-
Microbiology Spectrum Jun 2024Post-kala-azar dermal leishmaniasis (PKDL) patients are a key source of parasites, hindering the goal of eliminating visceral leishmaniasis (VL). Monitoring treatment...
UNLABELLED
Post-kala-azar dermal leishmaniasis (PKDL) patients are a key source of parasites, hindering the goal of eliminating visceral leishmaniasis (VL). Monitoring treatment response and parasite susceptibility is essential due to increasing drug resistance. We assessed the drug susceptibility of PKDL isolates ( = 18) from pre-miltefosine (MIL) era (1997-2004) with isolates ( = 16) from the post-miltefosine era (2010-2019) and post-miltefosine treatment relapse isolates ( = 5) towards miltefosine and amphotericin B (AmB) at promastigote stage and towards sodium antimony gluconate (SAG) at amastigote stage. PKDL isolates were examined for mutation in gene-encoding AQP1 transporter, C26882T mutation on chromosome 24, and miltefosine-transporter (MT). PKDL isolates from the post-miltefosine era were significantly more susceptible to SAG than SAG-resistant isolates from the pre-miltefosine era ( = 0.0002). There was no significant difference in the susceptibility of parasites to miltefosine between pre- and post-miltefosine era isolates. The susceptibility of PKDL isolates towards AmB remained unchanged between the pre- and post-miltefosine era. However, the post-miltefosine era isolates had a higher IC value towards AmB compared with PKDL relapse isolates. We did not find any association between AQP1 gene sequence variation and susceptibility to SAG, or between miltefosine susceptibility and single nucleotide polymorphisms (SNPs in the MT gene. This study demonstrates that recent isolates of have resumed susceptibility to antimonials . The study also offers significant insights into the intrinsic drug susceptibility of parasites over the past two decades, covering the period before the introduction of miltefosine and after its extensive use.
IMPORTANCE
Post-kala-azar dermal leishmaniasis (PKDL) patients, a key source of parasites, hinder eliminating visceral-leishmaniasis. Assessment of the susceptibility of PKDL isolates to antimony, miltefosine (MIL), and amphotericin-B indicated that recent isolates remain susceptible to antimony, enabling its use with other drugs for treating PKDL.
Topics: Humans; Leishmania donovani; Phosphorylcholine; Leishmaniasis, Visceral; Antiprotozoal Agents; Antimony; Leishmaniasis, Cutaneous; Drug Resistance; Amphotericin B; Parasitic Sensitivity Tests; Antimony Sodium Gluconate; Mutation
PubMed: 38712926
DOI: 10.1128/spectrum.04026-23 -
Cytokine Jul 2024Leishmaniasis, a major globally re-emerging neglected tropical disease, has a restricted repertoire of chemotherapeutic options due to a narrow therapeutic index, drug...
Leishmaniasis, a major globally re-emerging neglected tropical disease, has a restricted repertoire of chemotherapeutic options due to a narrow therapeutic index, drug resistance, or patient non-compliance due to toxicity. The disease is caused by the parasite Leishmania that resides in two different forms in two different environments: as sessile intracellular amastigotes within mammalian macrophages and as motile promastigotes in sandfly gut. As mitogen-activated protein kinases (MAPKs) play important roles in cellular differentiation and survival, we studied the expression of Leishmania donovani MAPKs (LdMAPKs). The homology studies by multiple sequence alignment show that excepting LdMAPK1 and LdMAPK2, all thirteen other LdMAPKs share homology with human ERK and p38 isoforms. Expression of LdMAPK4 and LdMAPK5 is less in avirulent promastigotes and amastigotes. Compared to miltefosine-sensitive L. donovani parasites, miltefosine-resistant parasites have higher LdMAPK1, LdMAPK3-5, LdMAPK7-11, LdMAPK13, and LdMAPK14 expression. IL-4-treatment of macrophages down-regulated LdMAPK11, in virulent amastigotes whereas up-regulated LdMAPK5, but down-regulated LdMAPK6, LdMAPK12-15, expression in avirulent amastigotes. IL-4 up-regulated LdMAPK1 expression in both virulent and avirulent amastigotes. IFN-γ-treatment down-regulated LdMAPK6, LdMAPK13, and LdMAPK15 in avirulent amastigotes but up-regulated in virulent amastigotes. This complex profile of LdMAPKs expression among virulent and avirulent parasites, drug-resistant parasites, and in amastigotes within IL-4 or IFN-γ-treated macrophages suggests that LdMAPKs are differentially controlled at the host-parasite interface regulating parasite survival and differentiation, and in the course of IL-4 or IFN-γ dominated immune response.
