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PLoS Neglected Tropical Diseases Apr 2024The severe late stage Human African Trypanosomiasis (HAT) caused by Trypanosoma brucei rhodesiense (T.b.r) is characterized by damage to the blood brain barrier, severe...
BACKGROUND
The severe late stage Human African Trypanosomiasis (HAT) caused by Trypanosoma brucei rhodesiense (T.b.r) is characterized by damage to the blood brain barrier, severe brain inflammation, oxidative stress and organ damage. Melarsoprol (MelB) is currently the only treatment available for this disease. MelB use is limited by its lethal neurotoxicity due to post-treatment reactive encephalopathy. This study sought to assess the potential of Ginkgo biloba (GB), a potent anti-inflammatory and antioxidant, to protect the integrity of the blood brain barrier and ameliorate detrimental inflammatory and oxidative events due to T.b.r in mice treated with MelB.
METHODOLOGY
Group one constituted the control; group two was infected with T.b.r; group three was infected with T.b.r and treated with 2.2 mg/kg melarsoprol for 10 days; group four was infected with T.b.r and administered with GB 80 mg/kg for 30 days; group five was given GB 80mg/kg for two weeks before infection with T.b.r, and continued thereafter and group six was infected with T.b.r, administered with GB and treated with MelB.
RESULTS
Co-administration of MelB and GB improved the survival rate of infected mice. When administered separately, MelB and GB protected the integrity of the blood brain barrier and improved neurological function in infected mice. Furthermore, the administration of MelB and GB prevented T.b.r-induced microcytic hypochromic anaemia and thrombocytopenia, as well as T.b.r-driven downregulation of total WBCs. Glutathione analysis showed that co-administration of MelB and GB prevented T.b.r-induced oxidative stress in the brain, spleen, heart and lungs. Notably, GB averted peroxidation and oxidant damage by ameliorating T.b.r and MelB-driven elevation of malondialdehyde (MDA) in the brain, kidney and liver. In fact, the co-administered group for the liver, registered the lowest MDA levels for infected mice. T.b.r-driven elevation of serum TNF-α, IFN-γ, uric acid and urea was abrogated by MelB and GB. Co-administration of MelB and GB was most effective in stabilizing TNFα levels. GB attenuated T.b.r and MelB-driven up-regulation of nitrite.
CONCLUSION
Utilization of GB as an adjuvant therapy may ameliorate detrimental effects caused by T.b.r infection and MelB toxicity during late stage HAT.
Topics: Animals; Mice; Trypanosomiasis, African; Oxidative Stress; Plant Extracts; Ginkgo biloba; Trypanosoma brucei rhodesiense; Melarsoprol; Male; Blood-Brain Barrier; Anti-Inflammatory Agents; Disease Models, Animal; Brain; Antioxidants; Inflammation
PubMed: 38620045
DOI: 10.1371/journal.pntd.0012103 -
Molecules (Basel, Switzerland) Apr 2024Folk medicine is widely used in Angola, even for human African trypanosomiasis (sleeping sickness) in spite of the fact that the reference treatment is available for...
Folk medicine is widely used in Angola, even for human African trypanosomiasis (sleeping sickness) in spite of the fact that the reference treatment is available for free. Aiming to validate herbal remedies in use, we selected nine medicinal plants and assessed their antitrypanosomal activity. A total of 122 extracts were prepared using different plant parts and solvents. A total of 15 extracts from seven different plants exhibited in vitro activity (>70% at 20 µg/mL) against bloodstream forms. The dichloromethane extract of (leaves and leaflets) and the ethanolic extract of (leaves) had IC values ≤ 10 µg/mL. These two aquatic plants are of particular interest. They are being co-applied in the form of a decoction of leaves because they are considered by local healers as male and female of the same species, the ethnotaxon "longa dia simbi". Bioassay-guided fractionation led to the identification of eight active molecules: gallic acid (IC 0.5 µg/mL), methyl gallate (IC 1.1 µg/mL), 2,3,4,6-tetragalloyl-glucopyranoside, ethyl gallate (IC 0.5 µg/mL), 1,2,3,4,6-pentagalloyl-β-glucopyranoside (IC 20 µg/mL), gossypetin-7--β-glucopyranoside (IC 5.5 µg/mL), and hypolaetin-7--glucoside (IC 5.7 µg/mL) in , and 5-[(8Z,11Z,14Z)-heptadeca-8,11,14-trienyl] resorcinol (IC 5.3 µg/mL) not described to date in . Five of these active constituents were detected in the traditional preparation. This work provides the first evidence for the ethnomedicinal use of these plants in the management of sleeping sickness in Angola.
