RESUMEN
An integrated approach to innovatively counter the transmission of various arthropod-borne diseases to humans would benefit from strategies that sustainably limit onward passage of infective life cycle stages of pathogens and parasites to the insect vectors and vice versa. Aiming to accelerate the impetus towards a disease-free world amid the challenges posed by climate change, discovery, mindful exploitation and integration of active natural products in design of pathogen transmission-blocking interventions is of high priority. Herein, we provide a review of natural compounds endowed with blockade potential against transmissible forms of human pathogens reported in the last 2 decades from 2000 to 2021. Finally, we propose various translational strategies that can exploit these pathogen transmission-blocking natural products into design of novel and sustainable disease control interventions. In summary, tapping these compounds will potentially aid in integrated combat mission to reduce disease transmission trends.
Asunto(s)
Artrópodos , Productos Biológicos , Animales , Productos Biológicos/farmacología , Cambio Climático , Humanos , Insectos Vectores/parasitologíaRESUMEN
Intracellular effects exerted by phytochemicals eliciting insect growth-retarding responses during vector control intervention remain largely underexplored. We studied the effects of Zanthoxylum chalybeum Engl. (Rutaceae) (ZCE) root derivatives against malaria (Anopheles gambiae) and arbovirus vector (Aedes aegypti) larvae to decipher possible molecular targets. We report dose-dependent biphasic effects on larval response, with transient exposure to ZCE and its bioactive fraction (ZCFr.5) inhibiting acetylcholinesterase (AChE) activity, inducing larval lethality and growth retardation at sublethal doses. Half-maximal lethal concentrations (LC50) for ZCE against An. gambiae and Ae. aegypti larvae after 24-h exposure were 9.00 ppm and 12.26 ppm, respectively. The active fraction ZCFr.5 exerted LC50 of 1.58 ppm and 3.21 ppm for An. gambiae and Ae. aegypti larvae, respectively. Inhibition of AChE was potentially linked to larval toxicity afforded by 2-tridecanone, palmitic acid (hexadecanoic acid), linoleic acid ((Z,Z)-9,12-octadecadienoic acid), sesamin, ß-caryophyllene among other compounds identified in the bioactive fraction. In addition, the phenotypic larval retardation induced by ZCE root constituents was exerted through transcriptional modulation of ecdysteroidogenic CYP450 genes. Collectively, these findings provide an explorative avenue for developing potential mosquito control agents from Z. chalybeum root constituents.
Asunto(s)
Aedes , Culex , Insecticidas , Zanthoxylum , Animales , Trastornos del Crecimiento , Insecticidas/toxicidad , Larva , Control de Mosquitos , Mosquitos Vectores , Extractos VegetalesRESUMEN
OBJECTIVES: We and others have shown that Aspilia pluriseta is associated with various biological activities. However, there is a lack of information on its cytotoxicity. This has created an information gap about the safety of A. pluriseta extracts. As an extension to our recent publication on the antimicrobial activity and the phytochemical characterization of A. pluriseta root extracts, here we report on cytotoxicity of tested solvent fractions. We evaluated the potential cytotoxicity of these root extract fractions on Vero cell lines by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. RESULTS: We show that all solvent extract fractions (except methanolic solvent fractions) had cytotoxic concentration values that killed 50% of the Vero cells (CC50) greater than 20 µg/mL and selectivity index (SI) greater than 1.0. Taken together, we demonstrate that, A. pluriseta extract fractions' earlier reported bioactivities are within the acceptable cytotoxicity and selective index limits. This finding scientifically validates the potential use of A. pluriseta in the discovery of safe therapeutics agents.
