scholarly journals A method to identify and validate mitochondrial modulators using mammalian cells and the worm C. elegans

2014 ◽  
Vol 4 (1) ◽  
Author(s):  
Pénélope A. Andreux ◽  
Laurent Mouchiroud ◽  
Xu Wang ◽  
Virginija Jovaisaite ◽  
Adrienne Mottis ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Mammalian Cells ◽  
Screening Strategy ◽  
Culture Conditions ◽  
Metabolic Effects ◽  
Mitochondrial Activity ◽  
Exact Nature ◽  
C Elegans ◽  
Beneficial Effects ◽  
Multiple Parameters

Abstract Mitochondria are semi-autonomous organelles regulated by a complex network of proteins that are vital for many cellular functions. Because mitochondrial modulators can impact many aspects of cellular homeostasis, their identification and validation has proven challenging. It requires the measurement of multiple parameters in parallel to understand the exact nature of the changes induced by such compounds. We developed a platform of assays scoring for mitochondrial function in two complementary models systems, mammalian cells and C. elegans. We first optimized cell culture conditions and established the mitochondrial signature of 1,200 FDA-approved drugs in liver cells. Using cell-based and C. elegans assays, we further defined the metabolic effects of two pharmacological classes that emerged from our hit list, i.e. imidazoles and statins. We found that these two drug classes affect respiration through different and cholesterol-independent mechanisms in both models. Our screening strategy enabled us to unequivocally identify compounds that have toxic or beneficial effects on mitochondrial activity. Furthermore, the cross-species approach provided novel mechanistic insight and allowed early validation of hits that act on mitochondrial function.

scholarly journals Feeding recombinant Royalactin: Measures of improved lifespan and mitochondrial function in Caenorhabditis elegans

2020 ◽  
Author(s):  
Xia Li ◽  
Thomas L. Ingram ◽  
Ying Wang ◽  
Kamila Derecka ◽  
Nathan Courtier ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Mitochondrial Function ◽  
Royal Jelly ◽  
Biological Functions ◽  
C Elegans ◽  
Beneficial Effects ◽  
Physiological Processes ◽  
Royal Jelly Protein ◽  
Insight Into ◽  
Over Time

AbstractAgeing, the decline of biological functions over time, is inherent to eukaryotes. Female honeybees attain a long-lived queen phenotype upon continuous consumption of royal jelly, whereas restricted supply of this nutritional substance promotes the development of worker bees, which are short-lived. An abundant protein found within royal jelly is major royal jelly protein 1 (MRJP1), also known as ‘Royalactin’. Health- and lifespan promoting effects have been attributed to Royalactin in species from diverse animal taxa, suggesting it acts on phylogenetically conserved physiological processes. Here, we explore the effects of feeding the nematode Caenorhabditis elegans with Escherichia coli that express a recombinant form of Royalactin (RArec). We confirm that consumption of RArec increases body size, improves locomotion and extends lifespan. We discover a link between Royalactin and mitochondria, organelles which play a key part in the ageing process: both spare respiratory capacity and morphology indicate improved mitochondrial function in RArec fed C. elegans. These results demonstrate the feasibility of using recombinant Royalactin to gain further insight into processes of healthy ageing in many species.RArec production allows insight into potential beneficial effects across species.

scholarly journals Hydralazine targets cAMP-dependent protein kinase leading to sirtuin1/5 activation and lifespan extension in C. elegans

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Esmaeil Dehghan ◽  
Mohammad Goodarzi ◽  
Bahar Saremi ◽  
Rueyling Lin ◽  
Hamid Mirzaei
Keyword(s):  
Protein Kinase ◽  
Mitochondrial Function ◽  
Dependent Protein Kinase ◽  
In Vivo Models ◽  
C Elegans ◽  
Beneficial Effects ◽  
Camp Dependent Protein Kinase ◽  
Dependent Protein

Abstract Therapeutic activation of mitochondrial function has been suggested as an effective strategy to combat aging. Hydralazine is an FDA-approved drug used in the treatment of hypertension, heart failure and cancer. Hydralazine has been recently shown to promote lifespan in C. elegans, rotifer and yeast through a mechanism which has remained elusive. Here we report cAMP-dependent protein kinase (PKA) as the direct target of hydralazine. Using in vitro and in vivo models, we demonstrate a mechanism in which binding and stabilization of a catalytic subunit of PKA by hydralazine lead to improved mitochondrial function and metabolic homeostasis via the SIRT1/SIRT5 axis, which underlies hydralazine’s prolongevity and stress resistance benefits. Hydralazine also protects mitochondrial metabolism and function resulting in restoration of health and lifespan in C. elegans under high glucose and other stress conditions. Our data also provide new insights into the mechanism(s) that explain various other known beneficial effects of hydralazine.

