Lin C et al. (2019) Food Funct "Effects of Momordica saponin extract on alleviating fat accumulation in Caenorhabditis elegans."

Lin Y, Su Z, Xu J, Li J, Cao Y, Chen Y, Lin C

[Food Funct, 2019]

Momordica saponins have diverse biological activities and are widely used to improve obesity. Here, we investigated the alleviation of fat accumulation and mechanism of action of the saponin-enriched ethanol extract from Momordica charantia (MSE) in Caenorhabditis elegans (C. elegans). First, MSE had a strong fat-reduction capacity in normal and high-fat worms. Second, MSE significantly increased the proportion of small lipid droplets and reduced the average particle size in ZXW618. Meanwhile, it improved lifespan and healthspan and physiological functions, such as age pigmentation and neuroprotection. Furthermore, MSE mediated fat reduction gets involved neither in energy intake nor in energy expenditure. Finally, MSE might down-regulate sbp-1 and nhr-49 via mdt-15, and up regulate age-1 via daf-2. And these targets genes together down-regulated the expression of fat-5, fat-6 and fat-7 to decrease fat accumulation. Our results provided new insights into the inhibition of fat accumulation and underlying mechanisms of Momordica saponins in C. elegans, which might be developed into a nutraceutical to ameliorate obesity.

Lin C et al. (2019) Food Funct "Effects on longevity extension and mechanism of action of carnosic acid in Caenorhabditis elegans."

Zhong Q, Kuang Y, Lin C, Zhang X, Chen Y, Cao Y, Xiao J

[Food Funct, 2019]

The beneficial effects of carnosic acid (CA) on health in terms of antioxidative, anti-inflammatory, antibacterial, anti-cancer and neuroprotective properties have long been recognized. However, the role of CA in aging remains unknown. In the present study, we examined the effects on longevity extension, as well as the mechanism of action, of CA in Caenorhabditis elegans (C. elegans). The results suggest that CA increased the lifespan of C. elegans. Meanwhile, CA was absorbed by the worms and promoted the healthspan of C. elegans by improving the mobility, reducing the accumulation of age pigment, delaying A-induced and polyQ-dependent paralysis and increasing the resistance to heat and oxidative stress. In terms of the mechanism underlying the longevity extension induced by CA, the beneficial effects were associated with the increased expression of SOD-3 but not with ROS scavenging activity. The CA-mediated longevity extension involved the upregulating of the expression of the skn-1, sek-1, sod-5, hsf-1, hsp-16.1 and hsp-16.2 genes but acted independently of the insulin/insulin-like growth factor signaling (IIS) pathway. Furthermore, CA treatment had no impact on the lifespan of skn-1 and hsf-1 mutants, confirming that mitogen-activated protein kinase (MAPK) and heat-shock transcription factor-1 (HSF-1) pathways were associated with the longevity mechanism of CA. These findings contribute to our knowledge of the lifespan extension and underlying mechanism of action of CA in C. elegans.

Lin C et al. (1998) West Coast Worm Meeting "GENES THAT CONTROL NMDA RECEPTOR EXPRESSION IN THE PVC COMMAND INTERNEURONS"

Poulson S, Lin C, Maricq AV, Brockie PJ

[West Coast Worm Meeting, 1998]

Two genes that encode putative NMDA subtypes of ionotropic glutamate receptors, nmr-1 and nmr-2, have been identified in C. elegans. In vertebrates, NMDA receptors are known to play pivotal roles in a number of diverse processes such as learning and memory, excitotoxicity and cell death. However, little is known about what controls the expression and localization of these receptors. As a first step towards addressing these problems, we have undertaken a visual-based screen to identify recessive mutations in genes that control the expression and localization of NMDA receptor subunits in C. elegans. We have generated a transgenic strain that expresses the reporter Green Fluorescent Protein (GFP) under the control of nmr-1 regulatory regions. In hermaphrodites, GFP expression is seen in only a small subset of neurons. Amongst these are the "command" interneurons, AVA, AVB, AVD, AVE, and PVC, whose function is required for the control of locomotion. What controls the expression of nmr-1 in these neurons? By mutagenizing the transgenic strain, we hoped to identify genes that affect the normal expression of GFP. These genes are expected to be required for either expression of nmr-1, or for differentiation of nmr-1 expressing neurons. We screened 20,000 hapolid genomes and found mutants with aberrant GFP expression, including those with defects in GFP expression levels, absent or additional cellular GFP expression, aberrant axonal outgrowth, and abnormal neuronal migration. Two mutations show a striking decrease in GFP expression in PVC. One has greatly reduced GFP expression only in PVC. The other has faint GFP expression in PVC and completely lacks GFP expression in AVB. In both cases, examiniation by Nomarski optics revealed that PVC was still in its usual location. We have mapped both mutants: one lies near unc-29 on LG I, the other lies near dpy-7 on LG X. We are now pursueing cosmid rescue experiments in an effort to clone the two genes.

