Racette BA et al. (2012) Neurotoxicology "Pathophysiology of manganese-associated neurotoxicity."

Guilarte TR, Zheng W, Criswell SR, Dydak U, Aschner M, Racette BA

[Neurotoxicology, 2012]

Manganese (Mn) is a well established neurotoxin associated with specific damage to the basal ganglia in humans. The phenotype associated with Mn neurotoxicity was first described in two workers with occupational exposure to Mn oxide (Couper, 1837). Although the description did not use modern clinical terminology, a parkinsonian illness characterized by slowness of movement (bradykinesia), masked facies, and gait impairment (postural instability) appears to have predominated. Nearly 100 years later an outbreak of an atypical parkinsonian illness in a Chilean Mn mine provided a phenotypic description of a fulminant neurologic disorder with parkinsonism, dystonia, and neuropsychiatric symptoms (Rodier, 1955). Exposures associated with this syndrome were massive and an order of magnitude greater than modern exposures (Rodier, 1955; Hobson et al., 2011). The clinical syndrome associated with Mn neurotoxicity has been called manganism. Modern exposures to Mn occur primarily through occupations in the steel industry and welding. These exposures are often chronic and varied, occurring over decades in the healthy workforce. Although the severe neurologic disorder described by Rodier and Couper are no longer seen, several reports have suggested a possible increased risk of neurotoxicity in these workers (Racette et al., 2005b; Bowler et al., 2007; Harris et al., 2011). Based upon limited prior imaging and pathologic investigations into the pathophysiology of neurotoxicity in Mn exposed workers (Huang et al., 2003), many investigators have concluded that the syndrome spares the dopamine system distinguishing manganism from Parkinson disease (PD), the most common cause of parkinsonism in the general population, and a disease with characteristic degenerative changes in the dopaminergic system (Jankovic, 2005). The purpose of this symposium was to highlight recent advances in the understanding of the pathophysiology of Mn associated neurotoxicity from Caenorhabditis elegans to humans. Dr. Aschner's presentation discussed mechanisms of dopaminergic neuronal toxicity in C. elegans and demonstrates a compelling potential role of Mn in dopaminergic degeneration. Dr. Guilarte's experimental, non-human primate model of Mn neurotoxicity suggests that Mn decreases dopamine release in the brain without loss of neuronal integrity markers, including dopamine. Dr. Racette's presentation demonstrates a unique pattern of dopaminergic dysfunction in active welders with chronic exposure to Mn containing welding fumes. Finally, Dr. Dydak presented novel magnetic resonance (MR) spectroscopy data in Mn exposed smelter workers and demonstrated abnormalities in the thalamus and frontal cortex for those workers. This symposium provided some converging evidence of the potential neurotoxic impact of Mn on the dopaminergic system and challenged existing paradigms on the pathophysiology of Mn in the central nervous system.

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

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

[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.

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

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

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

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

[Biomed Pharmacother, 2022]

Obesity is an ingrained health problem with &#1072; multifactorial origin and &#1072; 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 &#1072; 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 &#956;M) or orlistat (12 &#956;M) 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.

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

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

[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.

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

[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.

Ding J et al. (2024) Antioxidants (Basel) "Transcriptomic Approaches to Investigate the Anti-Aging Effects of Blueberry Anthocyanins in a Caenorhabditis Elegans Aging Model."

Ding J, Guo Q, Liu J, Zhang N

[Antioxidants (Basel), 2024]

This study investigates the anti-aging effects of various concentrations of blueberry anthocyanins (BA) on the lifespan and health-related phenotypes of Caenorhabditis elegans. Blueberry anthocyanins were administered at concentrations of 50.0 &#x3bc;g/mL, 200.0 &#x3bc;g/mL, and 500.0 &#x3bc;g/mL, and their effects on nematode lifespan, locomotion, pharyngeal pumping rate, and the accumulation of lipofuscin and reactive oxygen species (ROS) were examined. Transcriptomic analysis was conducted to explore the regulatory effects of BA on anti-aging molecular pathways and key genes in <i>C. elegans</i>. Results showed a significant, dose-dependent extension of lifespan, improvement in locomotion and pharyngeal pumping rate, and reduction in lipofuscin and ROS accumulation. Transcriptomic analysis revealed that BA activated anti-aging pathways such as FOXO, IIS, and PI3K/Akt, upregulating critical genes like <i>daf-16</i>. These findings highlight the potential of blueberry anthocyanins as promising anti-aging agents through multiple physiological and molecular mechanisms.

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

Yan C, Li S, Liu Y

[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.

Weisblat D et al. (1975) Worm Breeder's Gazette "Electrophysiological Studies of Ascaris Muscle"

Weisblat D, Russell RL, Byerly L

[Worm Breeder's Gazette, 1975]

Using Ascaris as a model system, we are studying ionic mechanisms of the spontaneous electrical activity in nematode somatic muscle. The fast spike potentials appear to be Ca+2 mediated; their amplitude depends on the external Ca+2 concentration, they are TTX insensitive, they persist when Na+ is replaced by Tris+, choline+, or Cs+, and they are blocked by Co+2 and La+3. When the normal solution is replaced by one containing 11 mM Ba+2 and 0.15 mM Ca+2 as the only divalent cations, the slow waves underlying the normal spike activity appear to increase dramatically in amplitude and duration; spike activity gradually disappears. The duration and amplitude of the slow waves at steady state under these conditions increase with Ba+2 concentration, reaching values of 1-2 minutes and 50-60 mV, respectively, in 26 mM Ba+2. These results and others lead us to conclude that the slow waves are also Ca+2 mediated. The muscles are depolarized by 0.1 mM ouabain, suggesting some involvement of an electrogenic pump in maintaining the membrane potential. TEA, in concentrations as low as 1 mM, has pronounced effects on the spontaneous myogenic activity, consistent with the effects observed when TEA is injected iontophoretically into C. elegans.

Rajkumari J et al. (2018) Microb Pathog "Attenuation of quorum sensing controlled virulence factors and biofilm formation in Pseudomonas aeruginosa by pentacyclic triterpenes, betulin and betulinic acid."

Murali A, Suchiang K, Borkotoky S, Mohanty SK, Busi S, Rajkumari J

[Microb Pathog, 2018]

The production of virulence determinants and biofilm formation in numerous pathogens is regulated by the cell-density-dependent phenomenon, Quorum sensing (QS). The QS system in multidrug resistant opportunistic pathogen, P. aeruginosa constitutes of three main regulatory circuits namely Las, Rhl, and Pqs which are closely linked to its pathogenicity and establishment of chronic infections. In spite intensive antibiotic therapy, P. aeruginosa continue to be an important cause of nosocomial infections and also the major cause of mortality in Cystic Fibrosis patients with 80% of the adults suffering from chronic P. aeruginosa infection. Hence, targeting QS circuit offers an effective intervention to the ever increasing problem of drug resistant pathogens. In the present study, the pentacyclic triterpenes i.e. Betulin (BT) and Betulinic acid (BA) exhibited significant attenuation in production of QS-regulated virulence factors and biofilm formation in P. aeruginosa, at the sub-lethal concentration. The test compound remarkably interfered in initial stages of biofilm development by decreasing the exopolysaccharide production and cell surface hydrophobicity. Based on the in vivo studies, the test compounds notably enhanced the survival of Caenorhabditis elegans infected with P. aeruginosa. Furthermore, molecular docking analysis revealed that BT and BA can act as a strong competitive inhibitor for QS receptors, LasR and RhlR. The findings suggest that BT and BA can serve as potential anti-infectives in the controlling chronic infection of P. aeruginosa.