Repurposing Glyburide as Antileishmanial Agent to Fight Against Leishmaniasis

2019 ◽  
Vol 26 (5) ◽  
pp. 371-376 ◽  
Author(s):  
Abdur Rub ◽  
Kamal Shaker ◽  
Mohammad Kashif ◽  
Mohd Arish ◽  
Abdul Aziz Bin Dukhyil ◽  
...  
Keyword(s):  
Leishmania Donovani ◽  
Culture Media ◽  
Drug Repurposing ◽  
Parasite Growth ◽  
High Rate ◽  
Mammalian Host ◽  
Dependent Manner ◽  
The World

Background: Leishmaniasis is caused by a protozoan parasite, Leishmania. It is common in more than 98 countries throughout the world. Due to insufficient availability of antileishmanial chemotherapeutics, it is an urgent need to search for new molecules which have better efficacy, low toxicity and are available at low cost. Objectives: There is a high rate of diabetic cases throughout the world that is why we planned to test the antileishmanial activity of glyburide, an effective sugar lowering drug used for the treatment of diabetes. In this study, glyburide showed a significant decrease in the parasite growth and survival in vitro in a dose-dependent manner. Methods: Anti-leishmanial activity of glyburide was checked by culturing Leishmania donovani promastigotes in the presence of glyburide in a dose and time dependent manner. Docking study against Leishmania donovani-Trypanothione synthetase (LdTrySyn) protein was performed using Autodock Vina tool. Results: Growth reversibility assay shows that growth of treated parasite was not reversed when transferred to fresh culture media after 7 days. Moreover, docking studies show efficient interactions of glyburide with key residues in the catalytic site of Leishmania donovani- Trypanothione synthetase (LdTrySyn), a very important leishmanial enzyme involved in parasite’s survival by detoxification of Nitric Oxide (NO) species, generated by the mammalian host as a defense molecule. Thus this study proves that the drug-repurposing is a beneficial strategy for identification of new and potent antileishmanial molecules. Conclusion: The results suggest that glyburide binds to LdTrySyn and inhibits its activity which further leads to the altered parasite morphology and inhibition of parasite growth. Glyburide may also be used in combination with other anti-leishmanial drugs to potentiate the response of the chemotherapy. Overall this study provides information about combination therapy as well as a single drug treatment for the infected patients suffering from diabetes. This study also provides raw information for further in vivo disease model studies to confirm the hypothesis.

scholarly journals Cell Cycle Inhibition To Treat Sleeping Sickness

mBio ◽  
2017 ◽  
Vol 8 (5) ◽  
Author(s):  
Conrad L. Epting ◽  
Brian T. Emmer ◽  
Nga Y. Du ◽  
Joann M. Taylor ◽  
Ming Y. Makanji ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Ribonucleotide Reductase ◽  
De Novo ◽  
Protozoan Parasite ◽  
Parasite Growth ◽  
High Rate ◽  
Mammalian Host ◽  
African Trypanosomiasis

ABSTRACTAfrican trypanosomiasis is caused by infection with the protozoan parasiteTrypanosoma brucei. During infection, this pathogen divides rapidly to high density in the bloodstream of its mammalian host in a manner similar to that of leukemia. Like all eukaryotes,T. bruceihas a cell cycle involving thede novosynthesis of DNA regulated by ribonucleotide reductase (RNR), which catalyzes the conversion of ribonucleotides into their deoxy form. As an essential enzyme for the cell cycle, RNR is a common target for cancer chemotherapy. We hypothesized that inhibition of RNR by genetic or pharmacological means would impair parasite growthin vitroand prolong the survival of infected animals. Our results demonstrate that RNR inhibition is highly effective in suppressing parasite growth bothin vitroandin vivo. These results support drug discovery efforts targeting the cell cycle, not only for African trypanosomiasis but possibly also for other infections by eukaryotic pathogens.IMPORTANCEThe development of drugs to treat infections with eukaryotic pathogens is challenging because many key virulence factors have closely related homologues in humans. Drug toxicity greatly limits these development efforts. For pathogens that replicate at a high rate, especially in the blood, an alternative approach is to target the cell cycle directly, much as is done to treat some hematologic malignancies. The results presented here indicate that targeting the cell cycle via inhibition of ribonucleotide reductase is effective at killing trypanosomes and prolonging the survival of infected animals.