Lin, C. et al. (2015) International Worm Meeting "Histone Methylation as a Putative Mechanism of Behavioral Alcohol Tolerance in C. elegans."

Shih, J., Lin, C., Huang, A., Sunthoram, A., Rankin, C.

[International Worm Meeting, 2015]

A key risk factor in alcoholism is the genetic predisposition for high alcohol tolerance. Tolerance, as defined in DSM-IV, refers to a "diminished effect with continued use of the same amount of alcohol". However, the mechanisms underlying alcohol tolerance are poorly understood. Studies of postmortem human alcoholic brains suggested that alcoholism is associated with epigenetic driven gene expression changes that involve methylation of histones lysine residues via histone methyltransferases (HMTs). Two complexes that methylate H3 histone lysine residue 4 (H3K4) and residue 9 (H3K9) are of particular interest because H3K4 methylation is often associated with H3K9 demethylation, and vice versa. H3K4 methylation is associated with active transcription and H3K9 methylation is associated with repressed transcription, suggesting an antagonistic gene activation/repression mechanism. To determine whether H3K4/H3K9 HMTs in C. elegans play a role in alcohol tolerance, we developed a behavioral model of tolerance in C. elegans based on the DSM-IV definition, then characterized the tolerance phenotypes of the H3K4 HMT mutant, set-2, and H3K9 HMTs mutant, set-11. To develop a tolerance model, we pre-exposed worms to 0mM, 200mM, and 400mM ethanol in agar for 1, 2, 6, 12, and 24 hrs in Day 1 or Day 2 adult worms cultured at 20oC, and examined locomotor movement of the worms on 0mM, 200mM or 400mM ethanol the next day using Multi-Worm Tracker. We found that wild type worms that were pre-exposed to 200mM ethanol for 24 hours, allowed to recover off alcohol for 2 hours, and then exposed again to 200mM ethanol showed diminished effect of alcohol on locomotor speed compared to that of worms pre-exposed to 0mM ethanol and then exposed to 200mM the next day. This suggests worms exposed to alcohol the 2nd time showed a behavioral tolerance to ethanol. On the other hand, worms in the withdrawal group (pre-exposed to 200mM and exposed to 0mM the next day) moved at the same speed as worms in the naive group (pre-exposed to 0mM and exposed to 0mM the next day), suggesting that pre-exposure did not affect locomotor speed. Using this tolerance model, we evaluated the effect of tolerance in set-2 and set-11 mutants, and found that neither mutant showed tolerance to ethanol. Second-exposure set-2 and set-11 mutant groups moved at the same speed as the first-time exposure groups, suggesting that the first exposure did not produce tolerance as it did in WT worms. In addition, mutant withdrawal groups moved at the same speed as naive groups, suggesting set-2 and set-11 do not play a role in withdrawal. Together our results suggest that H3K4/H3K9 HMTs might play a critical role in the development of alcohol tolerance.

Lin C et al. (2024) Nat Commun "Molecular and circuit mechanisms underlying avoidance of rapid cooling stimuli in C. elegans."

