Lin Y et al. (2024) ACS Infect Dis "Antifungal and Antiparasitic Activities of Metallocene-Containing Fluconazole Derivatives."

Salinas G, Sakanari JA, Vinck R, Lin Y, Scalese G, Blacque O, Bulman CA, Cariou K, Weil T, Gasser G, Gambino D, Paulino M, Mitreva M, Pé\;rez Dí\;az L, Ballesteros-Casallas A

[ACS Infect Dis, 2024]

The search for new anti-infectives based on metal complexes is gaining momentum. Among the different options taken by researchers, the one involving the use of organometallic complexes is probably the most successful one with a compound, namely, ferroquine, already in clinical trials against malaria. In this study, we describe the preparation and in-depth characterization of 10 new (organometallic) derivatives of the approved antifungal drug fluconazole. Our rationale is that the sterol 14&#x3b1;-demethylase is an enzyme part of the ergosterol biosynthesis route in <i>Trypanosoma</i> and is similar to the one in pathogenic fungi. To demonstrate our postulate, docking experiments to assess the binding of our compounds with the enzyme were also performed. Our compounds were then tested on a range of fungal strains and parasitic organisms, including the protozoan parasite <i>Trypanosoma cruzi</i> (<i>T. cruzi</i>) responsible for Chagas disease, an endemic disease in Latin America that ranks among some of the most prevalent parasitic diseases worldwide. Of high interest, the two most potent compounds of the study on <i>T. cruzi</i> that contain a ferrocene or cobaltocenium were found to be harmless for an invertebrate animal model, namely, <i>Caenorhabditis elegans</i> (<i>C. elegans</i>), without affecting motility, viability, or development.

Lin Y et al. (2020) Food Funct "Luteolin reduces fat storage in Caenorhabditis elegans by promoting the central serotonin pathway."

Yang N, Wang L, Lin Y, Chen J, Liu J, Bao B

[Food Funct, 2020]

Serotonin plays a critical role in regulating energy homeostasis and fat metabolism. Various dietary flavonoids, e.g. luteolin and quercetin, possess potential anti-obesity properties. However, it is unclear whether the flavonoids exert their anti-obesity actions via central serotonin signaling. Here, employing a classic animal model C. elegans, we assessed the effects of six dietary flavonoids (flavones apigenin, chrysin, and luteolin and flavonols kaempferol, myricetin, and quercetin) on fat accumulation. The dose-dependent study revealed the substantial inhibitory actions of the six flavonoids on C. elegans fat accumulation and the strongest inhibitory activity of luteolin among the tested flavonoids. Meanwhile, flavonoid treatments did not have an obvious influence on worm growth, fecundity and feeding. Furthermore, the mutation of tph-1, which encodes the conserved rate-limiting enzyme of serotonin synthesis, fully abolished luteolin-induced fat loss but did not affect fat reduction by the other five flavonoids. In wild-type N2 worms, luteolin treatment not only elevated the expression of tph-1, but also enhanced the mRNA levels of mod-1 and ser-6, which are two serotonin-related receptors and play specific roles in serotonin-mediated fat reduction. The mutation of either mod-1 or ser-6 also fully abolished luteolin-induced fat loss. Finally, we found that luteolin treatment elevated serotonin synthesis in ADF neurons to promote lipolysis and fatty acid -oxidation in C. elegans. Together, the results indicated that luteolin reduced C. elegans fat storage by promoting central serotonin signaling, suggesting new insights into elucidating the mechanism underlying fat regulation by luteolin.

Lin, Y. et al. (2019) International Worm Meeting "Phosphatidylinositol transfer protein-1 regulates lifespan via TOR signaling in C. elegans."

Lin, Y., Wang, H., Ching, T., Shen, W., Shanmugam, M.