Asunto(s)
Asteraceae , Extractos Vegetales , Animales , Chlorocebus aethiops , Fitoquímicos , Extractos Vegetales/toxicidad , Células VeroRESUMEN
Aspilia pluriseta is associated with various bioactivities, although with limited scientific justification. In this study, we evaluated the antimicrobial activity, and characterized the phytochemicals of root extracts of A. pluriseta aimed at validating its therapeutic potential. We used BACTEC MGIT™ 960 system to test for antitubercular activity, disc-diffusion together with the microdilution method to evaluate antimicrobial activities and qualitative phytochemical tests together with gas chromatography-mass spectrometry (GC-MS) analysis to determine the phytochemicals that associated with A. pluriseta extracts activity. We show that methanolic crude extract (at 1 g/mL) had high Mycobacterium tuberculosis (MTB) inhibitory activity (0 growth unit) and considerable potency against Escherichia coli (11.7 mm), Staphylococcus aureus (9.0 mm), and Candida albicans (7.7 mm). All the extract fractions exerted remarkable antimycobacterial activities with minimum inhibitory activity of between 6.26 - 25 µg/mL. The highest antimicrobial activity of petroleum ether and dichloromethane fraction was against E. coli at inhibition zone diameters of 8.3 mm, and 8.0 mm, respectively, while ethyl acetate fraction was against S. aureus with an inhibition zone of 8.7 mm. Methanolic fraction exhibited broad-spectrum activity against 87.5% of the tested microbes (inhibition zones 6.3-8.3 mm). Furthermore, we qualitatively detected terpenoids, alkaloids, and phenolics such as flavonoids, and anthraquinones in extract fractions. GC-MS analysis detected an abundance of fatty acid esters, 2-hydroxy-1-(hydroxymethyl) ethyl ester-hexadecanoic acid, and 2,3-dihydroxy propyl ester-octadecanoic acid and four alkanes. Taken together, we show that A. pluriseta extract fractions (especially ethyl acetate and methanolic fractions) have strong selective antitubercular activity, and thus, we scientifically validate the use of A. pluriseta as a potential source for the discovery of novel antitubercular agents.
RESUMEN
Aneuploidy can instigate tumorigenesis. However, mutations in genes that control chromosome segregation are rare in human tumors as these mutations reduce cell fitness. Screening experiments indicate that the knockdown of multiple classes of genes that are not directly involved in chromosome segregation can lead to aneuploidy induction. The possible contribution of these genes to cancer formation remains yet to be defined. Here we identified gene knockdowns that lead to an increase in aneuploidy in checkpoint-deficient human cancer cells. Computational analysis revealed that the identified genes overlap with recurrent mutations in human cancers. The knockdown of the three strongest selected candidate genes (ORP3, GJB3, and RXFP1) enhances the malignant transformation of human fibroblasts in culture. Furthermore, the knockout of Orp3 results in an aberrant expansion of lymphoid progenitor cells and a high penetrance formation of chromosomal instable, pauci-clonal B-cell lymphoma in aging mice. At pre-tumorous stages, lymphoid cells from the animals exhibit deregulated phospholipid metabolism and an aberrant induction of proliferation regulating pathways associating with increased aneuploidy in hematopoietic progenitor cells. Together, these results support the concept that aneuploidy-inducing gene deficiencies contribute to cellular transformation and carcinogenesis involving the deregulation of various molecular processes such as lipid metabolism, proliferation, and cell survival.
Asunto(s)
Aneuploidia , Proteínas de Unión a Ácidos Grasos/deficiencia , Proteínas de Unión a Ácidos Grasos/genética , Técnicas de Silenciamiento del Gen , Linfoma de Células B/genética , Animales , Línea Celular Tumoral , Transformación Celular Neoplásica , Fibroblastos/patología , Humanos , Linfoma de Células B/patología , RatonesRESUMEN
Malaria presents an overwhelming public health challenge, particularly in sub-Saharan Africa where vector favourable conditions and poverty prevail, potentiating the disease burden. Behavioural variability of malaria vectors poses a great challenge to existing vector control programmes with insecticide resistance already acquired to nearly all available chemical compounds. Thus, approaches incorporating plant-derived compounds to manipulate semiochemical-mediated behaviours through disruption of mosquito olfactory sensory system have considerably gained interests to interrupt malaria transmission cycle. The combination of push-pull methods and larval control have the potential to reduce malaria vector populations, thus minimising the risk of contracting malaria especially in resource-constrained communities where access to synthetic insecticides is a challenge. In this review, we have compiled information regarding the current status of knowledge on manipulation of larval ecology and chemical-mediated behaviour of adult mosquitoes with plant-derived compounds for controlling mosquito populations. Further, an update on the current advancements in technologies to improve longevity and efficiency of these compounds for field applications has been provided.
