Basanez MG et al. (2001) Trends Parasitol "Models for the population biology and control of human onchocerciasis."

Basanez MG, Ricardez-Esquinca J

[Trends Parasitol, 2001]

The absence of animal models in which to reproduce successfully the complete life cycle of Onchocerca volvulus has hindered progress towards unravelling the processes involved in the regulation of parasite abundance in the vertebrate host. Mathematical frameworks have been developed to explore the consequences of such processes in determining parasite population dynamics and the effect on these of control interventions. Post-control predictions are strongly influenced by the assumptions concerning the reproductive life span of the adult female worm (the longest-lived parasite stage) and the distribution of its survival times, and this notion is important to all frameworks. Here, we review the development of models concerning onchocerciasis and discuss the various approaches that have been used, presenting a deterministic framework with parameter values estimated from the Mexican onchocerciasis control programme. This model is used to evaluate interventions combining the removal of adult worms (nodulectomy) and the microfilaricidal and possibly sterilizing effect of ivermectin.

Basanez MG et al. (1999) Philos Trans R Soc Lond B Biol Sci "Population biology of human onchocerciasis."

Basanez MG, Boussinesq M

[Philos Trans R Soc Lond B Biol Sci, 1999]

Human onchocerciasis (river blindness) is the filarial infection caused by Onchocerca volvulus and transmitted among people through the bites of the Simulium vector. Some 86 million people around the world are at risk of acquiring the nematode, with 18 million people infected and 600,000 visually impaired, half of them partially or totally blind. 99% of cases occur in tropical Africa; scattered foci exist in Latin America. Until recently control programmes, in operation since 1975, have consisted of antivectorial measures. With the introduction of ivermectin in 1988, safe and effective chemotherapy is now available. With the original Onchocerciasis Control Programme of West Africa coming to an end, both the new African Programme for Onchocerciasis Control and the Onchocerciasis Elimination Programme for the Americas, rely heavily on ivermectin self-sustained mass delivery. In consequence, the need for understanding the processes regulating parasite abundance in human and simuliid populations is of utmost importance. We present a simple mathematical framework built around recent analyses of exposure- and density-dependent processes operating, respectively, within the human and vector hosts. An expression for the basic reproductive ratio, R0, is derived and related to the minimum vector density required for parasite persistence in localities of West Africa in general and northern Cameroon in particular. Model outputs suggest that constraints acting against parasite establishment in both humans and vectors are necessary to reproduce field observations, but those in humans may not fully protect against reinfection. Analyses of host age-profiles of infection prevalence, intensity, and aggregation for increasing levels of endemicity and intensity of transmission in the Vina valley of northern Cameroon are in agreement with these results and discussed in light of novel work on onchocerciasis immunology.

Basanez MG et al. (2000) Parasitology "Onchocerca-Simulium complexes in Venezuela: can human onchocerciasis spread outside its present endemic areas?"

Villamizar NJ, Basanez MG, Frontado HL, Yarzabal L

[Parasitology, 2000]

The compatibility between sympatric and allopatric combinations of Onchocerca volvulus-anthropophilic species of Simulium was studied in the north-eastern focus of human onchocerciasis as well as in a densely populated locality of the Amazonas State in Venezuela. The objectives were to test the conjecture that local adaptation exists between the parasite and its vectors (the Onchocerca-Simulium complex hypothesis), and assess the possibility of the infection spreading from its present distributional range. For the homologous combination, O. volvulus-S. metallicum cytospecies E in Anzoategui State (north-eastern focus), parasite yield was 45% in contrast to 1% for the heterologous, southern parasite-S. metallicum infection. This was significantly lower than the parasite yield (4-10%) expected after allowing for the effect of density-dependent limitation of infective larval output described in this paper for S. metallicum. The population of S. exiguum s.l. from southern Venezuela allowed no larval development beyond the L1 stage of either northern or southern parasites. Mechanisms for such refractoriness probably operate at the level of the thoracic muscles, not affecting microfilarial uptake or migration out of the bloodmeal. The parasite yield of southern O. volvulus in S. oyapockense s.l. flies biting man at Puerto Ayacucho (Amazonas) was about 1%, in agreement with the figures recorded for highly compatible sympatric combinations such as O. volvulus-S. ochraceum s.l. in Guatemala. No infective larval development of the northern parasite was observed in southern S. oyapockense. These results, together with considerations of typical worm burdens in the human host, presence/absence of armed cibaria in the simuliids, parasite-induced vector mortality, and fly biting rates, suggest a lower potential for onchocerciasis to spread between the northern and southern endemic areas of Venezuela than that between Amazonian hyperendemic locations and settlements outside this focus with high densities of S. oyapockense s.l.