He J, Peng H, Wu Z, Shen W, Li R, Wang P, Shan Y, Wang Z, Guo M, Lin C

[Nat Commun, 2024]

The mechanisms by which animals respond to rapid changes in temperature are largely unknown. Here, we found that polymodal ASH sensory neurons mediate rapid cooling-evoked avoidance behavior within the physiological temperature range in C. elegans. ASH employs multiple parallel circuits that consist of stimulatory circuits (AIZ, RIA, AVA) and disinhibitory circuits (AIB, RIM) to respond to rapid cooling. In the stimulatory circuit, AIZ, which is activated by ASH, releases glutamate to act on both GLR-3 and GLR-6 receptors in RIA neurons to promote reversal, and ASH also directly or indirectly stimulates AVA to promote reversal. In the disinhibitory circuit, AIB is stimulated by ASH through the GLR-1 receptor, releasing glutamate to act on AVR-14 to suppress RIM activity. RIM, an inter/motor neuron, inhibits rapid cooling-evoked reversal, and the loop activities thus equally stimulate reversal. Our findings elucidate the molecular and circuit mechanisms underlying the acute temperature stimuli-evoked avoidance behavior.

Lin C et al. (2019) Biofactors "Rosmarinic acid improved antioxidant properties and healthspan via the IIS and MAPK pathways in Caenorhabditis elegans."

Xi Y, Lin C, Zhong Q, Zhang X, Zheng H, Xiao J, Cao Y, Chen Y

[Biofactors, 2019]

Rosmarinic acid (RA) has a wide range of biological effects, including the antioxidation and antiaging. However, the detailed mechanisms remain unclear but highly attractive. Herein, RA promoted lifespan and motoricity in a dose-dependent manner, and reduced fat store without threatening fertility in Caenorhabditis elegans. In term of antioxidant efficacy, catalase activity, glutathione peroxidas activity, reduced glutathione content, and reduced glutathione/oxidized glutathione ratio were enhanced. And malondialdehyde content was diminished significantly. Moreover, RA increased survival under acute oxidative and thermal stress, and suppressed intestinal lipofuscin accumulation. So the improvement of lifespan mediated by RA could be related with its strong antioxidant properties. Furthermore, RA was absorbed by worms. Further research in pursuit of the mechanism showed that longevity induced by RA was involved with the genes sod-3, sod-5, ctl-1, daf-16, ins-18, skn-1, and sek-1, but was independent of subcellular localization of DAF-16. These findings indicated that RA had a potential for promoting healthy lifespan.

Lin C et al. (2020) Eur J Nutr "Antistress and anti-aging activities of Caenorhabditis elegans were enhanced by Momordica saponin extract."

Lin Y, Lin C, Chen Y, Cao Y, Hu L, Wang X

[Eur J Nutr, 2020]

BACKGROUND: Momordica saponin extract (MSE) was found to not only improve longevity and neuroprotection but also alleviate fat accumulation in Caenorhabditis elegans in our previous study. However, the lipid-lowering activity of MSE alone could not fully explain its ability to improve health, so the antistress effects of MSE were further studied. METHODS: stress were tested. RESULTS: MSE significantly improved the lifespan of C. elegans under stress and normal conditions. Meanwhile, the mobility of C. elegans was also improved. Moreover, the activities of SOD and CAT and the ratio of GSH/GSSG were elevated. Consistently, the levels of ROS and lipid oxidation (the NEFA and MDA content) were reduced. Furthermore, MSE treatment upregulated the expression of the sod-3, sod-5, clt-1, clt-2, hsp-16.1 and hsp-16.2 genes. All biomarkers indicated that the antistress and anti-aging activities of MSE were due to its strong antioxidant activities. Finally, MSE induced nuclear DAF-16::GFP localization. Studies with mutants revealed that skn-1 and hsf-1 were involved in the activity of MSE, which might upregulate the expression of downstream stress-responsive genes. CONCLUSIONS: Therefore, in addition to its lipid-lowering property, the ability of MSE to improve healthspan was also attributed to the stress resistance effect. Together, MSE might serve as a lead nutraceutical in geriatric research.

Lin C et al. (2020) Oxid Med Cell Longev "Healthspan Improvements in Caenorhabditis elegans with Traditional Chinese Herbal Tea."

