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5'-Hydroxy-6, 7, 8, 3', 4'-pentamethoxyflavone (5-HPF), a polymethoxyflavone compound found in dikamali gum, has been shown to exert a range of beneficial effects on health. We have previously reported that 5-HPF improves the cholinergic dysfunction and also possesses antioxidant properties in Caenorhabditis elegans. In this study, we have identified the effect of 5-HPF on the worm lifespan and its underlying molecular mechanisms. Out of the five tested pharmacological doses of 5-HPF, viz. 6.25, 12.5, 25, 50, and 100 μM, the 50 μM dose maximally extended the mean life of C. elegans by 28%. The present study revealed that 5-HPF supplementation leads to dietary restriction (DR)-like effects in the worms without altering bacterial metabolism. The analysis of mutant animals fed with 5-HPF suggested that the extended lifespan of C. elegans depends upon multiple DR-related signaling pathways, with NRF2 and FOXA being critical factors. Further investigation into the mechanistic aspects indicated that 5-HPF utilizes autophagy pathway induced by DR through the upregulation of autophagy genes bec-1 and lgg-1, evident from the increase in autophagic puncta in the seam cells of lgg-1::gfp tagged worms. This study identifies the longevity-promoting activity of 5-HPF in C. elegans regulated by oxidative stress-resistance genes and DR-induced autophagy pathway.

Parkinsonism is an age-associated neurodegenerative disorder characterized by aggregation of α-synuclein (α-syn) protein in the substantia nigra region, degeneration of dopaminergic neurons, and deregulated lipid metabolism. Currently, only symptomatic relief has been provided by FDA-approved therapeutic approaches for Parkinson's disease (PD). The present study aims to evaluate the potential of wedelolactone (WDL), a natural occurring coumestan found in Eclipta alba to mitigate the parkinsonism in Caenorhabditis elegans disease model. In the present studies, supplementation with 37.5 μM WDL exhibited a reduction in the level of α-syn in an age-dependent manner (22% at day 5, p < 0.05; and 16% at day 10, p < 0.001, n = 30), along with improvement in neuronal health through basal movement, and elevated the dopamine levels evident through 1-nonanol repulsion results in wild-type and diseased worms. Moreover, WDL augmented the mitochondrial health in wild-type, PD-diseased, and mev-1 mutant worms that establish the inherent activity of WDL in the alleviation of oxidative stress. Furthermore, WDL supplementation significantly decreases the neutral lipid and triglyceride level and also alleviates protein carbonyl level in PD disease condition. The overall investigation will provide a pioneer to the future insights of PD research related to plant-based drugs. qPCR studies after WDL supplementation revealed alteration of genes involved in the regulation of various stress-responsive (sod-5, gst-4, skn-1), α-syn-suppressing (lrk-1, ymel-1, lagr-1, grk-1), and mitochondrial (pink-1) genes. All together, these findings support that the WDL is a promising candidate to combat age-related multi-factorial PD pathology associated with protein misfolding and accumulation. The results provide sufficient information in the development of therapeutic medicines from natural products for improving the health.

Plant-based dietary supplements that delay aging are of significant interest now a days because these naturally occurring bioactive molecules effectively provide pharmaceuticals/neutraceuticals to deal with diseases related to the advanced life expectancy. In this paper, we aimed to investigate the effect of Shatavarin IV (SIV), a steroidal saponin isolated from Asparagus racemosus Willd. on dietary restriction (DR) induced longevity in Caenorhabditis elegans. SIV significantly increased the lifespan to 18% which is independent of antimicrobial activity and reduced the aging by-product, lipofuscin along with increased locomotion, and chemotaxis behavior in wild type worms. The longevity effect has been dependent on eat-2, which was further validated via reduced pharyngeal pumping rate that established the effect similar to DR induced longevity. Moreover, like eat-2 mutant worms, SIV reduces the total progeny number of wild type worm along with a significant alleviation of stored fat, which reconfirms the involvement of eat-2 mediated longevity. Further, it was also observed that DR induced longevity mechanism by SIV requires mTOR which works in PHA-4/FOXA dependent manner. In addition to this, the role of autophagy mechanism concerning SIV mediated DR was confirmed via bec-1, unc-51, and lgg-1. The longevity effect achieved by SIV was also dependent on SKN-1/NRF-2 and partially dependent on DAF-16/FOXO. Furthermore, the DR-induced longevity by SIV was found to be independent of hsf-1 exhibiting non-significant alteration in the mRNA expression of downstream target genes hsp-16.2 and hsp-70. Altogether, this study provides first-hand information on the pro-longevity effect of SIV in worms that have been mediated by the DR-regulating gene induced autophagy.

Protein-protein interaction (PPI) studies are gaining momentum these days due to the plethora of various high-throughput experimental methods available for detecting PPIs. Proteins create complexes and networks by functioning in harmony with other proteins and here in silico network biology hold the promise to reveal new functionality of genes as it is very difficult and laborious to carry out experimental high-throughput genetic screens in living organisms. We demonstrate this approach by computationally screening C. elegans conserved homologs of already reported human tumor suppressor and aging associated genes. We select by this nhr-6, vab-3 and gst-23 as predicted longevity genes for RNAi screen. The RNAi results demonstrated the pro-longevity effect of these genes. Nuclear hormone receptor nhr-6 RNAi inhibition resulted in a C. elegans phenotype of 23.46% lifespan reduction. Moreover, we show that nhr-6 regulates oxidative stress resistance in worms and does not affect the feeding behavior of worms. These findings imply the potential of nhr-6 as a common therapeutic target for aging and cancer ailments, stressing the power of in silico PPI network analysis coupled with RNAi screens to describe gene function.

