-
[
Geroscience,
2020]
Terpenes and their derivatives have been used conventionally as potential dietary supplements to boost the nutritional value of endless food products. Several plant-based complex terpenoid and their derivatives have been reported for a wide range of medicinal and nutritional properties. However, their simple counterparts, whose production is relatively easy, sustainable, and economic from food-grade microbial sources, have not been studied yet for any such biological activities. The present study aimed to investigate the longevity-promoting property and neuromodulatory effects of 3,3-dimethylallyl alcohol (Prenol), one of the simplest forms of terpenoid and a constituent of fruit aroma, in the animal model Caenorhabditis elegans. Prenol supplementation (0.25mM) augmented the lifespan of wild-type nematodes by 22.8% over the non-treated worms. Moreover, a suspended amyloid- induced paralysis and reduced -synuclein aggregation were observed in Prenol-treated worms. The lifespan extending properties of Prenol were correlated with ameliorated physiological parameters and increased stress (heat and oxidative) tolerance in C. elegans. In silico and gene-specific mutant studies showed that pro-longevity transcription factors DAF-16, HSF-1, and SKN-1 were involved in the improved lifespan and health-span of Prenol-treated worms. Transgenic green fluorescent protein-reporter gene expression analysis and relative mRNA quantification (using real-time PCR) demonstrated an increase in the expression of DAF-16, HSF-1, and SKN-1 transcription factors and their downstream target genes in Prenol-treated worms. Together, the findings suggest that small molecules, like Prenol, could be explored as a potential alternate to develop therapeutics against aging and age-related ailments.
-
[
Pharmacogn Mag,
2015]
BACKGROUND: Bacopa monnieri (L.) Pennell, commonly known as Brahmi is an important medicinal plant traditionally used as memory enhancer and antiepileptic agent. OBJECTIVE: The present study investigated antioxidant and stress resistance potentials of B. monnieri aqueous extract (BMW) using Caenorhabditis elegans animal model system. MATERIALS AND METHODS: The antioxidant activity of the BMW was measured using in vitro (DPPH, reducing power and total polyphenol content) and in vivo (DCF-DA assay) assays. The antistress potential of BMW (0.1, 0.01, and 0.001 mg/ml) was evaluated through thermal stress (37C) and oxidative stress (10 mM paraquat) using C. elegans. Quantification of the HSP-16.2 level was done using CL2070 transgenic worms. RESULTS: Present study reveals that BMW possess in vitro and in vivo antioxidant activities. BMW significantly enhanced stress tolerance and increased the mean lifespan of worms during thermal and oxidative stress, although it did not extend lifespan at 20C and attenuated age dependent decline in physiological behaviors. Moreover, it was shown that BMW was able to up-regulate expression of stress associated gene
hsp-16.2, which significantly (P < 0.001) extends the mean lifespan of worms under stress conditions. CONCLUSION: The study strongly suggests that BMW acts as an antistressor and potent reactive oxygen species scavenger which enhances the survival of the worms in different stress conditions.
-
[
International Worm Meeting,
2019]
Isoprenoid, their derivatives, and isoprenoid-based food supplements have an ever-increasing impact on human health and shown positive implications on aging and age-related ailments. Isoprenol (3-methyl-3- buten-1-ol), a hemiterpene-based unsaturated C5 alcohol and one of the primary products of isoprenoid pathways is synthesised in biological system by dephosphorylation of isopentenyl pyrophosphate (IPP) by various endogenous phosphatases or pyrophosphatases. It is found in trace amounts in fruits, where, it acts as an important precursor for various biosynthetic pathways. The present investigation demonstrates the longevity-promoting effects of 3-methyl-3-buten-1-ol (isoprenol) in the animal model Caenorhabditis elegans that might be served as a lead nutraceutical in geriatric research. Our results showed that 0.5 mM isoprenol extended the mean lifespan of worms by 25% in comparison to control worms. Isoprenol also significantly enhanced survival of the worms under various stress conditions. It was found that the longevity-promoting effects of isoprenol were associated with improved age-associated physiological behavior and reduced intracellular reactive oxygen species (ROS) accumulation. Finally, studies with gene-specific mutants revealed the involvement of pro-longevity transcription factors (TFs) DAF-16 and SKN-1 with simultaneous over-expression of GST-4 and SOD-3 in isoprenol treated worms. In silico analysis revealed the binding affinity of isoprenol with DAF-16 and SKN-1 transcription factors. Together, the findings suggest that isoprenol is able to enhance the lifespan of C. elegans and embarks its potential in the developments of formulations for age-related ailments.