Topics: Humans; Animals; Nymphaea; Trypanosomiasis, African; Angola; Seeds; Antiprotozoal Agents; Plant Extracts
PubMed: 38611890
DOI: 10.3390/molecules29071611 -
PLoS Computational Biology Apr 2024The intensification of intervention activities against the fatal vector-borne disease gambiense human African trypanosomiasis (gHAT, sleeping sickness) in the last two...
The intensification of intervention activities against the fatal vector-borne disease gambiense human African trypanosomiasis (gHAT, sleeping sickness) in the last two decades has led to a large decline in the number of annually reported cases. However, while we move closer to achieving the ambitious target of elimination of transmission (EoT) to humans, pockets of infection remain, and it becomes increasingly important to quantitatively assess if different regions are on track for elimination, and where intervention efforts should be focused. We present a previously developed stochastic mathematical model for gHAT in the Democratic Republic of Congo (DRC) and show that this same formulation is able to capture the dynamics of gHAT observed at the health area level (approximately 10,000 people). This analysis was the first time any stochastic gHAT model has been fitted directly to case data and allows us to better quantify the uncertainty in our results. The analysis focuses on utilising a particle filter Markov chain Monte Carlo (MCMC) methodology to fit the model to the data from 16 health areas of Mosango health zone in Kwilu province as a case study. The spatial heterogeneity in cases is reflected in modelling results, where we predict that under the current intervention strategies, the health area of Kinzamba II, which has approximately one third of the health zone's cases, will have the latest expected year for EoT. We find that fitting the analogous deterministic version of the gHAT model using MCMC has substantially faster computation times than fitting the stochastic model using pMCMC, but produces virtually indistinguishable posterior parameterisation. This suggests that expanding health area fitting, to cover more of the DRC, should be done with deterministic fits for efficiency, but with stochastic projections used to capture both the parameter and stochastic variation in case reporting and elimination year estimations.
Topics: Animals; Humans; Trypanosomiasis, African; Democratic Republic of the Congo; Models, Theoretical; Forecasting; Markov Chains; Trypanosoma brucei gambiense
PubMed: 38557869
DOI: 10.1371/journal.pcbi.1011993 -
Heliyon Mar 2024African Trypanosomiasis caused by trypanosome parasites continues to be a major neglected health problem, particularly in developing countries. Current treatments are...