Ageing is a progressive deterioration in functional and structural well-being of the body, accompanied with age-associated neurological disorders such as Parkinson's disease (PD), Alzheimer's disease and Huntington's disease. PD is marked with motor function decline, progressive neurodegeneration due to aggregation of insoluble α-synuclein in the dopaminergic neuron. Here we investigated the effect of tambulin (3,5-dihydroxy-7,8-dimethoxy-2-(4-methoxyphenyl) chromen-4-one), a hydroxy substituted flavanol isolated from fruits of Zanthoxyllum armatum DC (Family-Rutaceae) for its longevity promoting and neuromodulatory activities using Caenorhabditis elegans model system. Our results show that tambulin treatment significantly enhance lifespan and stress tolerance in worms, along with mitigation of ageing biomarkers like lipofuscin and protein carbonyl. In line with the alleviated ROS levels, tambulin treatment led to upregulated mRNA expression of ROS scavenging genes viz., sod-1, sod-3, and ctl-2. Upregulation in daf-16 gene indicates the involvement of insulin signaling pathway in tambulin mediated longevity. Tambulin treatment exhibited curtailed PD manifestations in terms of reduced α-synuclein levels, lipid accumulation, improved locomotary behavior and dopamine levels. Altogether, our data suggest that tambulin mediated alleviation of PD manifestations possibly involved PD counter protective machinery as evident through upregulated mRNA expression of lagr-1, ymel-1, pdr-1, ubc-12, and lrk-1. Our studies present tambulin as a potential molecule for its properties against ageing and Parkinson's disease. Further studies are speculated to realize the mechanistic and pharmacological aspects of tambulin., (Copyright © 2019. Published by Elsevier Inc.)

Oxidative damage is accrual of molecular deterioration from reactive oxygen species (ROS) while decrease in generation of ROS is related with free radical scavenging enzymes. Boerhaavia diffusa L. (Nyctaginaceae) derived novel molecule Boeravinone B (BOB) possesses a variety of pharmacological activities, yet their anti-aging potential has not been explored. The aim of the present study was to elucidate the mechanism of BOB mediated oxidative stress resistance and lifespan extension in Caenorhabditis elegans. The results showed that the BOB significantly extends the lifespan of C. elegans with its anti-oxidative potential via reducing accumulation of reactive oxygen species (ROS). BOB was found to recover the shortened lifespan of oxidative stress prone mutants mev-1 and gas-1 (14.75 and 16.11%, respectively). Additionally, this finding supported by the reduced ROS levels seen in BOB treated worms. Further, the effective concentration of BOB (25 μM) significantly enhanced the expressions of target genes such as superoxide dismutase (SOD-3), glutathione-S-transferase (GST-4) and heat shock protein (HSP-16.2) fused to green fluorescent protein (GFP), and it does so by modulating the stress-related signaling pathways (SEK-1) and transcription factors (SKN-1/Nrf and DAF-16/Foxo). Moreover, BOB exposure (25 μM) caused significant changes of age-dependent biomarkers such as pharyngeal pumping, body bend, locomotor activity and lipofuscin accumulation were also showed that BOB retards the aging. Overall, the findings highlight the antioxidant supplement triggering pharmaceutical potential of BOB which may serve as a new future perspective for healthy aging or delayed onset of oxidative related diseases., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Shatavarin IV (SIV), a steroidal saponin, is a major bioactive phytomolecule present in roots of Asparagus racemosus (Liliaceae) known for its anticancer activity. Age-associated neurodegenerative Parkinson's disease (PD) is characterised by alpha-synuclein aggregation in dopaminergic neuron resulting in neurodegeneration. The invention of bioactive molecules that delay aging and age-associated disorders endorses development of natural phytomolecule as a therapeutic agent for curing age-related diseases. Therefore, the present study for the first time explores the potential of SIV against aging and Parkinsonism utilising Caenorhabditis elegans model system. SIV significantly attenuated oxidative stress in terms of intracellular reactive oxygen species (ROS) as well as oxidative damage including protein carbonylation and also promotes longevity. SIV also significantly increased the mRNA expression of stress responsive genes namely sod-1, sod-2, sod-3, gst-4, gst-7 and ctl-2 suggesting its anti-oxidant property that might be contributed in the modulation of oxidative stress and promoting lifespan. Additionally, SIV improved PD symptoms by reducing the alpha-synuclein aggregation, lipid accumulation and enhancing dopamine level. Altogether, present findings indicate that SIV possibly utilising ubiquitin-mediated proteasomal system and attenuating oxidative stress by up-regulating PD-associated genes pdr-1, ubc-12 and pink-1. Therefore, this study is a forward step in exploring the anti-aging and anti-Parkinsonism potential of bioactive compound SIV in C. elegans.

