Other important FTIs such as BMS-214662, LB42908, LB42708, etc are under clinical studies for the treatment of various cancers. This review concluded that the quantitative structural analysis report with an elaborative study on the natural product compounds provides ideas for development of novel molecules for the FTase inhibitory activity. The fragment based analysis is also needed to select the substituents, which provides significant inhibitory activities and can also have good pharmacokinetic properties in the clinical studies.
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PMID:Farnesyltransferase inhibitors: a comprehensive review based on quantitative structural analysis. 2405 35

Currently, no therapeutic options exist for castration-resistant prostate cancer (CRPC) patients who have developed resistance to the second generation anti-androgen receptor (AR) axis therapy. Here we report that co-deletion of Pten and p53 in murine prostate epithelium, often observed in human CRPC, leads to AR-independent CRPC and thus confers de novo resistance to second generation androgen deprivation therapy (ADT) in multiple independent yet complementary preclinical mouse models. In contrast, mechanism-driven co-targeting hexokinase 2 (HK2)-mediated Warburg effect with 2-deoxyglucose (2-DG) and ULK1-dependent autophagy with chloroquine (CQ) selectively kills cancer cells through intrinsic apoptosis to cause tumor regression in xenograft, leads to a near-complete tumor suppression and remarkably extends survival in Pten-/p53-deficiency-driven CRPC mouse model. Mechanistically, 2-DG causes AMPK phosphorylation, which in turn inhibits mTORC1-S6K1 translation signaling to preferentially block anti-apoptotic protein MCL-l synthesis to prime mitochondria-dependent apoptosis while simultaneously activates ULK1-driven autophagy for cell survival to counteract the apoptotic action of anti-Warburg effect. Accordingly, inhibition of autophagy with CQ sensitizes cancer cells to apoptosis upon 2-DG challenge. Given that 2-DG is recommended for phase II clinical trials for prostate cancer and CQ has been clinically used as an anti-malaria drug for many decades, the preclinical results from our proof-of-principle studies in vivo are imminently translatable to clinical trials to evaluate the therapeutic efficacy by the combination modality for a subset of currently incurable CRPC harboring PTEN and TP53 mutations.
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PMID:Co-targeting hexokinase 2-mediated Warburg effect and ULK1-dependent autophagy suppresses tumor growth of PTEN- and TP53-deficiency-driven castration-resistant prostate cancer. 2732 58

The myosin superfamily comprises of actin-dependent eukaryotic molecular motors important in a variety of cellular functions. Although well studied in many systems, knowledge of their functions in Plasmodium, the causative agent of malaria, is restricted. Previously, six myosins were identified in this genus, including three Class XIV myosins found only in Apicomplexa and some Ciliates. The well characterized MyoA is a Class XIV myosin essential for gliding motility and invasion. Here, we characterize all other Plasmodium myosins throughout the parasite life cycle and show that they have very diverse patterns of expression and cellular location. MyoB and MyoE, the other two Class XIV myosins, are expressed in all invasive stages, with apical and basal locations, respectively. Gene deletion revealed that MyoE is involved in sporozoite traversal, MyoF and MyoK are likely essential in the asexual blood stages, and MyoJ and MyoB are not essential. Both MyoB and its essential light chain (MCL-B) are localised at the apical end of ookinetes but expressed at completely different time points. This work provides a better understanding of the role of actomyosin motors in Apicomplexan parasites, particularly in the motile and invasive stages of Plasmodium during sexual and asexual development within the mosquito.
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PMID:Systematic analysis of Plasmodium myosins reveals differential expression, localisation, and function in invasive and proliferative parasite stages. 3128 2