African Trypanosomiasis caused by trypanosome parasites continues to be a major neglected health problem, particularly in developing countries. Current treatments are marked by serious side effects, low effectiveness, high toxicity, and drug resistance prompting the need to develop novel, safe, effective, and alternative antitrypanosomal compounds. is an ethnomedicinal plant used in West Africa to treat many ailments including protozoan diseases. In this study, we investigated the antitrypanosomal potential of stem bark extracts of through and approaches. extracts were tested for their antitrypanosomal activities against parasite using Alamar blue assay. In addition, the antioxidant and cytotoxic activities were determined. LC-ESI-QTOF-MS was used to identify potential bioactive compounds present in the extracts. Bioactive compounds identified were subjected to molecular docking studies against (TR) and Uridine Diphosphate Galactose 4'-Epimerase (UDP). The . extracts (methanol, hexane, chloroform, and ethyl acetate) exhibited potential anti-trypanosomal activities with IC values of 21.25 ± 0.755,4.35 ± 0.166,2.57 ± 0.153 and 22.92 ± 2.321 μg/mL respectively. Moreover, the methanolic crude extracts showed moderate cytotoxicity against HepG2 and PNT2 cells, with IC values of 68.0 ± 2.05 and 78.7 ± 2.63 μg/mL respectively. LC-MS analysis revealed the presence of 24 bioactive compounds with 5 being druglike. Risperidone, Ranolazine, Dihydro-7-Desacetyldeoxygedunin, 6 beta-Hydroxytriamcinolone acetonide, and Dimethylmatairesinol were identified as novel potential inhibitors of TR and UDP with binding affinities of -10.4, -7.9, -8.7, -8.4 and -7.1 kcal/mol respectively against TR and -10.8, -8.4, -8.4, -7.6 and -8.1 respectively against UDP. This study indicates that has potential antitrypanosomal properties and therefore may have the potential to be developed as a therapeutic intervention for treating African trypanosomiasis.
PubMed: 38545221
DOI: 10.1016/j.heliyon.2024.e28025 -
Pathogens (Basel, Switzerland) Mar 2024The potential danger to livestock from African animal trypanosomiasis is well known. However, the trypanosome species circulating in cattle and their genetics are poorly...
The potential danger to livestock from African animal trypanosomiasis is well known. However, the trypanosome species circulating in cattle and their genetics are poorly understood. After different alignments according to three regions (ITS1, gGAPDH and rRNA gene) of the trypanosome genome, phylogenetic analyses were used to show the genetic diversity of the different species that were circulating in the cattle in three regions (Bagoue, Poro and Tchologo) of Côte d'Ivoire. These analyses were performed by alignment of ITS1; by alignment of partial 18S, ITS1, 5.8S, ITS2 and partial 28S rRNA genes; and by alignment of gGAPDH gene with sequences of Trypanosomes found in GenBank. Three species were identified (, and ) in the cattle in the three northern regions of Côte d'Ivoire. and were the most abundant species in the present study. Contrary to the other primers used in this study, the ITS1 primers were not able to amplify . We observed mixed infections between and the other two species identified ( and ). As far as primers are concerned, in some cases, rRNA was able to identify the same species of trypanosomes that the ITS1 and gGAPDH primers were able to identify. Two main distinct groups of complex were identified. The and strains were close to African strains, such as those from Kenya, Nigeria and Cameroon, unlike the strain. Three trypanosome species (, and ) circulate in cattle in the Savannah district of Côte d'Ivoire. The genetic diversity of the trypanosome species encountered in this study cannot be classified as intraspecies according to geographical area and breed of cattle they infect.
PubMed: 38535605
DOI: 10.3390/pathogens13030262 -
Parasite (Paris, France) 2024Trypanosoma brucei gambiense (Tbg) group 2 is a subgroup of trypanosomes able to infect humans and is found in West and Central Africa. Unlike other agents causing...
Trypanosoma brucei gambiense (Tbg) group 2 is a subgroup of trypanosomes able to infect humans and is found in West and Central Africa. Unlike other agents causing sleeping sickness, such as Tbg group 1 and Trypanosoma brucei rhodesiense, Tbg2 lacks the typical molecular markers associated with resistance to human serum. Only 36 strains of Tbg2 have been documented, and therefore, very limited research has been conducted despite their zoonotic nature. Some of these strains are only available in their procyclic form, which hinders human serum resistance assays and mechanistic studies. Furthermore, the understanding of Tbg2's potential to infect tsetse flies and mammalian hosts is limited. In this study, 165 Glossina palpalis gambiensis flies were experimentally infected with procyclic Tbg2 parasites. It was found that 35 days post-infection, 43 flies out of the 80 still alive were found to be Tbg2 PCR-positive in the saliva. These flies were able to infect 3 out of the 4 mice used for blood-feeding. Dissection revealed that only six flies in fact carried mature infections in their midguts and salivary glands. Importantly, a single fly with a mature infection was sufficient to infect a mammalian host. This Tbg2 transmission success confirms that Tbg2 strains can establish in tsetse flies and infect mammalian hosts. This study describes an effective in vivo protocol for transforming Tbg2 from procyclic to bloodstream form, reproducing the complete Tbg2 cycle from G. p. gambiensis to mice. These findings provide valuable insights into Tbg2's host infectivity, and will facilitate further research on mechanisms of human serum resistance.