Species from lower invertebrates to a spectrum of mammals show antiaging health benefits of phytochemical(s). Here, we explored the pro-longevity effects of a natural triterpenoid, ursolic acid (3β-hydroxy-urs-12-en-28-oic acid; UA) in Caenorhabditis elegans with maximal life span being evident at 25 µM UA. Similar to eat-2 mutants, UA uptake by worm results in reduced fat storage and attenuation of reactive oxygen species (ROS), independent of superoxide dismutase(s) activation. The genetic requirements for UA-mediated longevity are quite similar to dietary restriction (DR) achieved through SKN-1/NRF-2 exhibiting upregulation of downstream target genes gcs-1 and daf-9. Longevity mechanism was independent of PHA-4/FOXA and attributed to partial dependence on sir-2.1. Altogether, our study suggests differential use of UA-elicited signaling cascades in nutrient sensing for longevity. Both the redox state and the proteostasis of an organism play critical role in aging and disease resistance. Interestingly, we observed a reduction of toxic protein aggregation in transgenic polyglutamine (polyQ) C. elegans model and UA-mediated JNK-1 (c-Jun-NH2-terminal kinase) activation in wild-type animals. Thus, our study demonstrates a small extent of prevention against proteotoxic stress by UA coupled with positive aspects of DR-mediated longevity., (© The Author 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Despite their well reported potent risk towards human health and environment Zinc oxide nanoparticles (ZnONPs) find an extensive commercial usage due to their antimicrobial properties. Here, we evaluated the efficacy of a natural triterpene ursolic acid (3β-hydroxy-urs-12-en-28-oic acid; UA) for overcoming the cytotoxic challenges of ZnONPs employing Ceanorhabditis elegans. The 24h LC 50 of Zn-ONPs (<50nm TEM) was deduced as 4.75mgL -1 . UA (25μM) was observed to defend against this toxicity by attenuating Reactive Oxygen Species (ROS) resulting into better survival at 2mgL -1 in a time dependent behavior. However, reproductive health remains compromised. Our study identifies UA as a natural inducer of metallothionein proteins along with antioxidant potential. We demonstrate that UA induces upregulation of predominantly antioxidant genes, including the superoxide dismutases (sod-1, sod-5 and sod-3), glutathione S-transferase 7 (gst-7), heat shock protein (hsp-16.2) along with the metal exposure responsive metallothionein (mtl-1 and mtl-2). Moreover, UA also restores elevated transcript levels of gst-4 during ZnONPs stress conditions to normal by directly scavenging ROS owing to its own antioxidant potential. Altogether, the toxic aspects of NPs that can be avoided compensated or postponed by supplementation of phytochemical(s) in biological system underscore their potential implications in near future., (Copyright © 2017 Elsevier B.V. All rights reserved.)

An Ayurvedic polyherbal extract (PHE) comprising six herbs viz. Berberis aristata, Cyperus rotundus, Cedrus deodara, Emblica officinalis, Terminalia chebula and Terminalia bellirica is mentioned as an effective anti-hyperglycemic agent in 'Charaka Samhita', the classical text of Ayurveda. Previously, antidiabetic drug metformin was found to elicit antiaging effects and PHE was also found to exhibit antidiabetic effects in humans. Therefore, we screened it for its in vivo antioxidant antiaging effect on stress and lifespan using human homologous Caenorhabditis elegans model system. The effect on aging is evaluated by studying effect of PHE on mean survival in worms. The stress modulatory potential was assessed by quantification of intracellular ROS level, autofluorescent age pigment lipofuscin, oxidative and thermal stress assays. Additionally, stress response was quantified using gene reporter assays. The 0.01 µg/ml dose of PHE was able to enhance mean lifespan by 16.09% (P < 0.0001) in C. elegans. Furthermore, PHE treated worms demonstrated oxidative stress resistance in both wild type and stress hypersensitive mev-1 mutant along with upregulation of stress response genes sod-3 and gst-4. The delayed aging under stress can be attributed to its direct reactive oxygen species-scavenging activity and regulation of some age associated genes like daf-2, daf-16, skn-1, sod-3 and gst-4 in wild-type worms. Additonally, PHE delayed age related paralysis phenotype in CL4176 transgenic worms. Altogether, our results suggest PHE significantly improves the oxidative stress and life span in C. elegans. Overall the present study suggests this polyherbal formulation might play important role in regultaing aging and related complications like diabetes.

