Quarantillo BA et al. (1987) International C. elegans Meeting "molecular analysis of X-chromosome dosage compensation continued."

Quarantillo BA, Wood WB, Donahue LM

[International C. elegans Meeting, 1987]

Chen H et al. (2022) Front Nutr "Betulinic acid increases lifespan and stress resistance via insulin/IGF-1 signaling pathway in Caenorhabditis elegans."

Han T, Chen H, Luan L, Li R, Li Z, Zhao F

[Front Nutr, 2022]

Numerous studies reported that betulinic acid (BA), a natural product extracted from birch bark, exhibited various beneficial effects in vitro. However, its pharmacological activities in aging are rarely understood. In this study, Caenorhabditis elegans was deployed as a whole animal model to investigate the impacts of BA on lifespan and stress resistance. Wild-type C. elegans were fed in the presence or absence of BA and tested for a series of phenotypes, including longevity, mobility, reproductive capacity, pharyngeal pumping, heat stress, and oxidative stress. BA at the optimal dose (50 μg/mL) extended the lifespan, improved the healthspan, and significantly evoked the increased oxidative stress resistance in C. elegans. Incorporating the genetic analysis with different types of longevity mutants, DAF-16, the downstream effector of the Insulin/IGF-1 receptor signaling, was revealed to mediate the protective effects of BA on lifespan and antioxidant activity. Together, these data showcased the potential of BA in promoting healthy aging, which shall facilitate its further development in the food and pharmaceutical industries.

Savova MS et al. (2022) Biomed Pharmacother "Betulinic acid counteracts the lipid accumulation in Caenorhabditis elegans by modulation of nhr-49 expression."

Georgiev MI, Savova MS, Apostolov AG, Yahubyan GT, Todorova MN

[Biomed Pharmacother, 2022]

Obesity is an ingrained health problem with а multifactorial origin and а long history, thereby innovations in the treatment strategies are of great importance. In the search of a remedy for excessive weight gain, we have directed our investigations to phytochemicals as valuable bioactive compounds. Betulinic acid (BA), among the other triterpenoids, is known for its anti-inflammatory and anti-neoplastic properties. In addition, a previous study of ours has demonstrated а potent anti-adipogenic effect of BA in human adipocytes. Therefore, we aimed here to further verify the anti-obesogenic effect of BA in vivo in Caenorhabditis elegans. Induction of lipid accumulation in the nematodes was modelled with glucose-supplemented media, followed by treatment with BA (10-50 μM) or orlistat (12 μM) as a control anti-obesity medication. Oil red O and Nile red staining were applied to provide quantification of accumulated lipids. Analysis of the relative expression of genes, related to lipid metabolism suggested molecular mechanism of lipid-reducing action of BA in C. elegans. Treatment of nematodes with BA significantly decreased the lipid accumulation, downregulated desaturases involved in lipogenesis (fat-5, fat-6 and fat-7), modulated key transcription factors (nhr-49 and hlh-11) and microRNAs (miR-60, lin-4, let-7 and miR-786) associated with the lipid metabolism. Collectively, the current research provides additional insight on the molecular mechanism of the BA's anti-obesogenic effect in vivo. Furthermore, it validates the potential of BA as a candidate compound in obesity management by reducing lipid accumulation.

Cui H et al. (2019) Int J Mol Sci "BA-12 Inhibits Angiogenesis via Glutathione Metabolism Activation."

Xu B, Cui H, Yuan Y, Wang S, Wang P, Li G, Zhang N, Zhang B, Li T, Guo W, Chu F, Yang Y, Feng W, Lei H

[Int J Mol Sci, 2019]

There is a need for an efficient and low-cost leading compound discovery mode. However, drug development remains slow, expensive, and risky. Here, this manuscript proposes a leading compound discovery strategy based on a combination of traditional Chinese medicine (TCM) formulae and pharmacochemistry, using a ligustrazine-betulinic acid derivative (BA-12) in the treatment of angiogenesis as an example. Blocking angiogenesis to inhibit the growth and metastasis of solid tumors is currently one recognized therapy for cancer in the clinic. Firstly, based on a traditional <i>Prunella vulgaris</i> plaster, BA-12 was synthesized according to our previous study, as it exhibited better antitumor activities than other derivatives on human bladder carcinoma cells (T24); it was then uploaded for target prediction. Secondly, the efficacy and biotoxicity of BA-12 on angiogenesis were evaluated using human umbilical vein endothelial cells (HUVECs), a quail chick chorioallantoic membrane, and <i>Caenorhabditis elegans</i>. According to the prediction results, the main mechanisms of BA-12 were metabolic pathways. Thus, multiple metabolomics approaches were applied to reveal the mechanisms of BA-12. Finally, the predictive mechanisms of BA-12 on glutathione metabolism and glycerophospholipid metabolism activation were validated using targeted metabolomics and pharmacological assays. This strategy may provide a reference for highly efficient drug discovery, with the aim of sharing TCM wisdom for unmet clinical needs.