-
[
Folia Parasitol (Praha),
1992]
The chemotherapeutic efficacy of mebendazole given in combination with Freund's complete adjuvant (FCA) against Brugia malayi in multimammate rat was evaluated. Animals treated with mebendazole, orally at 200 mg/kg x 5 consecutive days along with FCA given subcutaneously (s.c.) on day -10, day 0 and day +15 of the drug treatment killed 48.51% of the adult worms. This drug given alone at the same regimen and by the same route showed only 18.7% mortality rate on adults. Mebendazole given intraperitoneally along with FCA given s.c., however, was four times more efficacious as filaricide than mebendazole alone. Nevertheless, the animals receiving FCA alone also revealed 23.5% mortality rate of adult worms. The animals receiving a combination therapy or FCA alone showed significant increase in antibody titre to the filariae which however decreased in the later stages. No enhancement of antibody level could be detected in animals treated with mebendazole alone. The non-specific immunopotentiation induced by FCA appeared to play a major role in enhancing the activity of mebendazole.
-
[
Parasitol Res,
1988]
The rate of transmammary transmission of Stronglyloides ratti was examined in albino rats in terms of the route of subcutaneous (s.c.) migration from the infection site (the skin) to the cranium. Inoculation sites nearer the cranium resulted in less frequent transmammary infection. The maximum number of adult worms was recovered from the sucklings when the mother was inoculated in her hindquarter and sucklings were allowed to feed for 30-36 h after inoculation (AI). Few worms were recovered from sucklings when they were allowed to nurse during periods of less than 24 h AI or greater than 42 h AI. In lactating mothers, larval infection of the mammary glands was commonly observed, and these larvae showed an increased esophagus length. In nonlactating mothers, most larvae completed their migration to the cranium within 36 h AI.
-
Engelen M, Taylor MJ, Pionnier N, Lachaud S, Tayong DB, Fombad FF, Chounna PWN, Turner JD, Quirynen L, Njouendou AJ, Wanji S, Steven A, Gandjui NVT, Ward SA, Chunda VC, Tekle F, Ndzeshang BL, Baeten B, Aljayyoussi G, Akumtoh DN, Sjoberg HT, Metuge HM
[
PLoS Negl Trop Dis,
2019]
The Onchocerca ochengi adult implant and Brugia malayi microfilariemic Severe-Combined Immunodeficient (SCID) mouse models are validated screens to measure macrofilaricidal and microfilaricidal activities of candidate onchocerciasis drugs. The purpose of this study was to assess whether 5 daily sub-cutaneous (s.c.) injections of standard flubendazole (FBZ) suspension (10mg/kg), a single s.c. injection (10mg/kg) or 5 daily repeated oral doses of FBZ amorphous solid dispersion (ASD) formulation (0.2, 1.5 or 15mg/kg) mediated macrofilaricidal efficacy against O. ochengi male worms implanted into SCID mice. The direct microfilaricidal activity against circulating B. malayi microfilariae of single dose FBZ ASD formulation (2 or 40 mg/kg) was also evaluated and compared against the standard microfilaricide, ivermectin (IVM). Systemic exposures of FBZ/FBZ metabolites achieved following dosing were measured by pharmacokinetic (PK) bioanalysis. At necropsy, five weeks following start of FBZ SC injections, there were significant reductions in burdens of motile O. ochengi worms following multiple injections (93%) or single injection (82%). Further, significant proportions of mice dosed following multiple injections (5/6; 83%) or single injection (6/10; 60%) were infection negative (drug-cured). In comparison, no significant reduction in recovery of motile adult O. ochengi adult worms was obtained in any multiple-oral dosage group. Single oral-dosed FBZ did not mediate any significant microfilaricidal activity against circulating B. malayi mf at 2 or 7 days compared with >80% efficacy of single dose IVM. In conclusion, multiple oral FBZ formulation doses, whilst achieving substantial bioavailability, do not emulate the efficacy delivered by the parenteral route in vivo against adult O. ochengi. PK analysis determined FBZ efficacy was related to sustained systemic drug levels rather than achievable Cmax. PK modelling predicted that oral FBZ would have to be given at low dose for up to 5 weeks in the mouse model to achieve a matching efficacious exposure profile.