scholarly journals Expression of a Mycobacterium tuberculosis Arabinomannan Antigen In Vitro and In Vivo

2001 ◽  
Vol 69 (9) ◽  
pp. 5671-5678 ◽  
Author(s):  
J. Reid Schwebach ◽  
Arturo Casadevall ◽  
Rachel Schneerson ◽  
Zhongdong Dai ◽  
Xiaojuan Wang ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Culture Media ◽  
Extended Period ◽  
Tween 80 ◽  
Surface Expression ◽  
Dependent Manner ◽  
Bacteria Growth ◽  
Growth Changes

ABSTRACT The outermost layer of Mycobacterium tuberculosiscontains two major polysaccharides, arabinomannan (AM) and glucan (GC). We studied the in vitro and in vivo expression of anM. tuberculosis AM antigen using monoclonal antibody (MAb) 9d8 (2a), an isotype-switched variant of the immunoglobulin G3 (IgG3) MAb 9d8. MAb 9d8 had been previously shown to bind M. tuberculosis AM and the M. tuberculosis surface. Our in vitro experiments showed that MAb 9d8(2a) bound strongly to whole-cell M. tuberculosis Erdman but not to the CDC 1551 strain grown in medium for an extended period. However, AM antigen was detected in the culture supernatant of both strains, and its concentration increased in a time-dependent manner. The detection of AM antigen from both strains was decreased in the presence of Tween 80. In mice infected with M. tuberculosis Erdman, AM antigen accumulated in organ homogenates concomitant to an increase in bacterial organ burden and an increase in IgG and IgM titer to AM. These results (i) indicate that the surface expression of AM during in vitro growth changes with culture age, is strain dependent, and is affected by the presence of Tween 80 in the culture media; (ii) show that AM is produced by bacteria growth in vivo; and (iii) demonstrate that the amount of in vivo-detected AM can be dependent on the number of bacteria in the infected organ.

scholarly journals Inhibitory effect of naphthoquine phosphate against Babesia gibsoni in vitro and Babesia rodhaini in vivo

2021 ◽  
Author(s):  
Shengwei Ji ◽  
Mingming Liu ◽  
Eloiza May Galon ◽  
Mohamed Abdo Rizk ◽  
Bumduuren Tuvshintulga ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Treatment Strategies ◽  
Drug Repurposing ◽  
Significant Inhibition ◽  
Parasite Growth ◽  
New Drugs ◽  
Control Group ◽  
Babesia Gibsoni

Abstract Background: Drug resistance and severe side effects are major challenges in the treatment of babesiosis as they lead to less choices for treatment. Development of new drugs to enrich the treatment strategies and delay the emergence of drug resistance in parasites is still needed. Naphthoquine (NQ) combined with artemisinin treats Plasmodium infection by rapid parasite clearance. The current study repurposed NQ as a babesiosis drug treatment by evaluating the effects of naphthoquine phosphate (NQP) as a single dose treatment for babesiosis. Methods: In vitro anti-Babesia activity of NQP was tested on Babesia gibsoni cultures. The inhibition of parasite growth was verified using a SYBR green I-based fluorescence assay. In vivo efficacy of NQP was evaluated using BALB/c mice infected with Babesia rodhaini. The parasitemia level and hematocrit values were monitored. Results: The half maximal inhibitory concentration of NQP against B. gibsoni in vitro was 3.3 ± 0.5 μM. Oral administration of NQP for 5 successive days at a dose of 40 mg/kg of body weight resulted in significant inhibition on parasite growth compared with the control group. All mice in NQP-treated group survived, whereas the mice in control group died between days 6 and 9 post infection. Conclusion: This is the first study to evaluate the anti-Babesia activity of NQP in vitro and in vivo. The results showed that NQP is a promising drug for babesiosis treatment and drug repurposing may provide new treatment strategies for babesiosis.

scholarly journals Sesamol Induces Apoptosis-Like Cell Death in Leishmania donovani