Basanez MG et al. (2002) Am J Trop Med Hyg "Transmission intensity and the patterns of Onchocerca volvulus infection in human communities."

Collins RC, Porter CH, Brandling-Bennett D, Basanez MG, Little MP

[Am J Trop Med Hyg, 2002]

We focus on possible constraints upon Onchocerca volvulus establishment in humans in relation to exposure rates to infective larvae (L3) as measured by the annual transmission potential (ATP). We use mathematical and statistical modeling of pre-control west African (savanna), Mexican, and Guatemalan data to explore two hypotheses relating human infection to transmission intensity: microfilarial (mf) loads either saturate with increasing ATP or become (asymptotically) proportional to the ATP. The estimated proportion of L3 developing into adult worms ranged from 7% to 0.3% (low and high intensity areas, respectively). Relationships between mf prevalence and both mf and transmission intensity were nonlinear and statistically similar between west Africa (Simulium damnosum s.l.) and Meso America (S. ochraceum s.l.). This similarity extended to the relationship between mf intensity and ATP. The critical biting rates for onchocerciasis introduction and persistence (which depended on vector competence and host preference), were approximately 10-fold higher in settings where onchocerciasis is transmitted by S. ochraceum than in those where the vector is S. damnosum. A role for focal vector control in Mexico and Guatemala, in addition to nodulectomy and ivermectin, is suggested.

Basanez MG et al. (1994) Parasitology "Density-dependent processes in the transmission of human onchocerciasis: intensity of microfilariae in the skin and their uptake by the simuliid host."

Villamizar NJ, Prod'hon J, Medley GF, Frontado H, Anderson RM, Boussinesq M, Basanez MG

[Parasitology, 1994]

The transmission success of Onchocerca volvulus is thought to be influenced by a variety of regulatory or density-dependent processes that act at various points in the two-host life-cycle. This paper examines one component of the life-cycle, namely, the ingestion of microfilariae by the simuliid vector, to assess the relationship between intake of larvae and the density of parasites in the skin of the human host. Analysis is based on data from three areas in which onchocerciasis is endemic and includes published information as well as new data collected in field studies. The three areas are: Guatemala (Simulium ochraceum s.l.), West and Central Africa (savanna members of the S. damnosum complex), and South Venezuela (S. guianense). The data record experimental studies of parasite uptake by flies captured in the field and fed to repletion on locally infected subjects who harboured varying intensities of dermal microfilarial infection. Regression analyses of log transformed counts of parasite burdens ingested by the flies plotted against log transformed counts of microfilariae per mg of skin revealed little evidence for saturation in parasite uptake by the flies as the intensity in the human host increased. There was a positive and highly significant rank correlation between both variables for the three blackfly species. In an alternative analysis a model was fitted to data on prevalence of flies with ingested microfilariae (mff) versus dermal mean intensities. The model assumed an overdispersed distribution of the number of mff/fly and a given functional relationship between intake and skin load. The results of both approaches were consistent. It is concluded that parasite ingestion by the vector host is not strongly density dependent in the three geographical areas and ranges of dermal loads examined. It therefore appears that this transmission process is of reduced importance as a regulatory mechanism in the dynamics of parasite population growth.

Basanez MG et al. (2008) Lancet Infect Dis "Effect of single-dose ivermectin on Onchocerca volvulus: a systematic review and meta-analysis."

Boakes E, Boussinesq M, Pion SD, Filipe JA, Basanez MG, Churcher TS

[Lancet Infect Dis, 2008]

The broad-spectrum antiparasitic drug ivermectin was licensed for use against onchocerciasis in 1987, yet the mechanisms by which it exerts a fast decrease and long-lasting suppression of Onchocerca volvulus microfilaridermia, and inhibition of microfilarial release by female worms remain largely unknown. A better understanding of the effects of ivermectin on O volvulus microfilariae and macrofilariae is crucial to improve our ability to predict the long-term effect of treatment. We did a systematic review of individual and population-based ivermectin trials to investigate the temporal dynamics of the drug's microfilaricidal and embryostatic efficacy after administration of a single, standard dose (150 microg/kg). Meta-analyses on data from 26 microfilarial and 15 macrofilarial studies were linked by a mathematical model describing the dynamics of potentially fertile female parasites to skin microfilariae. The model predicts that after treatment, microfilaridermia would be reduced by half after 24 h, by 85% after 72 h, by 94% after 1 week, and by 98-99% after 1-2 months, the latter also corresponding to the time when the fraction of females harbouring live microfilariae is at its lowest (reduced by around 70% from its original value). Our results provide a baseline microfilarial skin repopulation curve against which to compare studies done after long-term treatment.

