Ellazar SA et al. (1997) International C. elegans Meeting "TGFb SIGNALING AND SPICULE DEVELOPMENT."

Ellazar SA, Baird SE

[International C. elegans Meeting, 1997]

TGFb-like signaling is required for spicule development. Mutations in daf-4, sma-2, sma-3, and sma-4, which affect TGFb-like signaling (Savage et al., PNAS 93: 790-794, 1996), result in males with short crumpled spicules. These spicule defects result from defects in the migrations of B.al/rapapa and B.al/rappv. In wild-type males these cells migrate dorsally and anteriorly during early to mid L4 to form the spicule trace. In TGFb signaling-defective mutants, these migrations are shortened or absent. The requirement for TGFb-like signaling, as determined from the daf-4 tsp for spicule development, is limited to a period from 34 to 35 hours post hatching. This period corresponds to the onset of B.al/rapapa and B.al/rappv migrations. The apparent source of the TGF-like signal is a cell or cells descended from M as ablation of M phenocopies B.al/rapapa and B.al/rappv cell migration defects. lin-31 also is required in this signaling pathway as mutations in lin-31 result in B cell migration defects identical to those observed in daf-4, sma-2, sma-3, and sma-4 males. In this context, Lin-31, a forkhead homologue (Miller et al., Genes & Dev, 7: 934-947, 1993) may be acting as a transciptional cofactor with Sma-2, Sma-3, and/or Sma-4 (Chen et al., Nature 383: 691-696, 1996).

Prithiviraj B et al. (2005) Infect Immun "Down regulation of virulence factors of Pseudomonas aeruginosa by salicylic acid attenuates its virulence on Arabidopsis thaliana and Caenorhabditis elegans."

Bais HP, Schweizer HP, Dayakar BV, Najarro EH, Vivanco JM, Prithiviraj B, Weir T, Suresh B

[Infect Immun, 2005]

Salicylic acid (SA) is a phenolic metabolite produced by plants and is known to play an important role in several physiological processes, such as the induction of plant defense responses against pathogen attack. Here, using the Arabidopsis thaliana-Pseudomonas aeruginosa pathosystem, we provide evidence that SA acts directly on the pathogen, down regulating fitness and virulence factor production of the bacteria. Pseudomonas aeruginosa PA14 showed reduced attachment and biofilm formation on the roots of the Arabidopsis mutants lox2 and cpr5-2, which produce elevated amounts of SA, as well as on wild-type Arabidopsis plants primed with exogenous SA, a treatment known to enhance endogenous SA concentration. Salicylic acid at a concentration that did not inhibit PA14 growth was sufficient to significantly affect the ability of the bacteria to attach and form biofilm communities on abiotic surfaces. Furthermore, SA down regulated three known virulence factors of PA14: pyocyanin, protease, and elastase. Interestingly, P. aeruginosa produced more pyocyanin when infiltrated into leaves of the Arabidopsis transgenic line NahG, which accumulates less SA than wild-type plants. This finding suggests that endogenous SA plays a role in down regulating the synthesis and secretion of pyocyanin in vivo. To further test if SA directly affects the virulence of P. aeruginosa, we used the Caenorhabiditis elegans-P. aeruginosa infection model. The addition of SA to P. aeruginosa lawns significantly diminished the bacterium''s ability to kill the worms, without affecting the accumulation of bacteria inside the nematodes'' guts, suggesting that SA negatively affects factors that influence the virulence of P. aeruginosa. We employed microarray technology to identify SA target genes. These analyses showed that SA treatment affected expression of 331 genes. It selectively repressed transcription of exoproteins and other virulence factors, while it had no effect on expression of housekeeping genes. Our results indicate that in addition to its role as a signal molecule in plant defense responses, SA works as an anti-infective compound by affecting the physiology of P. aeruginosa and ultimately attenuating its virulence.

Baird SE et al. (1999) Dev Biol "TGFbeta-like signaling and spicule development in Caenorhabditis elegans."