Topics: Animals; Humans; Mice; Trypanosoma brucei gambiense; Trypanosomiasis, African; Tsetse Flies; Trypanosoma; Life Cycle Stages; Trypanosoma brucei brucei; Mammals
PubMed: 38520091
DOI: 10.1051/parasite/2024009 -
Experimental Parasitology May 2024Suramin was the first effective drug for the treatment of human African sleeping sickness. Structural analogues of the trypanocide have previously been shown to be...
Suramin was the first effective drug for the treatment of human African sleeping sickness. Structural analogues of the trypanocide have previously been shown to be potent inhibitors of several enzymes. Therefore, four suramin analogues lacking the methyl group on the intermediate rings and with different regiochemistry of the naphthalenetrisulphonic acid groups and the phenyl rings were tested to establish whether they exhibited improved antiproliferative activity against bloodstream forms of Trypanosomes brucei compared to the parent compound. The four analogues exhibited low trypanocidal activity and weak inhibition of the antitrypanosomal activity of suramin in competition experiments. This indicates that the strong trypanocidal activity of suramin is most likely due to the presence of methyl groups on its intermediate rings and to the specific regiochemistry of naphthalenetrisulphonic acid groups. These two structural features are also likely to be important for the inhibition mechanism of suramin because DNA distribution and nucleus/kinetoplast configuration analyses suggest that the analogues inhibit mitosis while suramin inhibits cytokinesis.
Topics: Suramin; Trypanocidal Agents; Trypanosoma brucei brucei; Animals; Structure-Activity Relationship; DNA, Protozoan; DNA, Kinetoplast; Mice; Mitosis; Trypanosomiasis, African
PubMed: 38513971
DOI: 10.1016/j.exppara.2024.108744 -
Frontiers in Drug Delivery May 2023Human African Trypanosomiasis (HAT) is a neglected parasitic disease that continues to persist in sub-Saharan Africa. It is fatal if untreated. The first stage of the...
Human African Trypanosomiasis (HAT) is a neglected parasitic disease that continues to persist in sub-Saharan Africa. It is fatal if untreated. The first stage of the disease is associated with the presence of the parasite in the periphery and the second stage with the presence of the parasites in the CNS. The treatment of CNS stage HAT requires the drugs to cross the blood-brain barrier (BBB). Eflornithine is an amino acid analogue that is used to treat second stage HAT gambiense both alone and in combination with nifurtimox. Recent studies have identified that accumulation of eflornithine into the parasites (trypanosomes) involves the amino acid transporter ( AAT6). In this study we tested the hypothesis that eflornithine uses a cationic amino acid transport system to cross the BBB. We particularly focused on system-y and system-B. To do this we utilized specialist databases to compare the physicochemical characteristics of relevant molecules and an model of the BBB to explore the mechanisms of eflornithine delivery into the CNS. Our results confirmed that eflornithine is related to the endogenous amino acid, ornithine. At pH 7.4, eflornithine is predominately (92.39%) a zwitterionic (dipolar) amino acid and ornithine is predominately (99.08%) a cationic (tripolar) amino acid. In addition, the gross charge distribution at pH 7.4 of eflornithine is much smaller (+0.073) than that of ornithine (+0.99). Further results indicated that eflornithine utilized a saturable transport mechanism(s) to cross the hCMEC/D3 cell membranes and that transport was inhibited by the presence of other amino acids including ornithine. Eflornithine transport was also sodium-independent and sensitive to a y-system inhibitor, but not a B-system inhibitor. Eflornithine transport was also inhibited by pentamidine, suggestive of transport by organic cation transporters (OCT) which are expressed in this cell line. We confirmed expression of the y-system protein, CAT1, and the B-system protein, ATB, in the hCMEC/D3 cells. We conclude that eflornithine uses the cationic amino acid transporter, system y, and OCT to cross the BBB. This research highlights the potential of system-y to deliver drugs, including eflornithine, across the BBB to treat brain diseases.