Remarkably the c-Jun-NH2-terminal kinase (JNK) pathway is all evolutionarily conserved across species. In view of the hypothesis that increased stress resistance subdue aging, we investigated the role of ursolic acid (3β-Hydroxy-urs-12-en-28-oic acid; UA) in the pioneering aging model Caenorhabditis elegans with an increase in mean and maximum lifespan by up to 30%. Our genetic study unravelled the underlying pathway where JNK-1 is acting independently of insulin-IGF-1 signalling (IIS) pathway to modulate longevity. In support of in vivo results in silico docking study of UA with C. elegans JNK-1 ATP-binding site suggested promising binding affinity exhibiting binding energy of -8.11 kcalmol -1 . UA induced JNK-1 activation in wild-type animals underlie the importance of pharmacological interventions in the delineation of molecular targets for aging and associated pathologies., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The advancements in the field of gerontology have unraveled the signaling pathways that regulate life span, suggesting that it might be feasible to modulate aging. To this end, we isolated a novel phytomolecule Acacetin 7-O-α-l-rhamnopyranosyl (1-2) β-D-xylopyranoside (ARX) from Premna integrifolia and evaluated its antiaging effects in Caenorhabditis elegans The spectral data analysis revealed the occurrence of a new compound ARX. Out of the three tested pharmacological doses of ARX, viz. 5, 25, and 50 µM, the 25-µM dose was able to extend life span in C. elegans by more than 39%. The present study suggests that ARX affects bacterial metabolism, which in turn leads to dietary restriction (DR)-like effects in the worms. The effect of ARX on worms with mutations (mev-1, eat-2, sir-2.1, skn-1, daf-16, and hsf-1) indicates that ARX-mediated life-span extension involves mechanisms associated with DR and maintenance of cellular redox homeostasis. This study is the first time report on longevity-promoting activity of ARX in C. elegans mediated by stress and DR-regulating genes. This novel phytomolecule can contribute in designing therapeutics for managing aging and age-related diseases., (© The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Withanolide A (steroidal lactone) forms the major constituent of the most popular herbal drug in Ayurvedic medicine, Ashwagandha. It has been used since ancient times as an alternative medicine for the treatment of a variety of age related disorders. Here we provide multiple lines of evidence indicating that Withanolide A improves healthspan, delays age-associated physiological changes and also extends the lifespan of Caenorhabditis elegans. We also report several neuroprotective benefits of this natural product, including its anti-amyloidogenic effects, alleviation of α-synuclein aggregation and neuroprotection through modulation of neural mediators like acetylcholine. We observed that Withanolide A mediates lifespan extension and promotes stress resistance via insulin/insulin-like growth factor signaling pathway. Such findings could be helpful to develop a therapeutic medicine from this natural product for the prevention or reversal of age-related ailments and to improve the survival of patients suffering from Alzheimer's or Parkinson's disease., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Specioside (6-O-coumaroylcatalpol) is an iridoid glucoside which possesses multifunctional activities viz. analgesic, antidyspeptic, astringent, liver stimulating and wound healing properties. The present study for the first time delineates stress alleviating and lifespan prolonging action of specioside (SPC), isolated from Stereospermum suaveolens in the free living, multicellular nematode model Caenorhabditis elegans. A strong correlation between lifespan extension and stress modulation in adult worms was established in a dose dependent manner. The dietary intake of this phytomolecule elevated juglone induced oxidative and heat induced thermal stress tolerance in C. elegans. On evaluation, it was found that 25 μM dose of SPC significantly extended lifespan by 15.47% (P≤0.0001) with reduction in stress level. Furthermore, SPC enhanced mean survival in mev-1 mutant suggesting its oxidative stress reducing potential. Furthermore, SPC augmented stress modulatory enzymes superoxide dismutase (SOD) and catalase (CAT) level in C. elegans. Altogether, these findings broaden current perspectives concerning stress alleviating potentials of SPC and have implications in development of therapeutics for curing age related disorders., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The interaction of heavy metals such as hexavalent chromium, Cr (VI) with the environment drastically influences living organisms leading to an ecological imbalance. Caenorhabditis elegans, a saprophytic nematode having 60-80% homology with human genes offers a distinct advantage to be used as a biosensor for the appraisal of heavy metal-induced environmental toxicity and risk monitoring. The present study examines the toxicity effects of K2Cr2O7 as Cr (VI) on stress-related gene expression and morphometric parameters of C. elegans under in vitro conditions to identify genetic markers for environmental pollution. Alterations in growth and modified gene expression were observed in Cr (VI)-exposed N2 worms. The 24-h median lethal concentration for Cr (VI) was observed as 158.5 mgl(-1). Use of the responses of stress-related gene expression suggests that C. elegans can be used as an efficient biosensor for figuring out the precise route of Cr (VI)-induced environmental toxicity in a quick, simple, and inexpensive manner.

Since aging is the most important risk factor for variety of diseases, the discovery of a wide range of chemical modulators of aging in model organisms encourages new strategies for targeting age associated diseases. Simple genetic manipulation leads to long-lived and healthy animals, so any compound which could have similar effect would prove a boon to mankind. In the present study, effect of different pharmacological doses (1.0, 0.1, 0.01 and 0.001 mg/mL) of O. sanctum crude extract were used to determine their impact on life span, thermotolerance and ROS scavenging activities in C. elegans. The results revealed that 1 mg/mL of O. sanctum extract significantly extended the life span of C. elegans. The extract also proved to be a strong free radical scavenger and increased resistance against thermal stress. It is also suggested that the protective and life span extending action of the crude extract is not only due to its antioxidant capacity but may also be mediated by modulation of some signaling pathways. Thus, in addition to all the known medicinal property of Ocimum, it is capable of increasing stress tolerance and life span in C. elegans.

Aging, the major cause of several ailments has led to intense exploration of potential drugs that delay aging and its associated effects. We mined the information on traditional Indian medicines and identified an iridoid, 10-O-trans-p-Coumaroylcatalpol (OCC), a major ingredient of Premna integrifolia Linn. (syn: Premna serratifolia). OCC forms an important constituent of famous herbal formulation 'Dashmula', a ten herb formulation, commonly used for its various medicinal properties. Employing model system C. elegans, the effect of OCC on life span, stress resistance, chemotaxis, the content of reactive oxygen species (ROS) and on the aggregation of alpha synuclein was studied. OCC extended the mean life span of nematodes, increased their tolerance against chemical induced stress, improved the chemotaxis index and reduced the ROS content. Further, the aggregation of Parkinson's disease (PD) associated protein, alpha synuclein (asyn), was decreased when transgenic a-syn expressing worms were raised on OCC mixed diet. We extended the studies further to explore the possible genetic mechanism that mediates the observed effects of OCC. Employing the genetic knockout mutants TK22 [mev-1(kn1)III]; GR1307 [daf-16(mgDf50)I]; VC199 [sir-2.1(ok434)IV] and transgenic GFP expressing strain TJ356 [zls356; DAF-16::GFP], our studies revealed that the effects were mediated by daf-16 and not by sir-2.1 or mev-1. Our results indicate that OCC has the ability to ameliorate a-syn aggregation, reduce oxidative stress and promote longevity in C. elegans via activation of longevity promoting transcription factor DAF-16. Thus, OCC may serve as a lead compound of plant origin for important nutraceutical intervention against aging and age associated PD.