[International Worm Meeting, 2019]

Phosphatidylinositol transfer protein-1 (PITP-1) functions as phosphatidylinositol (PI) transporter in phosphoinositide (PPI) turnover to help the phospholipid recycling. However, whether PITP-1 participates in lifespan regulation remains unknown. Here, we report that two pitp-1 mutant worms and pitp-1(RNAi)-treated worms both reveal extended lifespan in C. elegans. On the other hand, overexpression of pitp-1 reduces lifespan. In addition, pitp-1 knockdown attenuates age-induced paralysis and decreased motility, suggesting reduced pitp-1 not only can promote longevity but also retard aging-related disorders. Since pitp-1 is majorly expressed in nervous system, we demonstrate that reduced pitp-1 in neuronal tissue is sufficient for lifespan extension. Decreased p-S6K level is detected in pitp-1-knockdown worms. Rapamycin treatment to inhibit TOR signaling cannot further enhance the extended lifespan in pitp-1-knockdown worms, and it can rescue the shortened lifespan of pitp-1-overexpressing worms. In addition, the longevity caused by reduced pitp-1 does not require daf-16/FOXO. Interestingly, DAF-16 acts as an upstream factor of pitp-1 to negatively regulate the transcription of pitp-1 for lifespan regulation. In summary, our findings uncover a new novel function of pitp-1 in lifespan regulation via TOR signaling.

Lin Y et al. (2023) Biomed Pharmacother "Caenorhabditis elegans as an in vivo model for the identification of natural antioxidants with anti-aging actions."

Lin C, Lin Y, Cao Y, Chen Y

[Biomed Pharmacother, 2023]

Natural antioxidants have recently emerged as a highly exciting and significant topic in anti-aging research. Diverse organism models present a viable protocol for future research. Notably, many breakthroughs on natural antioxidants have been achieved in the nematode Caenorhabditis elegans, an animal model frequently utilized for the study of aging research and anti-aging drugs in vivo. Due to the conservation of signaling pathways on oxidative stress resistance, lifespan regulation, and aging disease between C. elegans and multiple high-level organisms (humans), as well as the low and controllable cost of time and labor, it gradually develops into a trustworthy in vivo model for high-throughput screening and validation of natural antioxidants with anti-aging actions. First, information and models on free radicals and aging are presented in this review. We also describe indexes, detection methods, and molecular mechanisms for studying the in vivo antioxidant and anti-aging effects of natural antioxidants using C. elegans. It includes lifespan, physiological aging processes, oxidative stress levels, antioxidant enzyme activation, and anti-aging pathways. Furthermore, oxidative stress and healthspan improvement induced by natural antioxidants in humans and C. elegans are compared, to understand the potential and limitations of the screening model in preclinical studies. Finally, we emphasize that C. elegans is a useful model for exploring more natural antioxidant resources and uncovering the mechanisms underlying aging-related risk factors and diseases.

Lin Y et al. (2015) Nucleic Acids Res "RNA structure generates natural cooperativity between single-stranded RNA binding proteins targeting 5' and 3'UTRs."

Bundschuh R, Lin Y

[Nucleic Acids Res, 2015]

In post-transcriptional regulation, an mRNA molecule is bound by many proteins and/or miRNAs to modulate its function. To enable combinatorial gene regulation, these binding partners of an RNA must communicate with each other, exhibiting cooperativity. Even in the absence of direct physical interactions between the binding partners, such cooperativity can be mediated through RNA secondary structures, since they affect the accessibility of the binding sites. Here we propose a quantitative measure of this structure-mediated cooperativity that can be numerically calculated for an arbitrary RNA sequence. Focusing on an RNA with two binding sites, we derive a characteristic difference of free energy differences, i.e. G, as a measure of the effect of the occupancy of one binding site on the binding strength of another. We apply this measure to a large number of human and Caenorhabditis elegans mRNAs, and find that structure-mediated cooperativity is a generic feature. Interestingly, this cooperativity not only affects binding sites in close proximity along the sequence but also configurations in which one binding site is located in the 5'UTR and the other is located in the 3'UTR of the mRNA. Furthermore, we find that this end-to-end cooperativity is determined by the UTR sequences while the sequences of the coding regions are irrelevant.

Lin Y et al. (2019) BMC Biol "Peripheral cathepsin L inhibition induces fat loss in C. elegans and mice through promoting central serotonin synthesis."