Ma J et al. (2024) Pharmacol Res "Gut microbiota-brain bile acid axis orchestrates aging-related neuroinflammation and behavior impairment in mice."

Wang D, Yang Y, He X, Cui Z, Wang W, Li M, Zhu W, Wei W, Wang J, Liu Z, Gao X, Ma J, Zhou B, Zheng N, Ke Z, Bao Y, Huang W, Li H, Sheng L, Hong Y, Pan L

[Pharmacol Res, 2024]

Emerging evidence shows that disrupted gut microbiota-bile acid (BA) axis is critically involved in the development of neurodegenerative diseases. However, the alterations in spatial distribution of BAs among different brain regions that command important functions during aging and their exact roles in aging-related neurodegenerative diseases are poorly understood. Here, we analyzed the BA profiles in cerebral cortex, hippocampus, and hypothalamus of young and natural aging mice of both sexes. The results showed that aging altered brain BA profiles sex- and region- dependently, in which T&#x3b2;MCA was consistently elevated in aging mice of both sexes, particularly in the hippocampus and hypothalamus. Furthermore, we found that aging accumulated-T&#x3b2;MCA stimulated microglia inflammation in vitro and shortened the lifespan of C. elegans, as well as behavioral impairment and neuroinflammation in mice. In addition, metagenomic analysis suggested that the accumulation of brain T&#x3b2;MCA during aging was partially attributed to reduction in BSH-carrying bacteria. Finally, rejuvenation of gut microbiota by co-housing aged mice with young mice restored brain BA homeostasis and improved neurological dysfunctions in natural aging mice. In conclusion, our current study highlighted the potential of improving aging-related neuro-impairment by targeting gut microbiota-brain BA axis.

Donahue LM et al. (1985) International C. elegans Meeting "molecular analysis of dosage compensation."

Donahue LM, Wood WB, Quarantillo BA

[International C. elegans Meeting, 1985]

Donahue LM et al. (1987) Proc Natl Acad Sci U S A "Molecular analysis of X chromosome dosage compensation in Caenorhabditis elegans."

Wood WB, Donahue LM, Quarantillo BA

[Proc Natl Acad Sci U S A, 1987]

We used a convenient quantitative dot blot assay to measure transcript levels for two X chromosome-linked genes, myo-2 and act-4, in the nematode Caenorhabditis elegans. We show that there is dosage compensation of transcript levels for these two genes between XX hermaphrodites and X0 males and that a mutation in the dpy-21 gene, postulated from genetic analysis to be involved in control of X chromosome expression, can affect these transcript levels in the manner predicted. However, we observe the dpy-21 effects only at some stages of the life cycle and not at others. These results are generally consistent with earlier genetic and molecular evidence.

Donahue LM et al. (1985) Worm Breeder's Gazette "molecular analysis of dosage compensation continues."

Quarantillo BA, Donahue LM, Wood WB

[Worm Breeder's Gazette, 1985]