scholarly journals Tart Cherry Increases Lifespan in Caenorhabditis elegans by Altering Metabolic Signaling Pathways

Nutrients ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1482
Author(s):  
Shasika Jayarathne ◽  
Latha Ramalingam ◽  
Hunter Edwards ◽  
Siva A. Vanapalli ◽  
Naima Moustaid-Moussa
Keyword(s):  
Oxidative Stress ◽  
Caenorhabditis Elegans ◽  
Mitochondrial Function ◽  
Antioxidant Properties ◽  
Wild Type ◽  
Tart Cherry ◽  
C Elegans ◽  
Beneficial Effects ◽  
The Mean ◽  
And Oxidative Stress

Aging and healthspan are determined by both environmental and genetic factors. The insulin/insulin-like growth factor-1(IGF-1) pathway is a key mediator of aging in Caenorhabditis elegans and mammals. Specifically, DAF-2 signaling, an ortholog of human IGF, controls DAF-16/FOXO transcription factor, a master regulator of metabolism and longevity. Moreover, mitochondrial dysfunction and oxidative stress are both linked to aging. We propose that daily supplementation of tart cherry extract (TCE), rich in anthocyanins with antioxidant properties may exert dual benefits for mitochondrial function and oxidative stress, resulting in beneficial effects on aging in C. elegans. We found that TCE supplementation at 6 μg or 12 μg/mL, increased (p < 0.05) the mean lifespan of wild type N2 worms, respectively, when compared to untreated control worms. Consistent with these findings, TCE upregulated (p < 0.05) expression of longevity-related genes such as daf-16 and aak-2 (but not daf-2 or akt-1 genes) and genes related to oxidative stress such as sod-2. Further, we showed that TCE supplementation increased spare respiration in N2 worms. However, TCE did not change the mean lifespan of daf-16 and aak-2 mutant worms. In conclusion, our findings indicate that TCE confers healthspan benefits in C. elegans through enhanced mitochondrial function and reduced oxidative stress, mainly via the DAF-16 pathway.

scholarly journals Modulatory and Toxicological Perspectives on the Effects of the Small Molecule Kinetin

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 670
Author(s):  
Eman M. Othman ◽  
Moustafa Fathy ◽  
Amany Abdlrehim Bekhit ◽  
Abdel-Razik H. Abdel-Razik ◽  
Arshad Jamal ◽  
...  
Keyword(s):  
Plant Hormones ◽  
Adenosine Receptor ◽  
Mammalian Cells ◽  
Metabolic Effects ◽  
Renal Tubules ◽  
Dependent Manner ◽  
Animal Cells ◽  
Binding Interaction ◽  
Beneficial Effects ◽  
Adenosine Receptor A2a

Plant hormones are small regulatory molecules that exert pharmacological actions in mammalian cells such as anti-oxidative and pro-metabolic effects. Kinetin belongs to the group of plant hormones cytokinin and has been associated with modulatory functions in mammalian cells. The mammalian adenosine receptor (A2a-R) is known to modulate multiple physiological responses in animal cells. Here, we describe that kinetin binds to the adenosine receptor (A2a-R) through the Asn253 residue in an adenosine dependent manner. To harness the beneficial effects of kinetin for future human use, we assess its acute toxicity by analyzing different biochemical and histological markers in rats. Kinetin at a dose below 1 mg/kg had no adverse effects on the serum level of glucose or on the activity of serum alanine transaminase (ALT) or aspartate aminotransferase (AST) enzymes in the kinetin treated rats. Whereas, creatinine levels increased after a kinetin treatment at a dose of 0.5 mg/kg. Furthermore, 5 mg/kg treated kinetin rats showed normal renal corpuscles, but a mild degeneration was observed in the renal glomeruli and renal tubules, as well as few degenerated hepatocytes were also observed in the liver. Kinetin doses below 5 mg/kg did not show any localized toxicity in the liver and kidney tissues. In addition to unraveling the binding interaction between kinetin and A2a-R, our findings suggest safe dose limits for the future use of kinetin as a therapeutic and modulatory agent against various pathophysiological conditions.

scholarly journals Prolonged Lifespan, Ameliorated Cognition, and Improved Host Defense of Caenorhabditis elegans by Lactococcus lactis subsp. cremoris

2021 ◽  
Author(s):  
Tomomi Komura ◽  
Asami Takemoto ◽  
Hideki Kosaka ◽  
Toshio Suzuki ◽  
Yoshikazu Nishikawa
Keyword(s):  
Caenorhabditis Elegans ◽  
Cognitive Ability ◽  
Lactococcus Lactis ◽  
Host Defense ◽  
Mammalian Cells ◽  
Heme Oxygenase 1 ◽  
Host Defenses ◽  
C Elegans ◽  
Beneficial Effects ◽  
Physical Chemical