Lin Y, Zhao L, Bao B, Liu J, Shi GP, Feng A, Wang X, Nie X, Yang N, Yin H

[BMC Biol, 2019]

BACKGROUND: Cathepsin L and some other cathepsins have been implicated in the development of obesity in humans and mice. The functional inactivation of the proteases reduces fat accumulation during mammalian adipocyte differentiation. However, beyond degrading extracellular matrix protein fibronectin, the molecular mechanisms by which cathepsins control fat accumulation remain unclear. We now provide evidence from Caenorhabditis elegans and mouse models to suggest a conserved regulatory circuit in which peripheral cathepsin L inhibition lowers fat accumulation through promoting central serotonin synthesis. RESULTS: We established a C. elegans model of fat accumulation using dietary supplementation with glucose and palmitic acid. We found that nutrient supplementation elevated fat storage in C. elegans, and along with worm fat accumulation, an increase in the expression of cpl-1 was detected using real-time PCR and western blot. The functional inactivation of cpl-1 reduced fat storage in C. elegans through activating serotonin signaling. Further, knockdown of cpl-1 in the intestine and hypodermis promoted serotonin synthesis in worm ADF neurons and induced body fat loss in C. elegans via central serotonin signaling. We found a similar regulatory circuit in high-fat diet-fed mice. Cathepsin L knockout promoted fat loss and central serotonin synthesis. Intraperitoneal injection of the cathepsin L inhibitor CLIK195 similarly reduced body weight gain and white adipose tissue (WAT) adipogenesis, while elevating brain serotonin level and WAT lipolysis and fatty acid -oxidation. These effects of inhibiting cathepsin L were abolished by intracranial injection of p-chlorophenylalanine, inhibitor of a rate-limiting enzyme for serotonin synthesis. CONCLUSION: This study reveals a previously undescribed molecular mechanism by which peripheral CPL-1/cathepsin L inhibition induces fat loss in C. elegans and mice through promoting central serotonin signaling.

Lin S-Y et al. (2000) East Coast Worm Meeting "Initial Characterization of aph-1 Suppressors"

Lin S-Y, Libel C, Scangos K, Goutte C

[East Coast Worm Meeting, 2000]

The maternal-effect-lethal gene aph-1 is essential for early embryonic development. Mutations in aph-1 were isolated in the Priess lab and found to cause an embryonically arrested phenotype that is remarkably similar to that of glp-1 mutant embryos. The phenotype of aph-1 mutants suggests that the aph-1 gene product might be involved in the same specific cell induction events that are mediated by the GLP-1 receptor. As a way of learning more about the specific role of aph-1 in these cell communication events, we have carried out a screen for suppressors of the weak aph-1(zu147) allele. We have identified 6 independent mutations that suppress the partial maternal-effect lethality caused by aph-1(zu147). One of these mutations appears to map to the aph-1 gene locus (or at least very close), and is likely to be a revertant of the aph-1(zu147) allele. The other four mutations are unlinked to aph-1. Complementation and mapping analysis indicates that at least three different genes are represented by these mutations. These suppressor mutations do not appear to have phenotypes of their own other than suppression of aph-1(zu147). Allelespecificity and interactions with other genes are currently being tested. Our latest mapping information for these suppressors will also be presented.

Moss EG et al. (1995) International C. elegans Meeting "EXPRESSION OF THE lin-28 Y-BOX FACTOR IN POSTEMBRYONIC DEVELOPMENT"

Moss EG, Ambros VR

[International C. elegans Meeting, 1995]