Mutations in several unusual dpy genes appear to affect the general level of X-chromosome expression, implicating these genes in control of X chromosome dosage compensation (Hodgkin, 1983, Mol. Gen. Genet. 192:452 Meneely and Wood, 1984, C. elegans Newsletter, Vol. 8, #1, p. 6; Meneely and Wood, 1985 C. elegans Meeting Abstracts, p. 90; De Long et al., ibid., p. 99; Meyer and Champness, ibid. p. 101). For example, dpy-21 mutations appear to increase and dpy-22 mutations to decrease X expression by genetic tests. To determine whether these effects are occurring at the RNA level, we have employed a quantitative RNA dot blot procedure to compare ratios of X-linked to autosomal transcripts between males and hermaphrodites and between dpy- 21 or dpy-22 and wild-type hermaphrodites, using gene-specific probes for the X linked genes act-4 and myo-2 and the autosomal genes act-1, p. 100). We have previously reported that adult males and hermaphrodites have the same amount of act-4 mRNA relative to act-1 or unc-54 mRNA (ibid.). We have now shown that the same is true for myo-2 mRNA relative to myo-1 mRNA levels. Expression of these two genes would seem unlikely to differ for physiological reasons between males and hermaphrodites, because both code for myosins of the pharynx, which is not a sexually dimorphic structure. Therefore, the equivalence of these ratios in the two sexes supports the view that dosage compensation of these genes operates at the RNA level. Conceivably, our results could be explained by special regulatory controls on act-4 and myo-2, operating outside of, or in addition to, the general X-chromosome dosage compensation mechanism. To test this possibility, we are attempting to determine whether these genes, like other X-linked genes analyzed genetically, show dose-sensitive expression when present in extra copies because of a duplication or fewer copies because of a deficiency. We have preliminary evidence from quantitative Southern blot analysis that act-4 is covered by the duplication mnDp57 (X;I), given to us by R. Herman. If we confirm this result, we shall assay act-4 expression in mnDp57-containing strains. We are testing known duplications for extra copies of myo-2; so far we have found that this gene is not covered by mnDp10 (X;I). We previously reported that in L1 animals a dpy-21 mutation did not affect the ratio of act-4 mRNA to unc-54 mRNA (ibid.). We have now shown that in adult hermaphrodites, the dpy-21(e428) mutation increases the ratio of act-4 mRNA to unc-54 mRNA by a factor of 1.53 +- .08 relative to the same ratio in N2. We are presently testing the effect of dpy-21 in adult animals on myo-2 mRNA levels. One possible reason for the difference in results between L1's and adults with act- 4 could be that the dpy-21 gene is not active prior to the L1 stage of development. A more trivial possibility is that many of the animals in our L1 preparations were starved and could have degraded some of their RNA's by the time they were harvested. We are attempting to test these and other possible reasons for the apparent difference.

Saul N et al. (2015) Environ Sci Pollut Res Int "Adsorbable organic bromine compounds (AOBr) in aquatic samples: a nematode-based toxicogenomic assessment of the exposure hazard."

Putschew A, Lieke T, Kochan C, Baberschke N, Saul N, Menzel R, Chakrabarti S, Steinberg CE, Sturzenbaum SR

[Environ Sci Pollut Res Int, 2015]

Elevated levels of adsorbable organic bromine compounds (AOBr) have been detected in German lakes, and cyanobacteria like Microcystis, which are known for the synthesis of microcystins, are one of the main producers of natural organobromines. However, very little is known about how environmental realistic concentrations of organobromines impact invertebrates. Here, the nematode Caenorhabditis elegans was exposed to AOBr-containing surface water samples and to a Microcystis aeruginosa-enriched batch culture (MC-BA) and compared to single organobromines and microcystin-LR exposures. Stimulatory effects were observed in certain life trait variables, which were particularly pronounced in nematodes exposed to MC-BA. A whole genome DNA-microarray revealed that MC-BA led to the differential expression of more than 2000 genes, many of which are known to be involved in metabolic, neurologic, and morphologic processes. Moreover, the upregulation of cyp- and the downregulation of abu-genes suggested the presence of chronic stress. However, the nematodes were not marked by negative phenotypic responses. The observed difference in MC-BA and microcystin-LR (which impacted lifespan, growth, and reproduction) exposed nematodes was hypothesized to be likely due to other compounds within the batch culture. Most likely, the exposure to low concentrations of organobromines appears to buffer the effects of toxic substances, like microcystin-LR.

Li S et al. (2022) Front Neurosci "Energy efficiency and coding of neural network."

Yan C, Liu Y, Li S

[Front Neurosci, 2022]

Based on the Hodgkin-Huxley model, this study explored the energy efficiency of BA network, ER network, WS network, and Caenorhabditis elegans neural network, and explained the development of neural network structure in the brain from the perspective of energy efficiency using energy coding theory. The numerical simulation results showed that the BA network had higher energy efficiency, which was closer to that of the C. elegans neural network, indicating that the neural network in the brain had scale-free property because of satisfying high energy efficiency. In addition, the relationship between the energy consumption of neural networks and synchronization was established by applying energy coding. The stronger the neural network synchronization was, the less energy the network consumed.