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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 -
Research in Veterinary Science May 2024African animal trypanosomosis is a parasitic disease that causes significant economic losses in livestock due to anaemia, loss of condition, emaciation, and mortality....
African animal trypanosomosis is a parasitic disease that causes significant economic losses in livestock due to anaemia, loss of condition, emaciation, and mortality. It is a key impediment to increased cattle output and productivity in Ethiopia. Cross-sectional entomological and parasitological studies were performed in the Gambella Region state of southwestern Ethiopia to estimate the prevalence of bovine trypanosomosis, apparent fly density, and potential risk factors. Blood samples were taken from 546 cattle for the parasitological study and analyzed using the buffy coat technique and stained with Giemsa. A total of 189 biconical (89) and NGU (100) traps were deployed in the specified districts for the entomological survey. The overall prevalence of trypanosomosis at the animal level was 5.5% (95% CI: 3.86-7.75). Trypanosoma vivax (50.0%), T. congolense (30.0%), T. brucei (20.0%), and no mixed trypanosome species were found. The prevalence of trypanosomosis was significantly (p < 0.05) affected by altitude, body score conditions, age, mean packed cell volume (PCV), and peasant associations, while sex and coat color had no significant effect. According to the entomological survey results, a total of 2303 flies were captured and identified as tsetse (Glossina pallidipes (5.3%)) and G. fuscipes fuscipes (3.3%) and other biting flies (Tabanus (60.1%) and Stomoxys (31.3%)). In the current study, the overall apparent density was 4.1 flies/trap/day. This study shows that trypanosomosis remains a significant cattle disease in the Gambella regional state even during the dry season. Thus, the findings support the necessity to improve vector and parasite control measures in the area.
Topics: Cattle; Animals; Cross-Sectional Studies; Ethiopia; Tsetse Flies; Insect Vectors; Trypanosomiasis, Bovine; Trypanosomiasis; Prevalence; Trypanosomiasis, African; Cattle Diseases
PubMed: 38513458
DOI: 10.1016/j.rvsc.2024.105227 -
Toxicology Research Apr 2024Benzene is known to be a common toxic industrial chemical, and prolonged benzene exposure may cause nervous system damage. At present, there were few studies on...
Benzene is known to be a common toxic industrial chemical, and prolonged benzene exposure may cause nervous system damage. At present, there were few studies on benzene-induced neurological damage. This research aimed to identify the protein biomarkers to explore the mechanism of nervous system damage caused by benzene. We established a benzene poisoning model of C57 mice by gavage of benzene-peanut oil suspension and identified differentially expressed proteins (DEPs) in brain tissue using tandem mass tag (TMT) proteomics. The results showed a significant weight loss and decrease in leukocyte and neutrophil counts in benzene poisoning mice compared to the control group. We also observed local cerebral oedema and small vessel occlusion in the cerebral white matter of benzene poisoning mice. TMT proteomic results showed that a total 6,985 proteins were quantified, with a fold change (FC) > 1.2 (or < 1/1.2) and P value <0.05 were considered as DEPs. Compared with the control group, we identified 43 DEPs, comprising 14 upregulated and 29 downregulated proteins. Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis results showed that the candidate proteins were mainly involved in cholesterol metabolism, complement and coagulation cascades, african trypanosomiasis, PPAR signaling pathway, and vitamin digestion and absorption. Three proteins, 2-hydroxyacylsphingosine 1-beta-galactosyltransferase (UGT8), Apolipoprotein A-I (APOA1) and Complement C3 (C3) were validated using immunoblotting and immunohistochemical. In conclusion, our study preliminarily investigated the mechanism of benzene toxicity to the nervous system by analyzing DEPs changes in the brain.
PubMed: 38496383
DOI: 10.1093/toxres/tfae036 -
Acta Tropica Jun 2024Animal African trypanosomosis (AAT) is an important global disease of livestock that causes economic losses of up to 4.5 billion US dollars per year. Thus, eliminating...
Animal African trypanosomosis (AAT) is an important global disease of livestock that causes economic losses of up to 4.5 billion US dollars per year. Thus, eliminating AAT in endemic countries will improve agricultural productivity and economic growth. To prevent AAT, vector control and the development of prophylactic drugs are crucial. Ascofuranone (AF) is a bioactive fungal compound with proven in vitro trypanocidal potency and in vivo treatment efficacy. However, the complex stereoselective synthesis of AF has prevented its cost-effective industrial production. Recently, a genetically modified strain of Acremonium egyptiacum fungus that produces a high yield of AF was developed. Therefore, we hypothesized that the oral administration of the AF-producing fungus itself may be effective against AAT. Hence, this study aimed to evaluate the prophylactic activity of orally administered dry-heat-sterilized A. egyptiacum against Trypanosoma congolense IL3000 infection using a mouse model. The survival rate was significantly prolonged (p = 0.009), and parasitemia was suppressed in all AF-fungus-treated groups (Group 1-9) compared with that in the untreated control group (Group 10). Hence, the trypanocidal activity of AF was retained after dry-heat-sterilization of the AF-producing fungus and that its oral administration effectively prevented AAT. Since AAT is endemic to rural areas with underdeveloped veterinary infrastructure, dry-heat-sterilized A. egyptiacum would be the most cost-effective potential treatment for AAT.
Topics: Animals; Trypanosomiasis, African; Trypanosoma congolense; Administration, Oral; Mice; Disease Models, Animal; Acremonium; Female; Parasitemia; Mice, Inbred BALB C
PubMed: 38494059
DOI: 10.1016/j.actatropica.2024.107185 -
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