2021 ◽  
Vol 11 ◽  
Author(s):  
Rahat Ali ◽  
Shams Tabrez ◽  
Sajjadul Kadir Akand ◽  
Fazlur Rahman ◽  
Atahar Husein ◽  
...  
Keyword(s):  
Cell Death ◽  
Dna Fragmentation ◽  
Leishmania Donovani ◽  
Ex Vivo ◽  
Annexin V ◽  
Parasite Load ◽  
Ultrastructural Changes ◽  
Dependent Manner

BackgroundVisceral leishmaniasis (VL), caused by the protozoan parasite Leishmania donovani (L. donovani), is the most severe form of leishmaniasis. It is largely responsible for significant morbidity and mortality in tropical and subtropical countries. Currently, available therapeutics have lots of limitations including high-cost, adverse side-effects, painful route of administration, less efficacy, and resistance. Therefore, it is time to search for cheap and effective antileishmanial agents. In the present work, we evaluated the antileishmanial potential of sesamol against promastigotes as well as intracellular amastigotes. Further, we tried to work out its mechanism of antileishmanial action on parasites through different assays.MethodologyIn vitro and ex vivo antileishmanial assays were performed to evaluate the antileishmanial potential of sesamol on L. donovani. Cytotoxicity was determined by MTT assay on human THP-1-derived macrophages. Sesamol-induced morphological and ultrastructural changes were determined by electron microscopy. H2DCFDA staining, JC-1dye staining, and MitoSOX red staining were performed for reactive oxygen assay (ROS), mitochondrial membrane potential, and mitochondrial superoxide, respectively. Annexin V/PI staining for apoptosis, TUNEL assay, and DNA laddering for studying sesamol-induced DNA fragmentation were performed.ConclusionsSesamol inhibited the growth and proliferation of L. donovani promastigotes in a dose-dependent manner. It also reduced the intracellular parasite load without causing significant toxicity on host-macrophages. Overall, it showed antileishmanial effects through induction of ROS, mitochondrial dysfunction, DNA fragmentation, cell cycle arrest, and apoptosis-like cell death to parasites. Our results suggested the possible use of sesamol for the treatment of leishmaniasis after further in vivo validations.

scholarly journals Development of novel MOG analogues with increased stability to explore MCT2 and α-ketoglutarate biology in vivo

2021 ◽  
Author(s):  
Louise Fets ◽  
Patrícia M. Nunes ◽  
Sebastien Campos ◽  
Mariana Silva dos Santos ◽  
Natalie Bevan ◽  
...  
Keyword(s):  
Culture Media ◽  
Pharmacokinetic Profile ◽  
Monocarboxylate Transporter ◽  
Metabolic Effects ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Cell Culture Media ◽  
Pharmacokinetic Properties

ABSTRACTα-ketoglutarate (αKG) is a central metabolic node with far-reaching influence on cellular physiology. The αKG analogue N-oxalylglycine (NOG) and its membrane-permeable pro-drug derivative dimethyloxalylglycine (DMOG) have been broadly used as tool compounds both in vitro and in vivo to study αKG-dependent processes. In cell culture media, DMOG is rapidly converted to MOG, a substrate of the monocarboxylate transporter MCT2. The expression level of MCT2 determines the intracellular concentration of NOG, and, as such, influences the molecular targets NOG engages with. Here we show that DMOG and MOG are highly unstable also in mouse blood. We therefore designed and characterised a series of MOG analogues with two aims: to improve pharmacokinetic properties, and to explore the pharmacophore of MCT2, a relatively understudied member of the SLC16 family. We report MOG analogues that maintain MCT2-dependent uptake, including NOG-generating compounds that replicate the metabolic effects of MOG in a concentration-dependent manner. One such analogue, IPOG, shows significantly increased blood stability, and an improved overall pharmacokinetic profile, leading to increased NOG accumulation in MCT2-expressing tumours versus isogenic controls.

scholarly journals Monensin may inhibit melanoma by regulating the selection between differentiation and stemness of melanoma stem cells