Mutations in the heterochronic gene lin-28 cause most cell fates specific to the second larval stage to be skipped and third and later stage-specific fates to be expressed precociously. Genetically lin-28 appears to interact with the heterochronic gene lin-14 to negatively regulate many events that normally occur in the L3, including the division and differentiation of the vulva precursor cells. We have cloned the lin-28 gene, determined its sequence, and discovered that lin-28 encodes a member of the Y-box family of nucleic acid binding proteins. These proteins share a 'cold shock domain' which contains an RNP1 RNA-binding motif. We are investigating the possibility that LIN-28 is a direct negative regulator of genes that implement the events that characterize the L3 and that lin-28 itself is under temporal control. lin-28 is expressed in the L1 and is off by the L2 suggesting that LIN-28 participates in determining what fates are expressed by cells in the L2 before the L2 has begun. This observation is consistent with the possibility that lin-28 and lin-14 are involved in the same regulatory decisions, because the temperature-sensitive period of the lin-14 activity that is also required for normal L2-specific fates is in the late L1. Because genetic evidence indicates that lin-14 and lin-28 may act independently of one another, then if LIN-28 is a direct regulator of fate-specific targets, some of these targets may also be targets of LIN-14.

Perreault J et al. (2007) Mol Biol Evol "Ro-associated Y RNAs in metazoans: evolution and diversification."

Perreault J, Perreault JP, Boire G

[Mol Biol Evol, 2007]

The Y genes encode small non-coding RNAs whose functions remain elusive, whose numbers vary between species, and whose major property is to be bound by the Ro60 protein (or its ortholog in other species). To better understand the evolution of the Y gene family, we performed a homology search in 27 different genomes along with a structural search using Y RNA specific motifs. These searches confirmed that Y RNAs are well conserved in the animal kingdom and resulted in the detection of several new Y RNA genes, including the first Y RNAs in insects and a second Y RNA detected in Caenorhabditis elegans. Unexpectedly, Y5 genes were retrieved almost as frequently as Y1 and Y3 genes, and, consequently are not the result of a relatively recent apparition as is generally believed. Investigation of the organization of the Y genes demonstrated that the synteny was conserved among species. Interestingly, it revealed the presence of six putative "fossil" Y genes, all of which were Y4 and Y5 related. Sequence analysis led to inference of the ancestral sequences for all Y RNAs. In addition, the evolution of existing Y RNAs was deduced for many families, orders and classes. Moreover, a consensus sequence and secondary structure for each Y species was determined. Further evolutionary insight was obtained from the analysis of several thousand Y retropseudogenes among various species. Taken together, these results confirm the rich and diversified evolution history of Y RNAs.

Yamaguchi M et al. (2016) Biochim Biophys Acta "NF-Y in invertebrates."

Yoshida H, Ly LL, Yamaguchi M, Ali MS, Yoshioka Y

[Biochim Biophys Acta, 2016]

BothDrosophila melanogaster and Caenorhabditis elegans (C. elegans) are useful model organisms to study in vivo roles of NF-Y during development. Drosophila NF-Y (dNF-Y) consists of three subunits dNF-YA, dNF-YB and dNF-YC. In some tissues, dNF-YC-related protein Mes4 may replace dNF-YC in dNF-Y complex. Studies with eye imaginal disc-specific dNF-Y-knockdown flies revealed that dNF-Y positively regulates the sevenless gene encoding a receptor tyrosine kinase, a component of the ERK pathway and negatively regulates the Sensless gene encoding a transcription factor to ensure proper development of R7 photoreceptor cells together with proper R7 axon targeting. dNF-Y also controls the Drosophila Bcl-2 (debcl) to regulate apoptosis. In thorax development, dNF-Y is necessary for both proper Drosophila JNK (basket) expression and JNK signaling activity that is responsible for thorax development. Drosophila p53 gene was also identified as one of the dNF-Y target genes in this system. C. elegans contains two forms of NF-YA subunit, CeNF-YA1 and CeNF-YA2. C. elegans NF-Y (CeNF-Y) therefore consists of CeNF-YB, CeNF-YC and either CeNF-YA1 or CeNF-YA2. CeNF-Y negatively regulates expression of the Hox gene egl-5 (ortholog of Drosophila Abdominal-B) that is involved in tail patterning. CeNF-Y also negatively regulates expression of the tbx-2 gene that is essential for development of the pharyngeal muscles, specification of neural cell fate and adaptation in olfactory neurons. Negative regulation of the expression of egl-5 and tbx-2 by CeNF-Y provides new insight into the physiological meaning of negative regulation of gene expression by NF-Y during development. In addition, studies on NF-Y in platyhelminths are also summarized.