Baird SE, Ellazar SA

[Dev Biol, 1999]

A TGFbeta-like signal is required for spicule development in Caenorhabditis elegans males. This signal appears to originate in the male-specific musculature and is required for the migrations of cells within the proctodeum. The migrations of these cells form cellular molds, the spicule traces, in which the cuticle of the spicules is secreted. Mutations in daf-4, sma-2, sma-3, and sma-4, which disrupt TGFbeta-like signaling, result in aberrant migrations and morphologically abnormal spicules. daf-4, and hence the TGFbeta-like signal, is required prior to or during cell migrations. Therefore, the TGFbeta-like signal may act to prime the migrating cells or as a guidance cue. Mutations in lin-31 result in identical cell migration and spicule morphology defects. Thus, lin-31, which encodes a "winged helix" protein (Miller et al., Genes Dev. 7, 933-947, 1993), may be a component of this TGFbeta-like signaling pathway.

Nguyen TT et al. (2016) Aging (Albany NY) "Scavengers of reactive -ketoaldehydes extend Caenorhabditis elegans lifespan and healthspan through protein-level interactions with SIR-2.1 and ETS-7."

West JD, Zhu S, Aschner M, Roberts LJ, Fessel JP, Nguyen TT, Caito SW, Zackert WE

[Aging (Albany NY), 2016]

Isoketals (IsoKs) are highly reactive -ketoaldehyde products of lipid peroxidation that covalently adduct lysine side chains in proteins, impairing their function. Using C. elegans as a model organism, we sought to test the hypothesis that IsoKs contribute to molecular aging through adduction and inactivation of specific protein targets, and that this process can be abrogated using salicylamine (SA), a selective IsoK scavenger. Treatment with SA extends adult nematode longevity by nearly 56% and prevents multiple deleterious age-related biochemical and functional changes. Testing of a variety of molecular targets for SA's action revealed the sirtuin SIR-2.1 as the leading candidate. When SA was administered to a SIR-2.1 knockout strain, the effects on lifespan and healthspan extension were abolished. The SIR-2.1-dependent effects of SA were not mediated by large changes in gene expression programs or by significant changes in mitochondrial function. However, expression array analysis did show SA-dependent regulation of the transcription factor ets-7 and associated genes. In ets-7 knockout worms, SA's longevity effects were abolished, similar to sir-2.1 knockouts. However, SA dose-dependently increases ets-7 mRNA levels in non-functional SIR-2.1 mutant, suggesting that both are necessary for SA's complete lifespan and healthspan extension.

Prasansuklab A et al. (2017) BMC Complement Altern Med "Ethanolic extract of Streblus asper leaves protects against glutamate-induced toxicity in HT22 hippocampal neuronal cells and extends lifespan of Caenorhabditis elegans."

Tencomnao T, Prasansuklab A, Sobhon P, Meemon K

[BMC Complement Altern Med, 2017]

BACKGROUND: Although such local herb as Streblus asper (family Moraceae) has long been recognized for traditional folk medicines and important ingredient of traditional longevity formula, its anti-neurodegeneration or anti-aging activity is little known. This study aimed to investigate the neuroprotective effect of S. asper leaf extracts (SA-EE) against toxicity of glutamate-mediated oxidative stress, a crucial factor contributing to the neuronal loss in age-associated neurodegenerative diseases and the underlying mechanism as well as to evaluate its longevity effect. METHODS: Using mouse hippocampal HT22 as a model for glutamate oxidative toxicity, we carried out MTT and LDH assays including Annexin V-FITC/propidium iodide staining to determine the SA-EE effect against glutamate-induced cell death. Antioxidant activities of SA-EE were evaluated using the radical scavenging and DCFH-DA assays. To elucidate the underlying mechanisms, SA-EE treated cells were analyzed for the expressions of mRNA and proteins interested by immunofluorescent staining, western blot analysis and quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) techniques. The longevity effect of SA-EE was examined on C. elegans by lifespan assay. RESULTS: We demonstrate that a concentration-dependent reduction of glutamate-induced cytotoxicity was significant after SA-EE treatment as measured by MTT and LDH assays. Annexin V-FITC/propidium iodide and immunofluorescent staining showed that co-treatment of glutamate with SA-EE significantly reduced apoptotic-inducing factor (AIF)-dependent apoptotic cell death. DCFH-DA assay revealed that this extract was capable of dose dependently attenuating the ROS caused by glutamate. Western blot analysis and qRT-PCR showed that nuclear factor erythroid 2-related factor 2 (Nrf2) protein levels in the nucleus, as well as mRNA levels of antioxidant-related genes under Nrf2 regulation were significantly increased by SA-EE. Furthermore, this extract was capable of extending the lifespan of C. elegans. CONCLUSIONS: SA-EE possesses both longevity effects and neuroprotective activity against glutamate-induced cell death, supporting its therapeutic potential for the treatment of age-associated neurodegenerative diseases.