In modern times, there has been a major increase in the use of plants or herbal constituents for the prevention of age-related disorders. 4-Hydroxy-E-globularinin (4-HEG) is an iridoid and a major component of Premna integrifolia. This investigation represents a breakthrough in geriatrics by showing the longevity-promoting activity of 4-HEG in the animal model Caenorhabditis elegans. 4-HEG (20μM) enhanced the mean life span of worms by over 18.8% under normal culture conditions and also enhanced their survival under oxidative stress. The longevity-promoting activity was associated with reduced reactive oxygen species (ROS) levels and fat accumulation in the worms. Gene-specific mutant studies verified the role of ROS detoxification pathways and simultaneous nuclear translocation of DAF-16 in the 4-HEG-mediated effects. Quantitative real-time PCR estimations and observations of transcriptional reporters indicated that 4-HEG was able to upregulate stress-inducible genes, viz., hsp-16.2 and sod-3. Thus, 4-HEG may serve as a lead compound of plant origin for the development of important nutraceuticals superseding the aging process., (Copyright © 2012 Elsevier Inc. All rights reserved.)

During the last decade, advancement of nanotechnology has revolutionized various fields such as electronics, optics, materials science as well as architecture, and medicine. However, their health and environmental impact is not fully understood. TiO2 and ZnO nanoparticles (NPs), which are abundantly used for commercial purposes, pose a great risk to environment. In this context, we examined the adverse effects of TiO2 and ZnO NPs of < 25 nm and < 100 nm sizes to nematode Caenorhabditis elegans. < 25 nm TiO2 and ZnO NPs showed LC50 of 77 mg/L and 0.32 mg/L respectively, while < 100 nm TiO2 NPs were non-toxic and LC50 of 2 mg/L was obtained for < 100 nm ZnO NPs. Our studies indicate that in both cases, smaller particle sizes are more toxic than larger NPs and ZnO NPs are more toxic than TiO2 NPs. Further, we observed low LC50 values for ZnO NPs, probably reflecting the sensitivity of C. elegans as a model for eco-toxicity studies of NPs.

The 1 mm long Caenorhabditis elegans is one of the prime research tools to study different human neurodegenerative diseases. We have considered the case in which increase in the surrounding temperature of this multicellular model leads to abnormal bursts of neuronal cells that can be linked to seizure or convulsion. The induction of such seizure/convulsion mechanism was done by gradually increasing the temperature with 1x buffer (100 mM NaCl, 50 mM MgCl(2)) in adult C. elegans. In the present experiment it is demonstrated that Baccoside A can significantly reduce the seizure/convulsion in C. elegans at higher temperatures (26-28+/-1 degrees C). Furthermore, in T-type Ca(2+) channel cca-1 mutant worms, no convulsion was recorded. Our experimental results suggest that plant molecules from Bacopa monnieri may be useful in suppressing the seizure/convulsion in worms., (2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

The study elucidates the effect of ɑ‐linolenic acid (ALA) on mitochondrial stress, hypoxic cancer microenvironment, and intervention of cholinergic anti‐inflammatory pathway using N‐methyl‐N‐nitrosourea (MNU) induced estrogen receptor (ER+) mammary gland carcinoma and Caenorhabditis elegans model, respectively. The efficacy of ALA was scrutinized in vivo and in vitro using various experiments like hemodynamic studies, morphological analysis, antioxidants parameters, immunoblotting, and quantitative reverse transcription polymerase chain reaction. The effect of ALA was also validated using C. elegans worms. ALA administration had a positive effect on tissue architecture of the malignancy when scrutinized through the whole mount carmine staining, hematoxylin and eosin staining, and scanning electron microscopy. The proteomic and genomic checkpoint revealed the participation of mitochondrial dysfunction, alteration of hypoxic microenvironment, and involvement of cholinergic anti‐inflammatory response after treatment with ALA. ALA treatment has also increased the level of synaptic acetylcholine and acetylcholine esterase with a significant decrease in lipid content. It was concluded that ALA persuaded the mitochondrial stress, activation of downstream cholinergic anti‐inflammatory markers, and favorable regulation of hypoxia microenvironment through inhibition of fatty acid synthase and sterol regulatory element‐binding protein. ɑ‐Linolenic acid persuaded the mitochondrial stress, activation of downstream cholinergic anti‐inflammatory markers, and favorable regulation of hypoxia microenvironment through inhibition of fatty acid synthase and sterol regulatory element‐binding protein. [ABSTRACT FROM AUTHOR]

Background: The various herbal remedies have been used in Ayurveda which symbolizes traditional medicine system since ancient times. The increasing popularity of herbal medicines has prompted us toward the development of natural therapeutics for preventing neurodegenerative disease such as Alzheimer's disease (AD) in living organisms. This study focused on a flavonoid compound 5,7-dihydroxy-4-methoxyflavone (DMF) also known as acacetin which is a major constituent of Premna odorata (L.) plant. This bioactive flavonoid exhibits several medicinal properties such as antimicrobial, anti-inflammatory, antioxidant, and anti-carcinogenic. Objective: The aim is to determine the protective effects of DMF against amyloid beta (Aβ)-induced toxicity and oxidative stress in transgenic Caenorhabditis elegans model of AD. Materials and Methods: The therapeutic potential of DMF treatments (5, 25, and 50 μM) was investigated to counteract Aβ paralysis and oxidative stress through paralysis assay, reactive oxygen species (ROS) detection, protein carbonylation, aldicarb assay, and mRNA quantification using transgenic C. elegans model of AD. Results: The present study reports that DMF effectively delayed Aβ-induced paralysis, attenuated ROS level reduced protein carbonylation and conferred aldicarb resistance. In addition, DMF was also found to up-regulate the expression of stress modulating (sod-1, sod-2, sod-3, ctl-1, hsp-16.2, and gst-4), acetylcholine transporter(unc-17), regulator of nicotinic acetylcholine receptor (unc-50), and choline acetyltransferase (cha-1) related genes. Conclusion: These findings suggest DMF may provide protection against Aβ toxicity and oxidative stress due to its antioxidant activity. Therefore, the bioactive flavonoid DMF may provide invaluable medicinal and health benefits which can delay the onset of age-related diseases. [ABSTRACT FROM AUTHOR]