Topics: Leishmania donovani; Animals; Host-Parasite Interactions; Mitogen-Activated Protein Kinases; Mice; Macrophages; Humans; Mice, Inbred BALB C; Phosphorylcholine; Leishmaniasis, Visceral; Protozoan Proteins; Interferon-gamma; Drug Resistance
PubMed: 38703436
DOI: 10.1016/j.cyto.2024.156627 -
Bioactive Materials Jul 2024Thrombosis and infection are two major complications associated with central venous catheters (CVCs), which significantly contribute to morbidity and mortality....
Thrombosis and infection are two major complications associated with central venous catheters (CVCs), which significantly contribute to morbidity and mortality. Antifouling coating strategies currently represent an efficient approach for addressing such complications. However, existing antifouling coatings have limitations in terms of both duration and effectiveness. Herein, we propose a durable zwitterionic polymer armor for catheters. This armor is realized by pre-coating with a robust phenol-polyamine film inspired by insect sclerotization, followed by grafting of poly-2-methacryloyloxyethyl phosphorylcholine (pMPC) via radical polymerization. The resulting pMPC coating armor exhibits super-hydrophilicity, thereby forming a highly hydrated shell that effectively prevents bacterial adhesion and inhibits the adsorption and activation of fibrinogen and platelets . In practical applications, the armored catheters significantly reduced inflammation and prevented biofilm formation in a rat subcutaneous infection model, as well as inhibited thrombus formation in a rabbit jugular vein model. Overall, our robust zwitterionic polymer coating presents a promising solution for reducing infections and thrombosis associated with vascular catheters.
PubMed: 38698921
DOI: 10.1016/j.bioactmat.2024.04.002 -
Biomolecules Mar 2024Originally developed as a chemotherapeutic agent, miltefosine (hexadecylphosphocholine) is an inhibitor of phosphatidylcholine synthesis with proven antiparasitic... (Review)
Review
Originally developed as a chemotherapeutic agent, miltefosine (hexadecylphosphocholine) is an inhibitor of phosphatidylcholine synthesis with proven antiparasitic effects. It is the only oral drug approved for the treatment of Leishmaniasis and American Trypanosomiasis (Chagas disease). Although its precise mechanisms are not yet fully understood, miltefosine exhibits broad-spectrum anti-parasitic effects primarily by disrupting the intracellular Ca homeostasis of the parasites while sparing the human hosts. In addition to its inhibitory effects on phosphatidylcholine synthesis and cytochrome c oxidase, miltefosine has been found to affect the unique giant mitochondria and the acidocalcisomes of parasites. Both of these crucial organelles are involved in Ca regulation. Furthermore, miltefosine has the ability to activate a specific parasite Ca channel that responds to sphingosine, which is different to its L-type VGCC human ortholog. Here, we aimed to provide an overview of recent advancements of the anti-parasitic mechanisms of miltefosine. We also explored its multiple molecular targets and investigated how its pleiotropic effects translate into a rational therapeutic approach for patients afflicted by Leishmaniasis and American Trypanosomiasis. Notably, miltefosine's therapeutic effect extends beyond its impact on the parasite to also positively affect the host's immune system. These findings enhance our understanding on its multi-targeted mechanism of action. Overall, this review sheds light on the intricate molecular actions of miltefosine, highlighting its potential as a promising therapeutic option against these debilitating parasitic diseases.
Topics: Humans; Phosphorylcholine; Chagas Disease; Calcium; Leishmaniasis; Homeostasis; Animals; Antiprotozoal Agents; Mitochondria; Leishmania; Trypanosoma cruzi
PubMed: 38672424
DOI: 10.3390/biom14040406 -
Ecotoxicology and Environmental Safety Jun 2024Perfluorooctane sulfonate (PFOS) is a persistent chemical that has long been a threat to human health. However, the molecular effects of PFOS on various organs are not...