Shamalnasab M et al. (2018) Aging Cell "A salicylic acid derivative extends the lifespan of Caenorhabditis elegans by activating autophagy and the mitochondrial unfolded protein response."

Jager S, Shamalnasab M, Breton L, Gravel SP, St-Pierre J, Aguilaniu H

[Aging Cell, 2018]

Plant extracts containing salicylates are probably the most ancient remedies to reduce fever and ease aches of all kind. Recently, it has been shown that salicylates activate adenosine monophosphate-activated kinase (AMPK), which is now considered as a promising target to slow down aging and prevent age-related diseases in humans. Beneficial effects of AMPK activation on lifespan have been discovered in the model organism Caenorhabditis elegans (C.elegans). Indeed, salicylic acid and acetylsalicylic acid extend lifespan in worms by activating AMPK and the forkhead transcription factor DAF-16/FOXO. Here, we investigated whether another salicylic acid derivative 5-octanoyl salicylic acid (C8-SA), developed as a controlled skin exfoliating ingredient, had similar properties using C. elegans as a model. We show that C8-SA increases lifespan of C. elegans and that a variety of pathways and genes are required for C8-SA-mediated lifespan extension. C8-SA activates AMPK and inhibits TOR both in nematodes and in primary human keratinocytes. We also show that C8-SA can induce both autophagy and the mitochondrial unfolded protein response (UPR^mit ) in nematodes. This induction of both processes is fully required for lifespan extension in the worm. In addition, we found that the activation of autophagy by C8-SA fails to occur in worms with compromised UPR^mit , suggesting a mechanistic link between these two processes. Mutants that are defective in the mitochondrial unfolded protein response exhibit constitutive high autophagy levels. Taken together, these data therefore suggest that C8-SA positively impacts longevity in worms through induction of autophagy and the UPR^mit .

Penna B et al. (2021) Sci Rep "Comparative genomics of MRSA strains from human and canine origins reveals similar virulence gene repertoire."

Silva-Carvalho MC, Ferreira FA, Bandeira PT, Figueiredo AMS, Vieira-da-Motta O, Silva MB, Vasconcelos ATR, de Souza VS, Botelho AMN, Planet PJ, de Sousa VS, Soares AER, Rabello RF, Ramundo MS, Penna B

[Sci Rep, 2021]

Methicillin-resistant Staphylococcus aureus (MRSA) is an important pathogen associated with a wide variety of infections in humans. The ability of MRSA to infect companion animals has gained increasing attention in the scientific literature. In this study, 334 dogs were screened for MRSA in two cities located in Rio de Janeiro State. The prevalence of MRSA in dogs was 2.7%. Genotyping revealed isolates from sequence types (ST) 1, 5, 30, and 239 either colonizing or infecting dogs. The genome of the canine ST5 MRSA (strain SA112) was compared with ST5 MRSA from humans-the main lineage found in Rio de Janeiro hospitals-to gain insights in the origin of this dog isolate. Phylogenetic analysis situated the canine genome and human strain CR14-035 in the same clade. Comparative genomics revealed similar virulence profiles for SA112 and CR14-035. Both genomes carry S. aureus genomic islands SA, SA, and SA. The virulence potential of the canine and human strains was similar in a Caenorhabditis elegans model. Together, these results suggest a potential of canine MRSA to infect humans and vice versa. The circulation in community settings of a MRSA lineage commonly found in hospitals is an additional challenge for public health surveillance authorities.

Bernabo N et al. (2015) Int J Data Min Bioinform "Signal transduction in the activation of spermatozoa compared to other signalling pathways: a biological networks study."