Aging is an unavoidable phenomenon, often afflicting structure and functionality of body, marked with onset of age associated manifestations. Parkinson's disease (PD), the second most common form of dementia is manifested with Lewy body formation and dopaminergic dysfunction. Present study explores silymarin, a known hepatoprotective regimen for its efficacy in Aging and PD using Caenorhabditis elegans . Silymarin positively modulated longevity, reduced oxidative stress, independent of feeding behaviour. Up-regulation of longevity and stress related genes daf-16, sod-3, gst-4 and skn-1 indicate the possible involvement of these genes for regulating longevity. In-addition silymarin alleviated PD symptoms by reducing α-synuclein levels, lipid accumulation and enhanced dopamine function. Silymarin executes its beneficial effects through mitigation of free radicals, while achieving alleviation in Parkinsonism possibly through pdr-1 mediated recruitment of ubiquitin proteasome system as evident from qPCR studies. Altogether, silymarin emerged as a potent molecule for investigation in Aging and age related disorders. [ABSTRACT FROM AUTHOR]

The progression in lifespan has been associated with elevated intracellular reactive oxygen species (ROS) and oxidative stress level which contributes to development of age related disorders. The discovery of lifespan modulating phytomolecules may promote development of natural therapies against age related afflictions. Acacetin (5,7-dihydroxy-4-methoxyflavone), is a naturally occurring flavonoid known to possess therapeutic properties. To this end, the present study evaluates effect of acacetin (AC) on lifespan, stress and neurotoxicity for the first time by using well-established free living, multicellularCaenorhabditis elegansmodel system. The 25 μM dose of AC significantly prolonged the mean lifespan of worms by 27.31% in comparison to untreated control and other tested doses of AC. Additionally, AC enhanced stress resistance against oxidative and thermal stress in worms. Furthermore, AC attenuated age related intracellular ROS level, aggregation of age pigment lipofuscin and increased the mean survival in stress hypersensitivemev-1mutant by 40.5%. AC supplementation also reduced the alpha synuclein aggregation in transgenic worm model of Parkinson’s disease. The enhanced stress resistance, lifespan and alleviation of age related pathology can be attributed to increment in stress modulatory enzymes like superoxide dismutase (SOD) and catalase (CAT) level. Altogether the results suggest AC exposure maintains stress level, health span and extends mean lifespan ofC. elegans. The longevity promoting and neuromodulatory effects of AC are mediated by up regulation of the stress response genessod-3andgst-4. The present finding gives new insights of natural remedies and their future prospects in developing therapeutic interventions for managing age related diseases. [ABSTRACT FROM PUBLISHER]

Background: Bacopa monnieri (L.) Pennell, commonly known as Brahmi is an important medicinal plant traditionally used as memory enhancer and antiepileptic agent. Objective: The present study investigated antioxidant and stress resistance potentials of B. monnieri aqueous extract (BMW) using Caenorhabditis elegans animal model system. Materials and Methods: The antioxidant activity of the BMW was measured using in vitro (DPPH, reducing power and total polyphenol content) and in vivo (DCF-DA assay) assays. The antistress potential of BMW (0.1, 0.01, and 0.001 mg/ml) was evaluated through thermal stress (37°C) and oxidative stress (10 mM paraquat) using C. elegans. Quantification of the HSP-16.2 level was done using CL2070 transgenic worms. Results: Present study reveals that BMW possess in vitro and in vivo antioxidant activities. BMW significantly enhanced stress tolerance and increased the mean lifespan of worms during thermal and oxidative stress, although it did not extend lifespan at 20°C and attenuated age dependent decline in physiological behaviors. Moreover, it was shown that BMW was able to up-regulate expression of stress associated gene hsp-16.2, which significantly (P < 0.001) extends the mean lifespan of worms under stress conditions. Conclusion: The study strongly suggests that BMW acts as an antistressor and potent reactive oxygen species scavenger which enhances the survival of the worms in different stress conditions. [ABSTRACT FROM AUTHOR]

In traditional systems of medicine, plants belonging to the family Rutaceae have been used against ageing and associated debilitating changes. Considering the therapeutic potential of limonene (C10H16), the principal component of the Rutaceae family plants, the present study was designed to decipher lifespan and stress-modulating potential of monocyclic terpene limonene (LM) employing genetically tractable model system Caenorhabditis elegans. Furthermore, we tested oxidative stress tolerance and in vivo reactive oxygen species build-up, which was monitored with or without exposure to LM. Additionally, involvement of transcription factor DAF-16 was examined in terms of nuclear localization. Overall, this study has implications for developing future anti-ageing pharmacological strategies in the future. [ABSTRACT FROM AUTHOR]

The conserved EGFR pathway is linked with multiple cancers in humans including breast, ovarian, and lung carcinoma. Withanolide A, one of the major withanolidal active compounds isolated from the Withania somnifera , extends lifespan and ameliorates stress resistance in wild-type C . elegans by targeting the Insulin/IGF-1 signaling pathway. Up-regulation of IGF1 can transactivate EGFR which inturn reduces longevity and promotes tumor development in an organism. We examined the effects of Withanolide A on the lifespan of a human EGFR-driven C . elegans transgenic model exhibiting the multivulva (Muv) phenotype. The results showed that WA extends the lifespan of both wild human EGFR-driven C . elegans model (human wild-type tyrosine kinase) as well as models bearing single (L858R), and double mutations (T790M-L858R). The lifespan extension observed in these transgenic strains was 20.35, 24.21 and 21.27%, respectively. Moreover, the reduced fat levels were noticed in both wild-type N2 worms and transgenic strains. These observations support the heathspan promoting effect of WA as lipid-rich diet has been reported to promote tumor development. In view of the fact that most of the well known FDA approved drugs such as gefitinib fail to inhibit the EGFR-associated cancers because of these mutations, the present findings show the potential of Withanolide A as a foreseen future nutraceutical to improve the average survival of cancer patients. [ABSTRACT FROM AUTHOR]