Xie Z et al. (2020) Biomed Pharmacother "Magnolol alleviates Alzheimer's disease-like pathology in transgenic C. elegans by promoting microglia phagocytosis and the degradation of beta-amyloid through activation of PPAR-."

Zhang Z, Xu J, Jiang Y, Wang H, Xie Z, Holscher C, Zeng H, Yang Q, Fu Y, Zhao J

[Biomed Pharmacother, 2020]

This study aims to investigate whether magnolol (MG), a natural neolignane compound, can prevent AD induced by beta-amyloid (A) and the possible mechanisms involved. MG dose-dependently reduces A deposition, toxicity and memory impairment caused by A in transgenic C. elegans. More importantly, these effects are reversed by GW9662, a selective peroxisome proliferator-activated receptor- (PPAR-) antagonist. MG is more effective in enhancing PPAR- luciferase levels than honokiol (HK). Meanwhile, MG has the potential to bind with the ligand binding domain of PPAR- (PPAR--LBD). As expected, MG inhibited the luciferase activity of NF-B and its target genes of inflammatory cytokines, and this effect was blocked by GW9662. The luciferase activity of Nrf2-ARE expression can be activated by MG and decreased A-induced reactive oxygen species (ROS). The target gene LXR of PPAR- is activated by MG, which upregulates ApoE and promotes microglia phagocytosis and the degradation of A, and these effects were also reversed by GW9662. In summary, MG can attenuate A-induced AD and the underlying mechanism is the reduction of inflammation and promotion of phagocytosis and degradation of A, which is dependent on PPAR-.

Frandsen J et al. (2020) ACS Chem Neurosci "Neural Glyoxalase Pathway Enhancement by Morin Derivatives in an Alzheimer's Disease Model."

Frandsen J, Narayanasamy P, Choi SR

[ACS Chem Neurosci, 2020]

The gyloxalase pathway (GP) is an antioxidant defense system that detoxifies metabolic byproduct methylglyoxal (MG). Through sequential reactions, reduced glutathione (GSH), glyoxalase I (glo-1), and glyoxalase II (glo-2) convert MG into D-lactate. Spontaneous reactions involving MG alter the structure and function of cellular macromolecules through the formation of inflammatory advanced glycation endproducts (AGEs). Accumulation of MG and AGEs in neural cells contributes to oxidative stress (OS), a state of elevated inflammation commonly found in neurodegenerative diseases including Alzheimer's Disease (AD). Morin is a common plant-produced flavonoid polyphenol that exhibits the ability to enhance the GP-mediated detoxification of MG. We hypothesize that structural modifications to morin will improve its inherent GP enhancing ability. Here we synthesized a morin derivative, dibromo-morin (DBM) and formulated a morin encapsulated nanoparticle (MNP) - and examined their efficacy in enhancing neural GP activity. Cultured mouse primary cerebellar neurons and Caenorhabditis elegans were induced to a state of OS with MG, and treated with morin, DBM, and MNP. Results indicated the morin derivatives were more effective compared to the parent compound in neural GP enhancement and preventing MG-mediated OS.

Vladimir V Bakaev et al. (2003) Worm Breeder's Gazette "An attempt to slow aging in C. elegans. 32. No positive effect of peroxide"

Vladimir V Bakaev, Lyudmila M Bakaeva

[Worm Breeder's Gazette, 2003]

The purpose of this study was to investigate the effect of hydrogen peroxide in water solutions on the nematode life span. In this experiment hydrogen peroxide was used in following dilutions: 100 mg/L, 10 mg/L, 1 mg/L, 0.1 mg/L, 0.01 mg/L and 0.001 mg/L. Three adult animals (3-5 days old) were kept in microtitre wells containing 0.5 ml of liquid medium (with E. coli and without hydrogen peroxide) during 4 hours, then they were discarded and newborn larvae were transferred in next wells (without hydrogen peroxide in medium) every day (one worm in one well) beginning from third day. Then, beginning from 3rd day, these worms were transferred every day in next wells containing medium with hydrogen peroxide in any concentration. This investigation was carried out in temperature +21C and in the darkness. The obtained results are presented in the following table. Conclusion: If hydrogen peroxide solution was applied to C. elegans, it was not able to increase their mean longevity significantly in comparison with control.

Schulz-Key H et al. (1977) Tropenmed Parasitol "Isolation of living adult Onchocerca volvulus from nodules."

Albiez EJ, Buttner DW, Schulz-Key H

[Tropenmed Parasitol, 1977]

A technique for the isolation of adult Onchocerca volvulus from excised onchocercomata is described. The nodules are incubated in medium 199 containing 1-5 mg collagenase and 0.2 mg gentamicin per ml for 6-48 hours in a waterbath at 30-37 degrees C. A proportion of the worms can be isolated alive.