Bernabo N, Mattioli M, Barboni B

[Int J Data Min Bioinform, 2015]

In this paper we represented Spermatozoa Activation (SA) the process that leads male gametes to reach their fertilising ability of sea urchin, Caenorhabditis elegans and human as biological networks, i.e. as networks of nodes (molecules) linked by edges (their interactions). Then, we compared them with networks representing ten pathways of relevant physio-pathological importance and with a computer-generated network. We have found that the number of nodes and edges composing each network is not related with the amount of published papers on each specific topic and that all the topological parameters examined are similar in all the networks, thus conferring them a scale free topology and small world behaviour. In conclusion, SA topology, independently from the reproductive biology of considered organism, as others signalling networks is characterised by robustness against random failure, controllability and efficiency in signal transmission.

Mir DA et al. (2019) Front Cell Infect Microbiol "Global Proteomic Response of Caenorhabditis elegans Against PemKSa Toxin."

Mir DA, Balamurugan K

[Front Cell Infect Microbiol, 2019]

Bacterial exotoxins are major causative agents that infect by promoting cell and tissue damages through disabling the invading host immune system. However, the mode of action by which toxins modulate host immune system and lead cell death is still not completely understood. The nematode, <i>Caenorhabditis elegans</i> has been used as an attractive model host for toxicological studies. In this regard, the present study was undertaken to assess the impact of <i>Staphylococcus aureus</i> toxin (PemK) on the host <i>C. elegans</i> through global proteomics approach. Our proteomic data obtained through LC-MS/MS, subsequent bioinformatics and biochemical analyses revealed that in response to PemK_Sa a total of 601 proteins of <i>C. elegans</i> were differentially regulated in response to PemK_Sa. The identified proteins were found to mainly participate in ATP generation, protein synthesis, lipid synthesis, cytoskeleton, heat shock proteins, innate immune defense, stress response, neuron degeneration, and muscle assembly. Current findings suggested that involvement of several regulatory proteins that appear to play a role in various molecular functions in combating PemK_Sa toxin-mediated microbial pathogenicity and/or host <i>C. elegans</i> immunity modulation. The results provided a preliminary view of the physiological and molecular response of a host toward a toxin and provided insight into highly complex host-toxin interactions.

Richter K et al. (2017) ACS Appl Mater Interfaces "Taking the Silver Bullet- Colloidal Silver Particles for the Topical Treatment of Biofilm-Related Infections."

Thomas N, Richter K, Wormald PJ, Vandecandelaere I, Vreugde S, Cooksley C, Ramezanpour M, Coenye T, Facal P, Prestidge CA

[ACS Appl Mater Interfaces, 2017]

BACKGROUND: Biofilms are aggregates of bacteria residing in a self-assembled matrix, which protects these sessile cells against external stress, including antibiotic therapies. In light of emerging multidrug-resistant bacteria alternative strategies to antibiotics are emerging. The present study evaluated the activity of colloidal silver nanoparticles (AgNPs) of different shapes against biofilms formed by Staphylococcus aureus (SA), methicillin-resistant SA (MRSA) and Pseudomonas aeruginosa (PA). METHODS: Colloidal quasi-spherical, cubic and star-shaped AgNPs were synthesised and their cytotoxicity on macrophages (THP-1) and bronchial epithelial cells (Nuli-1) was analysed by the lactate dehydrogenase assay. The antibiofilm activity was assessed in vitro by the resazurin assay and in an in vivo infection model in Caenorhabditis elegans. RESULTS: Cubic and star-shaped AgNPs induced cytotoxicity, while quasi-spherical AgNPs were not toxic. Quasi-spherical AgNPs showed substantial antibiofilm activity in vitro with 96% (+/- 2%), 97% (+/- 1%) and 98% (+/- 1%) biofilm killing of SA, MRSA and PA, respectively, while significantly reducing mortality of infected nematodes. The in vivo antibiofilm activity was linked to the accumulation of AgNPs in the intestinal tract of C. elegans as observed by 3D X-ray tomography. Quasi-spherical AgNPs were physically stable in suspension for over 6 months with no observed loss in antibiofilm activity. CONCLUSIONS: While toxicity and stability limited the utilisation of cubic and star-shaped AgNPs, quasi-spherical AgNPs could be rapidly synthesised, were stable and non-toxic, and showed substantial in vitro and in vivo activity against clinically relevant biofilms. Quasi-spherical AgNPs hold potential as pharmacotherapy, e.g. as topical treatment for biofilm-related infections.