Zhuang C, Lin Y, Cao Y, Zhang X, Lin C, Chen Y

[Oxid Med Cell Longev, 2020]

Searching for natural and safe herbal tea with health benefits has attracted more and more attention, which is of great significance for reducing disease risk. A Chinese traditional herbal tea (HT) is rich in active ingredients extracted from natural plants. Numerous pharmacological studies showed that HT had the potential to improve health, including antidepression and antioxidant effects. In this study, we proposed a strategy to explore the role and underlying mechanism of HT in improving healthspan of a <i>Caenorhabditis elegans</i> model. First, we found that HT significantly prolonged the lifespan without reducing fertility in worms. Second, stress resistance (oxidative stress and heat stress) was enhanced and A<i></i>- and polyQ-induced toxicity was relieved significantly by HT treatment. Both fat deposition and age pigment accumulation were found to be significantly reduced in HT-treated worms. The locomotion in mid-late stages was improved, indicating that behavioral mobility was also significantly enhanced. Furthermore, the main components of HT were eighteen polyphenols and two terpenoids. Finally, it was found that this protective mechanism was positively correlated with the insulin/insulin-like growth factor signaling- (IIS-) dependent manner, which went through promoting the nuclear localization of DAF-16 and its downstream SOD-3 expression. These results suggested that HT had an important role in improving health, which might serve as a promising healthy tea.

Lin C et al. (2019) Oxid Med Cell Longev "Carnosol Improved Lifespan and Healthspan by Promoting Antioxidant Capacity in Caenorhabditis elegans."

Xiao J, Lv M, Su Z, Zhang X, Chen Y, Cao Y, Lin C

[Oxid Med Cell Longev, 2019]

Carnosol, a phenolic diterpene, is one of the main constituents of <i>Rosmarinus</i>. It is known to possess a range of bioactivities, including antioxidant, anticancer, antimicrobial, and anti-inflammatory properties. Nevertheless, the antiaging effects of carnosol have received little attention. This study first indicated that carnosol increased the healthspan of <i>Caenorhabditis elegans</i> (<i>C. elegans</i>). First, compared with the control condition, carnosol treatment effectively decreased ROS accumulation under normal or oxidative stress condition, significantly increased several key antioxidant enzyme activities, and significantly decreased MDA content. Second, carnosol effectively prolonged lifespan under normal and stress conditions and slowed aging-related declines, including mobility, age pigmentation, and neurodegenerative disease, but had no effect on fertility and fat deposition. Finally, carnosol-mediated longevity required the upregulated expression of <i>sod-3</i>, <i>sod-5</i>, <i>hsf-1</i>, <i>hsp-16.1</i>, and <i>hsp-16.2</i> and was dependent on the <i>hsf-1</i> gene. Increased DAF-16 translocation was observed, but <i>daf-16</i> was independent of the effects on lifespan induced by carnosol. These results suggested that carnosol might serve as a good source of natural antioxidants, and in particular, carnosol could be explored as a potential dietary supplement to slow aging.

Lin C et al. (2020) Food Funct "Anti-fat effect and mechanism of polysaccharide-enriched extract from Cyclocarya paliurus (Batal.) Iljinskaja in Caenorhabditis elegans."

Cao Y, Liang Y, Lian J, Lin C, Chen Y, Kuang Y, Lin Y, Meng T

[Food Funct, 2020]

Obesity is a global epidemic. Recent studies have shown that Cyclocarya paliurus (C. paliurus) leaves have the potential to alleviate fat deposits. However, the fat-reducing mechanism of it remains unclear. Using Caenorhabditis elegans (C. elegans) as a model, we found that C. paliurus polysaccharide (CPP) significantly decreased fat storage in both normal and high-fat worms without affecting the movement. Moreover, the size and number of lipid droplets were reduced in CPP-treated ZXW618 worms. In energy metabolism, CPP decreased Escherichia coli (E. coli) OP50 growth and pharyngeal pumping and increased the expression of vit-2. In lipid metabolism, CPP down-regulated the expression of the sbp-1 and nhr-49 genes by modulating mdt-15 to prevent the expression of the 9-desaturase genes (fat-5, fat-6 and fat-7). Meanwhile, the expression of the acs-2 genes, the downstream of nhr-49, was suppressed by CPP. These findings provided insights into the CPP-induced anti-fat mechanisms, which contributed to the application of CPP in anti-obesity drugs.