-
Bradley BA, Watnick T, Garcia-Gonzalez MA, Albrecht PJ, Germino GG, Inglis PN, Beales PL, Rice FL, Katsanis N, Tan PL, Caterina MJ, Barr T, Huang SM, Leroux MR, Coforio S, Mitsuma N
[
Proc Natl Acad Sci U S A,
2007]
Reception and interpretation of environmental stimuli is critical for the survival of all organisms. Here, we show that the ablation of BBS1 and BBS4, two genes mutated in Bardet-Biedl syndrome and that encode proteins that localize near the centrioles of sensory neurons, leads to alterations of s.c. sensory innervation and trafficking of the thermosensory channel TRPV1 and the mechanosensory channel STOML3, with concomitant defects in peripheral thermosensation and mechanosensation. The thermosensory phenotype is recapitulated in Caenorhabditis elegans, because BBS mutants manifest deficient thermosensory responses at both physiological and nociceptive temperatures and defective trafficking of OSM-9, a polymodal sensory channel protein and a functional homolog of TRPV1 or TRPV4. Our findings suggest a hitherto unrecognized, but essential, role for mammalian basal body proteins in the acquisition of mechano- and thermosensory stimuli and highlight potentially clinical features of ciliopathies in humans.
-
[
Acta Trop,
2011]
Filarial parasites survive by inducing tolerance in host but the antigens and mechanisms involved are not clear. Recently we found that BmAFI, a Sephadex G-200 eluted fraction of Brugia malayi adult worm extract, stimulates IL-10 release from THP-1 cells. In the present study, we determined the SDS-PAGE profile of BmAFI and infective 3rd stage larva (L3), investigated the effect of pre-sensitization of host with BmAFI on the survival and development of L3 in the non-permissive peritoneal cavity (p.c.) of the permissive host Mastomys coucha and in the p.c. of non-permissive Swiss mice, and studied immunological correlates for the observed effects. The parasite development and burden in p.c., was determined in sensitized infected M. coucha and Swiss mice and the release of TGF-, IL-4, IL-10, IL-13, IFN- and NO, cellular proliferative response to Con A and BmAFI and levels of IgG subclasses and IgE were determined in sensitized infected M. coucha. Cellular proliferative response to Con A and BmAFI, mRNA expression of GATA-3, CTLA-4 and T-bet were determined in sensitized Swiss mice. In addition, the parasitological parameter was also studied in BmAFI-sensitized M. coucha exposed to the infection by standard subcutaneous (s.c.) route to assess whether sensitization enhances the intensity of infection. BmAFI-sensitization permitted survival of L3 and their development to adult stage by day 60 p.i. in the p.c. of M. coucha; in non-sensitized animals L3 could molt to L4 only and no parasite could be recovered beyond day 30 p.i. In M. coucha that received infection by s.c. route, pre-sensitization with BmAFI enhanced the microfilaraemia and adult worm recovery. In sensitized Swiss mice L3 could successfully molt to L4 in p.c. with improved recovery of parasite. BmAFI sensitization upregulated TGF- and IL-10 release, IgG1 and IgG2b levels, GATA-3 and CTLA-4 mRNA expression, suppressed the cellular proliferative response and downregulated Con A stimulated response, IgE, IL-13, IFN- and NO responses. Immunoblot analysis showed that the BmAFI antiserum also strongly reacts with some L3 molecules. The results show, for the first time, that sensitization with the anti-inflammatory BmAFI which shares some of its molecules with those in L3, facilitates parasite survival in the non-permissive p.c. of the permissive host M. coucha, render a non-permissive Swiss mouse partially permissive to infection and enhances parasite load in M. coucha receiving the infection through permissive s.c. route by evoking a modified Th2 type of response and anti-inflammatory milieu. In conclusion, the findings suggest that the anti-inflammatory BmAFI fraction facilitates survival of B. malayi infection even in non-permissive environment.