This study evaluated whether the lactic acid bacteria Lactococcus lactis subsp. cremoris strain FC (FC) could ameliorate host defenses and cognitive ability and extend the lifespan of Caenorhabditis elegans, a model of senescence. The lifespan and resistance to physical, chemical, and biological stressors were compared between C. elegans fed FC and those fed Escherichia coli OP50 (OP), an international standard food for C. elegans. Living FC successfully extended the health span, enhanced host defense, and ameliorated the cognitive ability of the nematodes; even the exopolysaccharides (EPSes) of FC could extend the lifespan of C. elegans. The chemotaxis index, which was used to evaluate the senescence of sensory neurons, tended to decrease with aging; however, it was more stable in worms fed FC and was significantly higher than that of the control worms at 7 days of age. The worms fed FC were tolerant to Salmonella enterica serovar Enteritidis or Staphylococcus aureus infection and had better survival than the control worms fed OP. FC showed beneficial effects in C. elegans daf-16 and pmk-1 mutants, but not in skn-1 mutants. Since SKN-1 is the C. elegans ortholog of Nrf2, we measured the transcription of heme oxygenase-1 (HO-1), which is regulated by Nrf2, in murine macrophages and found that HO-1 mRNA expression was increased >5 times by inoculation with either FC cells or heat-killed bacteria with EPSes. Thus, both FC and the EPSes can affect longevity via the SKN-1/Nrf2 pathway in both nematodes and mammalian cells.

scholarly journals A conserved role of Parkinson-associated DJ-1 metabolites in sperm motility, mitosis, and embryonic development

2021 ◽  
Author(s):  
Susanne Bour ◽  
Yanina Dening ◽  
Melanie Balbach ◽  
Ina Poser ◽  
Inés Ramírez Álvarez ◽  
...  
Keyword(s):  
Sperm Motility ◽  
Mitochondrial Function ◽  
Sperm Quality ◽  
Model Systems ◽  
Mitochondrial Activity ◽  
Loss Of Function ◽  
C Elegans ◽  
Cellular Processes ◽  
Positive Effects

AbstractFertility rates in the developing world have dramatically dropped in the last decades. This drop is likely due to a decline in sperm quality and women having children at older ages. Loss of function mutations in DJ-1, a Parkinson’s associated gene, are linked to alterations in multiple cellular processes such as mitochondrial activity, ROS production or sperm motility and lead to an early onset of Parkinson’s disease and male infertility in humans and other species. Glycolate (GA) and D-lactate (DL), products of DJ-1 glyoxalase activity, sustain mitochondrial function and protect against environmental aggressions. We, therefore, tested whether these substances could also have a rescue effect on these phenotypes. Here, we show that DJ-1 loss of function not only affects sperm motility but also leads to defects in mitosis and an age-dependent increase in the abortion rate. Remarkably, whereas DL was only able to rescue embryonic lethality in C. elegans, GA rescued these phenotypes in all model systems tested and even increased sperm motility in wild-type sperm. These positive effects seem to be mediated through an increase in NAD(P)H production and the regulation of intracellular calcium. These findings not only strongly suggest GA as a new therapeutic candidate to improve male and female fertility but also show its potential to treat diseases associated with a decline in mitochondrial function or to improve mitochondrial function in aging.

scholarly journals Phosphoglycolate phosphatase homologs act as glycerol-3-phosphate phosphatase to control stress and healthspan in C. elegans

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Elite Possik ◽  
Clémence Schmitt ◽  
Anfal Al-Mass ◽  
Ying Bai ◽  
Laurence Côté ◽  
...  
Keyword(s):  
Calorie Restriction ◽  
Mammalian Cells ◽  
Healthy Aging ◽  
Model Organism ◽  
Metabolic Stress ◽  
Clinical Importance ◽  
C Elegans ◽  
Beneficial Effects ◽  
Age Related

AbstractMetabolic stress due to nutrient excess and lipid accumulation is at the root of many age-associated disorders and the identification of therapeutic targets that mimic the beneficial effects of calorie restriction has clinical importance. Here, using C. elegans as a model organism, we study the roles of a recently discovered enzyme at the heart of metabolism in mammalian cells, glycerol-3-phosphate phosphatase (G3PP) (gene name Pgp) that hydrolyzes glucose-derived glycerol-3-phosphate to glycerol. We identify three Pgp homologues in C. elegans (pgph) and demonstrate in vivo that their protein products have G3PP activity, essential for glycerol synthesis. We demonstrate that PGPH/G3PP regulates the adaptation to various stresses, in particular hyperosmolarity and glucotoxicity. Enhanced G3PP activity reduces fat accumulation, promotes healthy aging and acts as a calorie restriction mimetic at normal food intake without altering fertility. Thus, PGP/G3PP can be considered as a target for age-related metabolic disorders.