Clove (Syzygium aromaticum) is a popular medicinal plant which has been traditionally used in India as spice and medicine to counter various ailments. However, the stress modulatory and antiaging potential of this plant is yet to be characterized. Therefore, the present study evaluates the effect of clove oil (CO) on oxidative stress, lifespan, mobility, and the expression of aging-related proteins using Caenorhabditis elegans model system. The CO (10 ppm) was found to extend mean lifespan in worms by 21.4% (p < 0.001) under normal and by 63% (p < 0.0001) under juglone-induced oxidative stress conditions. The extension of mean lifespan in mev-1 mutant and elevated expression of gst-4 and sod-3 confirmed stress modulatory effects of CO. Additionally, the CO reduced intracellular ROS and Aβ1-42 proteotoxicity. Altogether, the present study unravels the anti-aging and stress modulatory potential of CO and suggests CO as a potential pharmaceutical entity in modulating aging process. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a multifactorial ailment that severely affects the viability of dopaminergic neurons leading to progressive loss of motor control. The current regimen for PD treatment includes synthetic drugs that lack efficacy and cause serious side effects. Consequently, recent drug development studies are focusing on alternative medicines from plant sources. Artemisia pallens Wall. ex DC, commonly known as davana, is an annual aromatic herb cultivated in southern India. Given the diverse traditional and scientifically documented therapeutic effects of A. pallens , the pharmacological potential of the isolates of the plant, namely bicyclogermacrene (D1), cis -davanone (D3), and cis -hydroxy davanone (D5), was tested for anti-Parkinson's activity in Caenorhabditis elegans model. The tested compounds alleviated α -synuclein (α -syn) aggregation and maximum decline was observed in 25 μM D1 supplemented worms. Additionally, D1 modulated dopamine regulated nonanol-1 repulsion and locomotory behaviour of C. elegans validating its future use as a dopamine-enhancing agent. The genetic regulation mediating the above effects validated through the qPCR study showed that D1 supplementation displayed its anti-Parkinson's effect through upregulation of the antioxidant defence system genes (superoxide dismutase (sod)-1 , sod-2, and sod-4) and PD associated pdr-1 gene that maintains the mitochondrial proteostasis. The molecular docking studies of C. elegans PDR-1 with D1 further confirmed its contribution in D1 induced abridgment of Parkinson disease linked pathologies in C. elegans disease model. Hence, this article proposes D1 as an effective regimen for curtailing the Parkinson disease linked pathologies through mechanism of maintaining cellular redox state and proteostasis. • Sesquiterpenoids from Artemisia pallens decreased α -synuclein levels in C. elegans. • Bicyclogermacrene(D1) was most effective, modulating the dopamine-dependent behaviour. • D1 upregulated sod-1, sod-2, sod-4 and pdr- 1 mRNA expression. • D1 also showed good binding affinity of −6.51 kcal mol-1 with C. elegans PDR-1. • D1's anti-Parkinson's effects are through cellular redox state and proteostasis regulation. [ABSTRACT FROM AUTHOR]

Distillery wastewater has significant amount of coloring compounds and organic substances even after the secondary treatment process, which poses many severe environmental and health threats. However, the recalcitrant coloured compounds have not yet been clearly identified. In this study, two bacterial strains DS3 and DS5 capable to decolorize distillery wastewater (DWW) pollutants were isolated and characterized as Staphylococcus saprophyticus (MF182113) and Alcaligenaceae sp. (MF182114), respectively. Results showed that mixed bacterial culture was found more effective decolorizing 71.83% DWW compared to axenic culture DS3 and DS5 resulting only 47.94% and 50.67% decolorization, respectively. The FT-IR and LC-MS/MS analysis of untreated DWW showed the presence of many recalcitrant compounds having different functional groups, but after bacterial treatment, most of compounds get diminished and the toxicity of DWW was reduced significantly. Further, the Nile red staining of Caenorhabditis elegans exposed to untreated and bacteria treated DWW for evaluation of toxicity assay and results revealed that the worms exposed to untreated DWW showed sharp reduction in total fat content having more profound effects, suggesting the diminished nAchR signaling as compare to bacterial treated DWW. Hence, this study revealed that inadequate disposal of untreated DWW may cause transfer of toxic substances into the environment and receiving water bodies. Image 1 • Distillery wastewater has a variety of chemical pollutants. • Bacteria Staphylococcus saprophyticus and Alcaligenaceae sp. were used to treat DWW. • FT-IR and LC-MS used to characterize the DWW pollutants and their metabolites. • Toxicity of DWW pollutants and metabolites was evaluated by Caenorhabditis elegans. • Study showed disposal of untreated DWW may cause severe environmental pollution. [ABSTRACT FROM AUTHOR]