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7354 ◽  
Author(s):  
Haoran Xin ◽  
Jie Li ◽  
Hao Zhang ◽  
Yuhong Li ◽  
Shuo Zeng ◽  
...  
Keyword(s):  
Stem Cells ◽  
Drug Repurposing ◽  
Melanoma Cells ◽  
Human Melanoma ◽  
High Rate ◽  
Chemotherapy Drugs ◽  
Human Melanoma Cells ◽  
Melanoma Treatment

Melanoma is the most lethal cutaneous malignancy that threatens human lives. Poor sensitivity to chemotherapy drugs and the high rate of resistance are the bottlenecks of melanoma treatment. Thus, new chemotherapy drugs are needed. Drug repurposing is a safe, economical and timesaving way to explore new chemotherapy for diseases. Here, we investigated the possibility of repurposing the antibiotic monensin as an anti-melanoma agent. Using three human melanoma cells and two nomal human cell lines as cell models, we found that monensin is obviously toxic to human melanoma cells while safe to nomal human cells. It effectively inhibited cell proliferation and viability, while promoted apoptosis and differentiation of human melanoma cells in vitro. By establishment of an animal model of transplanted human melanoma in nude mice, we demonstrated that monensin suppressed the growth of xenografts in vivo. At the same time, we found that melanogenesis increased and the ability of sphere and cloning forming of melanoma decreased under the treatment of monensin. Further detection about differentiation and pluripotent regulations were executed. Our results suggest that monensin is a potent inhibitor of melanoma, and its anti-tumor mechanism may be through promoting the final differentiation of melanoma stem cells and inhibiting their stemness maintenance.

Sildenafil in combination therapy against cancer: A literature review

2020 ◽  
Vol 27 ◽  
Author(s):  
Rabah Iratni ◽  
Mohammed Akli Ayoub
Keyword(s):  
Combination Therapy ◽  
Drug Repurposing ◽  
In Vivo Studies ◽  
Dependent Manner ◽  
Beneficial Effects ◽  
Chemotherapy Drugs ◽  
Anti Cancer ◽  
Hypertensive Drug

: The concept of drug repurposing and Sildenafil or blue pill are tightly linked over the years. Indeed, in addition to its initial clinical application as an anti-hypertensive drug in the pulmonary system, Sildenafil is also known for its beneficial effects in erectile dysfunction. Moreover, evidence have been accumulated to support its value in anti-cancer therapy either alone or in a combination with other clinically efficient chemotherapy drugs. In this review, we focused on the old and recent in vitro and in vivo studies demonstrating the cellular and molecular rationale for the application of Sildenafil in combination therapy in many various types of cancer. We emphasized on the different molecular targets as well as the different signaling pathways involved in cancer cells. The pro-apoptotic effect of Sildenafil through nitric oxide (NO)/ phosphodiesterase type 5 (PDE5)-dependent manner seems to be one of the most common mechanisms. However, the activation of autophagy as well as the modulation of the anti-tumor immunity constitute the other pathways triggered by Sildenafil. Overall, the studies converged to reveal the complexity of the anti-cancer potential of Sildenafil. Thus, through our review we aimed to present an updated and simplified picture of such repurposing of Sildenafil in the field of oncology.

scholarly journals Drug Repurposing: In vitro and in vivo Antimicrobial and Antibiofilm Effects of Bithionol Against Enterococcus faecalis and Enterococcus faecium

2021 ◽  
Vol 12 ◽  
Author(s):  
Pengfei She ◽  
Yangxia Wang ◽  
Yingjia Li ◽  
Linying Zhou ◽  
Shijia Li ◽  
...  
Keyword(s):  
Enterococcus Faecalis ◽  
Bacterial Load ◽  
Drug Repurposing ◽  
Infection Model ◽  
Dependent Manner ◽  
Antibiotic Development ◽  
Vancomycin Resistant ◽  
Conventional Antibiotics

Widespread antibiotic resistance has been reported in enterococcal pathogens that cause life-threatening infections. Enterococci species rapidly acquire resistance and the pace of new antibiotic development is slow. Drug repurposing is a promising approach in solving this problem. Bithionol (BT) is a clinically approved anthelminthic drug. In this study, we found that BT showed significant antimicrobial and antibiofilm effects against Enterococcus faecalis and vancomycin-resistant Entercococcus faecium in vitro, in a dose-dependent manner, by disrupting the integrity of the bacterial cell membranes. Moreover, BT effectively reduced the bacterial load in mouse organs when combined with conventional antibiotics in a peritonitis infection model. Thus, BT has shown potential as a therapeutic agent against E. faecalis- and vancomycin-resistant E. faecium-related infections.