Antifungal Activity Directed Toward the Cell Wall by 2-Cyclohexylidenhydrazo- 4-Phenyl-Thiazole Against Candida albicans

2019 ◽  
Vol 19 (4) ◽  
pp. 428-438 ◽  
Author(s):  
Nívea P. de Sá ◽  
Ana P. Pôssa ◽  
Pilar Perez ◽  
Jaqueline M.S. Ferreira ◽  
Nayara C. Fonseca ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Antifungal Activity ◽  
Mammalian Cells ◽  
C Elegans ◽  
Buccal Epithelial Cells ◽  
Mutant Strains ◽  
Low Toxicity ◽  
High Concentrations ◽  
Mic Value

<p>Background: The increasing incidence of invasive forms of candidiasis and resistance to antifungal therapy leads us to seek new and more effective antifungal compounds. </P><P> Objective: To investigate the antifungal activity and toxicity as well as to evaluate the potential targets of 2- cyclohexylidenhydrazo-4-phenyl-thiazole (CPT) in Candida albicans. </P><P> Methods: The antifungal activity of CPT against the survival of C. albicans was investigated in Caenorhabditis elegans. Additionally, we determined the effect of CPT on the inhibition of C. albicans adhesion capacity to buccal epithelial cells (BECs), the toxicity of CPT in mammalian cells, and the potential targets of CPT in C. albicans. </P><P> Results: CPT exhibited a minimum inhibitory concentration (MIC) value of 0.4-1.9 µg/mL. Furthermore, CPT at high concentrations (>60 x MIC) showed no or low toxicity in HepG2 cells and <1% haemolysis in human erythrocytes. In addition, CPT decreased the adhesion capacity of yeasts to the BECs and prolonged the survival of C. elegans infected with C. albicans. Analysis of CPT-treated cells showed that their cell wall was thinner than that of untreated cells, especially the glucan layer. We found that there was a significantly lower quantity of 1,3-β-D-glucan present in CPT-treated cells than that in untreated cells. Assays performed on several mutant strains showed that the MIC value of CPT was high for its antifungal activity on yeasts with defective 1,3-β-glucan synthase. </P><P> Conclusion: In conclusion, CPT appears to target the cell wall of C. albicans, exhibits low toxicity in mammalian cells, and prolongs the survival of C. elegans infected with C. albicans.</p>

scholarly journals Beneficial Effects of Akkermansia muciniphila Are Not Associated with Major Changes in the Circulating Endocannabinoidome but Linked to Higher Mono-Palmitoyl-Glycerol Levels as New PPARα Agonists

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 185
Author(s):  
Clara Depommier ◽  
Rosa Maria Vitale ◽  
Fabio Arturo Iannotti ◽  
Cristoforo Silvestri ◽  
Nicolas Flamand ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Univariate Analysis ◽  
Metabolic Effects ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Akkermansia Muciniphila ◽  
Beneficial Effects ◽  
Daily Ingestion ◽  
Before And After ◽  
Palmitoyl Glycerol

Akkermansia muciniphila is considered as one of the next-generation beneficial bacteria in the context of obesity and associated metabolic disorders. Although a first proof-of-concept of its beneficial effects has been established in the context of metabolic syndrome in humans, mechanisms are not yet fully understood. This study aimed at deciphering whether the bacterium exerts its beneficial properties through the modulation of the endocannabinoidome (eCBome). Circulating levels of 25 endogenous endocannabinoid-related lipids were quantified by liquid chromatography with tandem mass spectrometry (LC-MS/MS) in the plasma of overweight or obese individuals before and after a 3 months intervention consisting of the daily ingestion of either alive or pasteurized A. muciniphila. Results from multivariate analyses suggested that the beneficial effects of A. muciniphila were not linked to an overall modification of the eCBome. However, subsequent univariate analysis showed that the decrease in 1-Palmitoyl-glycerol (1-PG) and 2-Palmitoyl-glycerol (2-PG), two eCBome lipids, observed in the placebo group was significantly counteracted by the alive bacterium, and to a lower extent by the pasteurized form. We also discovered that 1- and 2-PG are endogenous activators of peroxisome proliferator-activated receptor alpha (PPARα). We hypothesize that PPARα activation by mono-palmitoyl-glycerols may underlie part of the beneficial metabolic effects induced by A. muciniphila in human metabolic syndrome.

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