Curcumin (CUR) and β-caryophellene (BCP) are well known bioactive phytomolecules which are known to reduce oxidative stress in living organisms. Therefore, the present study was envisaged to explore the possible effects of CUR and BCP in suppression of cadmium quantum dots (CdTe QDs) induced toxicity in Caenorhabditis elegans. CdTe QD are luminescent nanoparticles extensively exploited for in vivo imaging, but long term bioaccumulation confer deleterious effects on living organisms. The 24-h LC 50 and LC 100 of CdTe QD were found to be 18.40 μg/ml and 100 μg/ml respectively. The CdTe QD exposure elevated HSP-16.2 expression mediating induction of the stress response. The CdTe QD lethality was due to increment in ROS and decline in SOD and GST expression. The present study demonstrates improved survival in BCP (50 μM) and CUR (20 μM) treated worms by over 60% ( P < 0.01) and 50% ( P < 0.029) in CdTe QD (100 μg/ml) exposed worms. Furthermore, BCP and CUR attenuate oxidative stress triggered by QD. The present study for the first time demonstrates CdTe QD toxicity remediation via BCP and CUR. The future investigations can unravel underlying protective effects of phytomolceules for remediating cyotoxicolgical effects of QDs. [ABSTRACT FROM AUTHOR]

The ever increasing popularity of herbal supplements modulating aging has shifted focus towards development of natural therapeutics for curing age related afflictions in living organisms. The progression in age is correlated with elevation in oxidative stress. The increment in oxidative stress ultimately affects human health, which led to search for new stress alleviating compounds, but very few bioactive molecules are available presently. To this end, we evaluated the effect of three aqueous extract viz. Ocimum basilicum (OCW), Premna integrifolia (PSW) and mixture of both herbs (OPW) on Caenorhabditis elegans . The present study delineates effect of OPW, PSW and OCW on lifespan using survival and stress assays. The maximal lifespan extension was observed in OPW (50 μg/ml) 32% ( P < 0.0001) followed by 27.9% ( P < 0.0001) in PSW (50 μg/ml) and 18.39% ( P < 0.0001) in OCW (50 μg/ml). Furthermore, all the three extracts were able to modulate both the oxidative as well as thermal stress. Altogether, OPW mediates maximal lifespan extension in the worm which can be attributed to modulation of stress level to a greater extent. These results may provide insights for designing evidence-based herbal therapy in future. [ABSTRACT FROM AUTHOR]

Beta-caryophyllene (BCP) is a natural bicyclic sesquiterpene and is a FDA approved food additive, found as an active ingredient in essential oils of numerous edible plants. It possesses a wide range of biological activities including anti-oxidant, anti-inflammatory, anti-cancerous and local anesthetic actions. We used the well established Caenorhabditis elegans model system to elucidate the stress modulatory and lifespan prolonging action of BCP. The present study for the first time reports the lifespan extension and stress modulation potential of BCP in C. elegans . Upon evaluation, it was found that 50 μM dose of BCP increased the lifespan of C. elegans by over 22% ( P ≤ 0.0001) and significantly reduced intracellular free radical levels, maintaining cellular redox homeostasis. Moreover, the results suggest that BCP modulates feeding behavior, pharyngeal pumping and body size effectively. Further, this compound also exhibited significant reduction in intestinal lipofuscin levels. In the present investigation, we have predicted possible biological molecular targets for BCP using molecular docking approaches and BCP was found to have interaction with SIR-2.1, SKN-1 and DAF-16. The prediction was further validated in vivo using mutants and transgenic strains unraveling underlying genetic mechanism. It was observed that BCP increased lifespan of mev-1 and daf-16 but failed to augment lifespan in eat-2 , sir-2.1 and skn-1 mutants. Relative quantification of mRNA demonstrated that several genes regulating oxidative stress, xenobiotic detoxification and longevity were modulated by BCP treatment. The study unravels the involvement of multiple signaling pathways in BCP mediated lifespan extension. [ABSTRACT FROM AUTHOR]

The ailments related to a malfunction in cholinergic functioning currently employ the use of inhibitors for acetylcholinesterase (AChE) and N -methyl- d -aspartate (NMDA) receptors. The present study was designed to elucidate the potential of swertiamarin (SW), a secoiridoidal glycoside isolated from Enicostemma littorale in curtailing the cholinergic dysfunction. Using Caenorhabditis elegans as a model, SW was found to enhance neurotransmission by modulating AChE and nicotinic acetylcholine receptor (nAChR) activity; being orchestrated through up-regulation of unc-17 and unc-50. SW exhibited AChE inhibition both in vivo and cell-free system. The in silico molecular docking of SW and human AChE (hAChE) displayed good binding energy of −6.02. Interestingly, the increase in aldicarb and levamisole sensitivity post SW treatment was curtailed to a significant level in daf-16 and skn-1 mutants. SW raised the level of the endogenous antioxidant enzymes through up-regulation of sod-3 and gst-4 that act downstream to DAF-16 and SKN-1, imparting protection against neurodegeneration. The outcome of our study displays SW as a potential natural molecule for the amelioration of cholinergic dysfunction. Moreover, the study also indicates that SW elicits antioxidant response via up-modulation of daf-16 possibly through unc-17 upregulation. Further research on SW pertaining to the underlying mechanism and potential is expected to significantly advance the current understanding and design of possible ameliorative or near ameliorative regimens for cholinergic dysfunction. • Swertiamarin, a secoiridoid glycoside elevates the cholinergic neurotransmission by modulating synaptic AChE and nicotinic acetylcholine receptor activity (nAChR) in Caenorhabditis elegans. • Swertiamarin activates unc - 17 and unc - 50 genes which are related to acetylcholine vesicular transport and receptor respectively. • Swertiamarin also provide neuroprotection through modulation of ROS scavenging genes viz. sod-1 , sod-3 , and gst-4. • SW elicits antioxidant response via up-modulation of daf-16 possibly through unc-17 upregulation. [ABSTRACT FROM AUTHOR]