-
[
International C. elegans Meeting,
1995]
Twelve contigs of cosmids and yeast artificial chromosomes (YACs) span more than 95Mb of the 100Mb C.elegans genome. 650 markers link the physical and genetic maps.Hybridisation of tag-sequenced cDNA clones to a map-representative set of YACs indicates that the map incorporates in excess of 99.8% of genes. The map is accessible in ACeDB. We (S.C.) are investigating the representation by bacterial artificial chromosomes (BACs) of regions of the genome not represented by cosmids. Two grids of YACs, of 958 clones ('Poly2') and 223 clones ('Suppoly') are available on request. The latter represents regions of the genome that have been characterised or better defined since the selection of clones for the former. Cosmid clones and YAC grids are available from the Sanger Centre (requests to alan@sanger.ac.uk; FAX 01223 494919). YAC clones and 'cm' series cDNA clones are available from the Sanger Centre or Washington University (rw@nematode. wustl.edu; FAX 314 362 2985).
-
[
Parasitol Res,
1989]
Litomosoides carinii-, Acanthocheilonema viteae- or Brugia malayi-infected Mastomys natalensis were sensitised against sheep red blood cells (SRBC) on various occasions after infection to determine the effect of filarial infections on the immune response to a non-filarial antigen. The phagocytic activity of the reticuloendothelial system (RES) was controlled in vivo by the elimination of 51Cr-labelled SRBC. Antibody titres against SRBC (agglutinating and lytic antibodies) were similar to those of uninfected controls in L. carinii- or B. malayi-infected Mastomys sensitised during prepatency or early patency up to 90 days post infection (p.i.) but were reduced in animals sensitised during patency. A significant inverse correlation existed between anti-SRBC antibody titres and microfilaraemia levels. In contrast, A. viteae-infected Mastomys showed reduced humoral anti-SRBC responses at the end of prepatency, whereas the response tended towards normal with increasing parasitaemia. Delayed-type hypersensitivity (DTH) against SRBC was measured as footpad swelling after sensitisation by the s.c. or i.v. route and intraplantar challenge. DTH reactions were reduced during prepatency in all infections after s.c. sensitisation. During patency, 24-h reactions were similar to those of age-matched controls but the swelling persisted 24 or 48 h longer than in the latter. In A. viteae infections, even enhanced 24-h reactions were found during patency. Histological investigations did not reveal differences in the type of cell infiltrations between infected and control animals. After i.v. sensitisation with SRBC, L. carinii- and A. viteae-infected animals showed weaker DTH reactions than the controls, independent of the period after infection. In the case of B. malayi infections, DTH reactions were similar to those of controls during early prepatency, whereas reduced DTH responses were observed later than 50 days p.i. As shown in L. carinii-infected animals, depressed DTH reactions after i.v. sensitisation did not depend on an altered expression phase but rather on an altered regulation during the inductive phase of the response: increases in the sensitising SRBC doses that caused decreasing DTH reactions in uninfected animals led to enhanced reactions in infected animals. Phagocytosis of i.v. injected 51Cr-labelled SRBC was enhanced during prepatency in L. carinii infection and during patency in all infections.