Perfluorooctane sulfonate (PFOS) is a persistent chemical that has long been a threat to human health. However, the molecular effects of PFOS on various organs are not well studied. In this study, male Sprague-Dawley rats were treated with various doses of PFOS through gavage for 21 days. Subsequently, the liver, lung, heart, kidney, pancreas, testis, and serum of the rats were harvested for lipid analysis. We applied a focusing lipidomic analytical strategy to identify key lipid responses of phosphorylcholine-containing lipids, including phosphatidylcholines and sphingomyelins. Partial least squares discriminant analysis revealed that the organs most influenced by PFOS exposure were the liver, kidney, and testis. Changes in the lipid profiles of the rats indicated that after exposure, levels of diacyl-phosphatidylcholines and 22:6-containing phosphatidylcholines in the liver, kidney, and testis of the rats decreased, whereas the level of 20:3-containing phosphatidylcholines increased. Furthermore, levels of polyunsaturated fatty acids-containing plasmenylcholines decreased. Changes in sphingomyelin levels indicated organ-dependent responses. Decreased levels of sphingomyelins in the liver, nonmonotonic dose responses in the kidney, and irregular responses in the testis after PFOS exposure are observed. These lipid responses may be associated with alterations pertaining to phosphatidylcholine synthesis, fatty acid metabolism, membrane properties, and oxidative stress in the liver, kidney, and testis. Lipid responses in the liver could have contributed to the observed increase in liver to body weight ratios. The findings suggest potential toxicity and possible mechanisms associated with PFOS in multiple organs.
Topics: Animals; Alkanesulfonic Acids; Fluorocarbons; Male; Rats, Sprague-Dawley; Rats; Liver; Kidney; Testis; Environmental Pollutants; Sphingomyelins; Phosphatidylcholines; Lipid Metabolism; Lipidomics; Lung
PubMed: 38669874
DOI: 10.1016/j.ecoenv.2024.116368 -
PLoS Neglected Tropical Diseases Apr 2024Currently available treatment options are mostly effective in achieving long-term cure in visceral leishmaniasis (VL) patients. However, there have been reports of...
BACKGROUND
Currently available treatment options are mostly effective in achieving long-term cure in visceral leishmaniasis (VL) patients. However, there have been reports of recurrence of this illness in both immunosuppressed and immunocompetent patients.
CASE PRESENTATION
We report the first case of recurrent VL relapse in a 19-year-old immunocompetent female with functional hypopituitarism (hypogonadotropic hypogonadism with central hypothyroidism) from Bangladesh, who has been treated three times previously with optimal dosage and duration- liposomal amphotericin B (LAmB) alone and in combination with miltefosine. We treated the patient successfully with a modified treatment regimen of 10 mg/kg body weight LAmB for two consecutive days along with oral miltefosine for seven days as loading dose. For secondary prophylaxis, the patient received 3 mg/kg body weight LAmB along with oral miltefosine for seven days monthly for five doses followed by hormonal replacement. The patient remained relapse free after 12 months of her treatment completion.
CONCLUSION
In the absence of protective vaccines against Leishmania species and standard treatment regimen, this modified treatment regimen could help the management of recurrent relapse cases.
Topics: Female; Humans; Young Adult; Amphotericin B; Antiprotozoal Agents; Bangladesh; Hypopituitarism; Leishmaniasis, Visceral; Phosphorylcholine; Recurrence; Treatment Outcome; Adult
PubMed: 38669211
DOI: 10.1371/journal.pntd.0012134 -
Biosensors Mar 2024Galactose monitoring in individuals allows the prevention of harsh health conditions related to hereditary metabolic diseases like galactosemia. Current methods of...
Galactose monitoring in individuals allows the prevention of harsh health conditions related to hereditary metabolic diseases like galactosemia. Current methods of galactose detection need development to obtain cheaper, more reliable, and more specific sensors. Enzyme-containing amperometric sensors based on galactose oxidase activity are a promising approach, which can be enhanced by means of their inclusion in a redox polymer coating. This strategy simultaneously allows the immobilization of the biocatalyst to the electroactive surface and hosts the electron shuttling units. An additional deposition of capping polymers prevents external interferences like ascorbic or uric acid as well as biofouling when measuring in physiological fuels. This work studies the protection effect of poly(2-methacryloyloxyethyl phosphorylcholine--glycidyl methacrylate (MPC) and polyvinylimidazole-polysulfostyrene (P(VI-SS)) when incorporated in the biosensor design for the detection of galactose in human plasma.
Topics: Biosensing Techniques; Humans; Galactose; Polymers; Galactose Oxidase; Methacrylates
PubMed: 38667160
DOI: 10.3390/bios14040167 -
Klinische Monatsblatter Fur... Apr 2024
Topics: Humans; Acanthamoeba Keratitis; Administration, Topical; Antifungal Agents; Antiprotozoal Agents; Drug Therapy, Combination; Phosphorylcholine; Treatment Outcome; Voriconazole; Middle Aged
PubMed: 38653269
DOI: 10.1055/a-2196-6011 -
PLoS Neglected Tropical Diseases Apr 2024With the current treatment options for visceral leishmaniasis (VL), recrudescence of the parasite is seen in a proportion of patients. Understanding parasite dynamics is...