Asunto(s)
Transmisión de Enfermedad Infecciosa/prevención & control , Repelentes de Insectos/farmacología , Malaria/prevención & control , Control de Mosquitos/métodos , Feromonas/farmacología , Fitoquímicos/farmacología , Animales , HumanosRESUMEN
Successful optimization of plant-derived compounds into control of nuisance insects would benefit from scientifically validated targets. However, the close association between the genotypic responses and physiological toxicity effects mediated by these compounds remains underexplored. In this study, we evaluated the sublethal dose effects of proanthocyanidins (PAs) sourced from green tea (Camellia sinensis) on life history traits of Anopheles gambiae (sensu stricto) mosquitoes with an aim to unravel the probable molecular targets. Based on the induced phenotypic effects, genes selected for study targeted juvenile hormone (JH) biosynthesis, signal transduction, oxidative stress response and xenobiotic detoxification in addition to vitellogenesis in females. Our findings suggest that chronic exposure of larval stages (L3/L4) to sublethal dose of 5 ppm dramatically extended larval developmental period for up to 12 days, slowed down pupation rates, induced abnormal larval-pupal intermediates and caused 100% inhibition of adult emergence. Further, females exhibited significant interference of fecundity and egg hatchability relative to controls (p < 0.001). Using reverse transcription quantitative polymerase chain reaction (RT-qPCR), our findings show that PA-treated larvae exhibited significant repression of AgamJHAMT (p < 0.001), AgamILP1 (p < 0.001) and AgamCYP6M2 (p < 0.001) with up-regulation of Hsp70 (p < 0.001). Females exposed as larvae demonstrated down-regulation of AgamVg (p = 0.03), AgamILP1 (p = 0.009), AgamCYP6M2 (p = 0.05) and AgamJHAMT (p = 0.02). Our findings support that C. sinensis proanthocyanidins affect important vectorial capacity components such as mosquito survival rates and reproductive fitness thus could be potentially used for controlling populations of malaria vectors.
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Anopheles/efectos de los fármacos , Sistema Enzimático del Citocromo P-450/genética , Insulina/metabolismo , Hormonas Juveniles/metabolismo , Larva/efectos de los fármacos , Metiltransferasas/metabolismo , Proantocianidinas/farmacología , Té/química , Animales , Anopheles/genética , Anopheles/crecimiento & desarrollo , Relación Dosis-Respuesta a Droga , Larva/crecimiento & desarrolloRESUMEN
BACKGROUND: Anopheles arabiensis and A. gambiae (sensu stricto) are the most prolific Afrotropical malaria vectors. Population control efforts of these two vectors have been hampered by extremely diverse larval breeding sites and widespread resistance to currently available insecticides. Control of mosquito larval stages using bioactive compounds of plant origin has the potential to suppress vector populations leading to concomitant reduction in disease transmission rates. In this study, we evaluated the efficacy of Camellia sinensis crude leaf extract and its fraction against the larvae of A. arabiensis and A. gambiae (s.s.). METHODS: Late third/early fourth instar larvae (L3/L4) of A. arabiensis and A. gambiae (s.s.) were exposed to increasing doses of C. sinensis leaf extract and its active fraction for 72 h, with mortality rates recorded every 24 h in both control and test groups. Ultra performance liquid chromatography electron spray ionization quadruple time of flight coupled with mass spectrometry (UPLC/ESI-Qtof/MS) was used to determine the main active constituents in the fraction. RESULTS: The major bioactive chemical constituents in the C. sinensis leaf extract were identified to be proanthocyanidins. The extract significantly interfered with larval survival and adult emergence in both species (ANOVA, F (5,24) = 1435.92, P < 0.001). Additionally, larval exposure to crude extract at 250 ppm and 500 ppm for 24 h resulted in larval mortality rates of over 90 % in A. gambiae (s.s.) and 75 % in A. arabiensis. A relatively lower concentration of 100 ppm resulted in moderate mortality rates of < 50 % in both species, but induced growth disruption effects evident as abnormal larval-pupal intermediates and disrupted adult emergence. The estimated LC50 concentrations of the crude leaf extract against A. arabiensis and A. gambiae (s.s.) larvae at 24 h were 154.58 ppm (95 % CI: 152.37-158.22) and 117.15 ppm (95 % CI: 112.86-127.04), respectively. The bioactive polar fraction caused 100 % larval mortality in both vector species at 25 ppm. CONCLUSIONS: Our findings demonstrate the potential of green tea extract and its active constituents in disrupting mosquito larval development. This could contribute to the control of mosquito populations and improved management of malaria.