scholarly journals Effect of N-Vinyl-2-Pyrrolidone (NVP), a Bromodomain-Binding Small Chemical, on Osteoblast and Osteoclast Differentiation and Its Potential Application for Bone Regeneration

2021 ◽  
Vol 22 (20) ◽  
pp. 11052
Author(s):  
Viviane A. Klemmer ◽  
Nupur Khera ◽  
Barbara M. Siegenthaler ◽  
Indranil Bhattacharya ◽  
Franz E. Weber ◽  
...  
Keyword(s):  
Bone Regeneration ◽  
Osteoclast Differentiation ◽  
Tumor Resection ◽  
Bone Diseases ◽  
High Rate ◽  
Bone Morphogenetic Protein 2 ◽  
Dependent Manner ◽  
Non Union

The human skeleton is a dynamic and remarkably organized organ system that provides mechanical support and performs a variety of additional functions. Bone tissue undergoes constant remodeling; an essential process to adapt architecture/resistance to growth and mechanical needs, but also to repair fractures and micro-damages. Despite bone’s ability to heal spontaneously, certain situations require an additional stimulation of bone regeneration, such as non-union fractures or after tumor resection. Among the growth factors used to increase bone regeneration, bone morphogenetic protein-2 (BMP2) is certainly the best described and studied. If clinically used in high quantities, BMP2 is associated with various adverse events, including fibrosis, overshooting bone formation, induction of inflammation and swelling. In previous studies, we have shown that it was possible to reduce BMP2 doses significantly, by increasing the response and sensitivity to it with small molecules called “BMP2 enhancers”. In the present study, we investigated the effect of N-Vinyl-2-pyrrolidone (NVP) on osteoblast and osteoclast differentiation in vitro and guided bone regeneration in vivo. We showed that NVP increases BMP2-induced osteoblast differentiation and decreases RANKL-induced osteoclast differentiation in a dose-dependent manner. Moreover, in a rabbit calvarial defect model, the histomorphometric analysis revealed that bony bridging and bony regenerated area achieved with NVP-loaded poly (lactic-co-glycolic acid (PLGA) membranes were significantly higher compared to unloaded membranes. Taken together, our results suggest that NVP sensitizes BMP2-dependent pathways, enhances BMP2 effect, and inhibits osteoclast differentiation. Thus, NVP could prove useful as “osteopromotive substance” in situations where a high rate of bone regeneration is required, and in the management of bone diseases associated with excessive bone resorption, like osteoporosis.

scholarly journals Treatment of Visceral Leishmaniasis with Sterically Stabilized Liposomes Containing Camptothecin

2001 ◽  
Vol 45 (9) ◽  
pp. 2623-2627 ◽  
Author(s):  
Marie-Eve Proulx ◽  
André Désormeaux ◽  
Jean-François Marquis ◽  
Martin Olivier ◽  
Michel G. Bergeron
Keyword(s):  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Intraperitoneal Administration ◽  
Dependent Manner ◽  
Sterically Stabilized Liposomes ◽  
Normochromic Anemia ◽  
Distribution Studies ◽  
Dose Dependent

ABSTRACT The efficacy of 20(S)-camptothecin (CPT), free and incorporated into sterically stabilized liposomes, has been investigated in vitro against Leishmania donovanipromastigotes and in vivo in a murine model of visceral leishmaniasis. Incubation of L. donovani promastigotes with free or liposomal CPT inhibited the growth of parasites in a dose-dependent manner. Tissue distribution studies revealed that the intraperitoneal administration of liposomal CPT was efficient for the delivery of high drug levels to the liver and spleen. Treatment of infected mice with intraperitoneal injections of free and liposomal CPT significantly reduced the parasite loads in the livers by 43 and 55%, respectively, compared with the loads for untreated controls. However, both treatments caused normochromic anemia and neutropenia.

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