Brown SA et al. (2005) Science "PERIOD1-associated proteins modulate the negative limb of the mammalian circadian oscillator."

Rosbash M, Brown SA, Fleury-Olela F, Kadener S, Vilbois F, Ripperger J, Schibler U

[Science, 2005]

The clock proteins PERIOD1 (PER1) and PERIOD2 (PER2) play essential roles in a negative transcriptional feedback loop that generates circadian rhythms in mammalian cells. We identified two PER1-associated factors, NONO and WDR5, that modulate PER activity. The reduction of NONO expression by RNA interference (RNAi) attenuated circadian rhythms in mammalian cells, and fruit flies carrying a hypomorphic allele were nearly arrhythmic. WDR5, a subunit of histone methyltransferase complexes, augmented PER-mediated transcriptional repression, and its reduction by RNAi diminished circadian histone methylations at the promoter of a clock gene.

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.

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 .

Shakambari G et al. (2015) Indian J Exp Biol "Phlorotannins from Brown Algae: inhibition of advanced glycation end products formation in high glucose induced Caenorhabditis elegans."

Ashokkumar B, Varalakshmi P, Shakambari G

[Indian J Exp Biol, 2015]

Advanced Glycation End products (AGE) generated in a non enzymatic protein glycation process are frequently associated with diabetes, aging and other chronic diseases. Here, we explored the protective effect of phlorotannins from brown algae Padina pavonica, Sargassum polycystum and Turbinaria ornata against AGEs formation. Phlorotannins were extracted from brown algae with methanol and its purity was analyzed by TLC and RP-HPLC-DAD. Twenty five grams of P. pavonica, S. polycystum, T. ornata yielded 27.6 +/- 0.8 g/ml, 37.7 g/ml and 37.1 +/- 0.74 g/ml of phloroglucinol equivalent of phlorotannins, respectively. Antioxidant potentials were examined through DPPH assay and their IC50 values were P. pavonica (30.12 +/- 0.99 g), S. polycystum (40.9 +/- 1.2 g) and T. ornata (22.9 +/- 1.3 g), which was comparatively lesser than the control ascorbic acid (46 +/- 0.2 g). Further, anti-AGE activity was examined in vitro by BSA-glucose assay with the extracted phlorotannins of brown algae (P. pavonica, 15.16 +/- 0.26 g/ml; S. polycystum, 35.245 +/- 2.3 g/ml; T. ornata, 22.7 +/- 0.3 g/ml), which revealed the required concentration to inhibit 50% of albumin glycation (IC50) were lower for extracts than controls (phloroglucinol, 222.33 +/- 4.9 g/ml; thiamine, 263 g/ml). Furthermore, brown algal extracts containing phlorotannins (100 l) exhibited protective effects against AGE formation in vivo in C. elegans with induced hyperglycemia.

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.

Michael A Beer (2005) International Worm Meeting "Systematic genome-wide identification of transcriptional cis-regulatory logic in C. elegans."

Michael A Beer

[International Worm Meeting, 2005]

We have developed a systematic approach for inferring cis-regulatory logic from whole-genome microarray expression data.[1] This approach identifies local DNA sequence elements and the combinatorial and positional constraints that determine their context-dependent role in transcriptional regulation. We use a Bayesian probabilistic framework that relates general DNA sequence features to mRNA expression patterns. By breaking the expression data into training and test sets of genes, we are able to evaluate the predictive accuracy of our inferred Bayesian network. Applied to S. cerevisiae, our inferred combinatorial regulatory rules correctly predict expression patterns for most of the genes. Applied to microarray data from C. elegans[2], we identify novel regulatory elements and combinatorial rules that control the phased temporal expression of transcription factors, histones, and germline specific genes during embryonic and larval development. While many of the DNA elements we find in S. cerevisiae are known transcription factor binding sites, the vast majority of the DNA elements we find in C. elegans and the inferred regulatory rules are novel, and provide focused mechanistic hypotheses for experimental validation. Successful DNA element detection is a limiting factor in our ability to infer predictive combinatorial rules, and the larger regulatory regions in C. elegans make this more challenging than in yeast. Here we extend our previous algorithm to explicitly use conservation of regulatory regions in C. briggsae to focus the search for DNA elements. In addition, we expand the range of regulatory programs we identify by applying to more diverse microarray datasets.[3] 1. Beer MA and Tavazoie S. Cell 117, 185-198 (2004). 2. Baugh LR, Hill AA, Slonim DK, Brown EL, and Hunter, CP. Development 130, 889-900 (2003); Hill AA, Hunter CP, Tsung BT, Tucker-Kellogg G, and Brown EL. Science 290, 809812 (2000). 3. Baugh LR, Hill AA, Claggett JM, Hill-Harfe K, Wen JC, Slonim DK, Brown EL, and Hunter, CP. Development 132, 1843-1854 (2005); Murphy CT, McCarroll SA, Bargmann CI, Fraser A, Kamath RS, Ahringer J, Li H, and Kenyon C. Nature 424 277-283 (2003); Reinke V, Smith HE, Nance J, Wang J, Van Doren C, Begley R, Jones SJ, Davis EB, Scherer S, Ward S, and Kim SK. Mol Cell 6 605-616 (2000).