BACKGROUND
With the current treatment options for visceral leishmaniasis (VL), recrudescence of the parasite is seen in a proportion of patients. Understanding parasite dynamics is crucial to improving treatment efficacy and predicting patient relapse in cases of VL. This study aimed to characterize the kinetics of circulating Leishmania parasites in the blood, during and after different antileishmanial therapies, and to find predictors for clinical relapse of disease.
METHODS
Data from three clinical trials, in which Eastern African VL patients received various antileishmanial regimens, were combined in this study. Leishmania kinetoplast DNA was quantified in whole blood with real-time quantitative PCR (qPCR) before, during, and up to six months after treatment. An integrated population pharmacokinetic-pharmacodynamic model was developed using non-linear mixed effects modelling.
RESULTS
Parasite proliferation was best described by an exponential growth model, with an in vivo parasite doubling time of 7.8 days (RSE 12%). Parasite killing by fexinidazole, liposomal amphotericin B, sodium stibogluconate, and miltefosine was best described by linear models directly relating drug concentrations to the parasite elimination rate. After treatment, parasite growth was assumed to be suppressed by the host immune system, described by an Emax model driven by the time after treatment. No predictors for the high variability in onset and magnitude of the immune response could be identified. Model-based individual predictions of blood parasite load on Day 28 and Day 56 after start of treatment were predictive for clinical relapse of disease.
CONCLUSION
This semi-mechanistic pharmacokinetic-pharmacodynamic model adequately captured the blood parasite dynamics during and after treatment, and revealed that high blood parasite loads on Day 28 and Day 56 after start of treatment are an early indication for VL relapse, which could be a useful biomarker to assess treatment efficacy of a treatment regimen in a clinical trial setting.
Topics: Leishmaniasis, Visceral; Humans; Antiprotozoal Agents; Adult; Female; Male; Young Adult; Adolescent; Africa, Eastern; Amphotericin B; Recurrence; DNA, Kinetoplast; Parasite Load; Middle Aged; Child; Antimony Sodium Gluconate; Child, Preschool; DNA, Protozoan; Nitroimidazoles; Phosphorylcholine
PubMed: 38640118
DOI: 10.1371/journal.pntd.0012078 -
Biomaterials Science May 2024Polymeric heart valves (PHVs) present a promising alternative for treating valvular heart diseases with satisfactory hydrodynamics and durability against structural... (Comparative Study)
Comparative Study
Polymeric heart valves (PHVs) present a promising alternative for treating valvular heart diseases with satisfactory hydrodynamics and durability against structural degeneration. However, the cascaded coagulation, inflammatory responses, and calcification in the dynamic blood environment pose significant challenges to the surface design of current PHVs. In this study, we employed a surface-initiated polymerization method to modify polystyrene--isobutylene--styrene (SIBS) by creating three hydrogel coatings: poly(2-methacryloyloxy ethyl phosphorylcholine) (pMPC), poly(2-acrylamido-2-methylpropanesulfonic acid) (pAMPS), and poly(2-hydroxyethyl methacrylate) (pHEMA). These hydrogel coatings dramatically promoted SIBS's hydrophilicity and blood compatibility at the initial state. Notably, the pMPC and pAMPS coatings maintained a considerable platelet resistance performance after 12 h of sonication and 10 000 cycles of stretching and bending. However, the sonication process induced visible damage to the pHEMA coating and attenuated the anti-coagulation property. Furthermore, the subcutaneous implantation studies demonstrated that the amphiphilic pMPC coating showed superior anti-inflammatory and anti-calcification properties. Considering the remarkable stability and optimal biocompatibility, the amphiphilic pMPC coating constructed by surface-initiated polymerization holds promising potential for modifying PHVs.
Topics: Phosphorylcholine; Animals; Hydrogels; Coated Materials, Biocompatible; Surface Properties; Materials Testing; Polyhydroxyethyl Methacrylate; Polymethacrylic Acids; Methacrylates; Polymers; Heart Valve Prosthesis; Heart Valves; Humans; Mice; Hydrophobic and Hydrophilic Interactions
PubMed: 38619816
DOI: 10.1039/d4bm00158c