PubMed: 38482132
DOI: 10.3389/fddev.2023.1113493 -
International Journal For Parasitology.... Apr 2024Earlier evidences showed that diglycosyl diselenides are active against the infective stage of African trypanosomes (top hits IC 0.5 and 1.5 μM) but poorly selective...
Earlier evidences showed that diglycosyl diselenides are active against the infective stage of African trypanosomes (top hits IC 0.5 and 1.5 μM) but poorly selective (selectivity index <10). Here we extended the study to 33 new seleno-glycoconjugates with the aim to improve potency and selectivity. Three selenoglycosides and three glycosyl selenenylsulfides displayed IC against bloodstream Trypanosoma brucei in the sub-μM range (IC 0.35-0.77 μM) and four of them showed an improved selectivity (selectivity index >38-folds vs. murine and human macrohages). For the glycosyl selenylsulfides, the anti-trypanosomal activity was not significantly influenced by the nature of the moiety attached to the sulfur atom. Except for a quinoline-, and to a minor extent a nitro-derivative, the most selective hits induced a rapid (within 60 min) and marked perturbation of the LMWT-redox homeostasis. The formation of selenenylsulfide glycoconjugates with free thiols has been identified as a potential mechanism involved in this process.
Topics: Animals; Mice; Humans; Trypanosoma brucei brucei; Trypanosoma; Homeostasis; Oxidation-Reduction; Trypanosomiasis, African; Trypanocidal Agents
PubMed: 38461700
DOI: 10.1016/j.ijpddr.2024.100529 -
Tidsskrift For Den Norske Laegeforening... Feb 2024African sleeping sickness is a neglected tropical disease seldom seen in European travellers.
BACKGROUND
African sleeping sickness is a neglected tropical disease seldom seen in European travellers.
CASE PRESENTATION
While working in Eastern Africa, a Norwegian man in his sixties developed weakness and fever. He was prescribed doxycycline after a negative malaria rapid test. On the third day of illness he returned to Norway and was admitted to the hospital upon arrival. On admission he was somnolent with fever, tachypnoea, tachycardia, jaundice, a hyperaemic rash, oliguria and haematuria. Blood tests revealed leukopenia, thrombocytopaenia, renal failure and liver dysfunction. Rapid tests were negative for malaria and dengue. Blood microscopy revealed high parasitaemia with trypanosomes indicating human African sleeping-sickness. He had been bitten by a tsetse fly 11 days prior in an area endemic for Trypanosoma brucei gambiense. However, the clinical picture was consistent with Trypanosoma brucei rhodesiense infection (East African sleeping sickness). Four days after starting treatment with suramin, spinal fluid examination revealed mild mononuclear pleocytosis but no visible parasites. Melarsoprol treatment for possible encephalitis was considered but suramin treatment was continued alone. He improved and remains healthy seven years later. PCR on blood was positive for T. b. rhodesiense.
INTERPRETATION
African sleeping sickness can also affect tourists to endemic areas. Onset can be acute, life-threatening and requires treatment with antiparasitic drugs not generally available in Norwegian hospitals.
Topics: Humans; Male; Doxycycline; Exanthema; Fever; Malaria; Suramin; Trypanosomiasis, African; Middle Aged; Aged
PubMed: 38451073
DOI: 10.4045/tidsskr.23.0614