Berberine extends healthspan and delays neurodegenerative diseases in Caenorhabditis elegans through ROS-dependent PMK-1/SKN-1 activation.

Oxidative stress, or the chronic generation of reactive oxygen species (ROS), is thought to contribute to the progression of aging and aging related diseases. However, low degree of ROS generation has repeatedly been shown to be associated with beneficial outcomes via activation of protective signaling pathways. Berberine, a natural alkaloid isolated from Rhizomacoptidis, has a long history of medicinal use in both Ayurvedic and traditional Chinese medicine, which possesses anti-cancer, anti-inflammatory and anti-neurodegenerative properties. In this study, we utilize Caenorhabditis elegans to examine the mechanisms by which berberine influences healthspan and neurodegenerative diseases. We find that 10 µM berberine significantly extends healthy lifespan in wild type C. elegans. We further show that berberine generates ROS, which is followed by activation of PMK-1/SKN-1 to extend healthspan. Intriguingly, berberine also delays neurodegenerative diseases such as Alzheimer's and polyglutamine diseases in a PMK-1/SKN-1dependent manner. Our work suggests that berberine may be a viable candidate for the prevention and treatment of aging and aging related diseases.

Hypoxia-reoxygenation Extends the Lifespan of Caenorhabditis elegans via SKN-1- and DAF-16A-Dependent Stress Hormesis.

AIMS: To study the role of hypoxia-reoxygenation and anoxia-starvation on the lifespan of C. elegans and elucidate the mechanism at molecular levels. BACKGROUND: Increasing evidence indicates that reactive oxygen species (ROS) act as signaling molecules that promote health. Hormesis occurs when a moderate stress level induces a beneficial adaptive response, protecting organisms against subsequent exposure to severe stress. Caenorhabditis elegans is a widely used model organism to study aging and displays a broad hormetic ability to couple with stress. To date, only few methods are available to induce stress hormesis in C. elegans. OBJECTIVES: The objectives of this study were to explore the effects of hypoxia-reoxygenation and anoxia-starvation on the lifespan of C. elegans, exploring the involvement of ROS and oxidative stress-related pathways, and examining the hormetic property of H/R. METHODS: The C. elegans were cultured in hypoxic conditions (1% O2) with OP50 bacteria for 24 h followed by reoxygenation (20% O2) (H/R) or in anoxic conditions (0% O2; 100% N2) without OP50 bacteria for 24 h followed by reoxygenation (20% O2) and food supplementation (A/S). Survivals were plotted and estimated for probability with Kaplan-Meier analysis. RESULTS: The H/R extended the lifespan of C. elegans, and H/R-pretreated worms showed improved resistance toward A/S compared to naïve worms. The C. elegans SKN-1 and DAF-16 are important oxidative stress response factors homologous to mammalian Nrf2 and FOXO3, respectively. Mutations in SKN-1 and DAF-16 blocked H/R-induced life extension. Next, H/R treatment in C. elegans activated both SKN-1 and DAF-16, as indicated by the upregulation of putative target genes of SKN-1 (gcs-1 and gss-1) and DAF-16 (sod-3). Moreover, pre-treatment with antioxidants (N-acetylcysteine, chlorogenic acid, and sulforaphane) reduced ROS levels and diminished the lifespan extension effect of H/R, indicating their dependency on ROS. CONCLUSION: These results provide evidence that H/R is beneficial for lifespan and stress resistance by activating the adaptive cellular response pathway (SKN-1 and DAF-16A) toward oxidative stress.

Anti-infective properties of mung bean (Vigna radiata (L.)R. Wilczek) coat extract on Pseudomonas aeruginosa-infected Caenorhabditis elegans: Transcriptomics and pathway analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Mung bean coat has long been known for its wide-ranging health benefits, including antibacterial, anti-inflammatory, and immune-modulatory properties. For many years in China, mung beans have been employed in the therapeutic management of inflammation induced by pathogenic bacteria infection, yet the precise underlying protective mechanisms remain to be comprehensively elucidated. AIM OF THE STUDY: Given the growing concern over antibiotic resistance, there is a necessity to explore new anti-infective agents. Here, the anti-infective properties of Mung bean coat extract (MBCE) were investigated using a model of Pseudomonas aeruginosa-infected nematodes. MATERIALS AND METHODS: The protective effects of MBCE on Pseudomonas aeruginosa (PA14) infected nematodes were assessed by lifespan assay, reactive oxygen species (ROS) levels, transcriptomics, and Quantitative real-time PCR (qRT-PCR). RESULTS: MBCE significantly improved the survival rates and reduced ROS levels in infected worms. Transcriptomic profiling disclosed predominant KEGG pathway enrichments in immune responses, energy metabolism processes such as oxidative phosphorylation and the tricarboxylic acid cycle, alongside aging-related neurodegenerative diseases and longevity regulatory pathways like PI3K-AKT, MAPK, mTOR, and FOXO. qRT-PCR validation showed that MBCE upregulated antimicrobial peptides (spp-3, lys-1, lys-7, abf-2, cnc-2, nlp-33, clec-85), gram-negative responses (irg-3, src-2, grd-3, col-179), and mitochondrial function (mev-1) gene expressions, while downregulated insulin signaling-related (age-1, akt-1, akt-2, daf-15) gene expressions. Mutant strains lifespan analysis indicated that the nsy-1, sek-1, pmk-1, daf-2, aak-2, sir-2.1, and skn-1 were necessary for lifespan extension mediated by MBCE under PA14 infection, but not clk-1, isp-1, mev-1, or daf-16. CONCLUSION: Collectively, our findings suggested that MBCE increased the survival rates of PA14-infected worms by activating downstream antimicrobial and antioxidant gene expressions through modulation of MAPK, daf-2, aak-2, sir-2.1, and skn-1 pathways. The research underscored the potential of natural plant compounds to strengthen the body's defenses against infections, potentially mitigating harmful ROS levels and improving survival. Additionally, these findings elucidated the mechanisms by which these plant-derived compounds enhance the immune system, implying their potential utility as dietary supplements or as an alternative to conventional antibiotics.

SKN-1 Activation During Infection of C. elegans Requires CDC-48 and ER Proteostasis.

During challenge of Caenorhabditis elegans with human bacterial pathogens such as Pseudomonas aeruginosa and Enterococcus faecalis, the elicited host response can be damaging if not properly controlled. The activation of Nrf (nuclear factor erythroid-related factor)/CNC (Cap-n-collar) transcriptional regulators modulates the response by upregulating genes that neutralize damaging molecules and promote repair processes. Activation of the C. elegans Nrf ortholog, SKN-1, is tightly controlled by a myriad of regulatory mechanisms, but a central feature is an activating phosphorylation accomplished by the p38 mitogen-activated kinase (MAPK) cascade. In this work, loss of CDC-48, an AAA+ ATPase was observed to severely compromise SKN-1 activation on pathogen and we sought to understand the mechanism. CDC-48 is part of the endoplasmic reticulum (ER) - associated degradation (ERAD) complex where it functions as a remodeling chaperone enabling the translocation of proteins from the ER to the cytoplasm for degradation by the proteosome. Interestingly, one of the proteins retrotranslocated by ERAD, a process necessary for its activation, is SKN-1A, the ER isoform of SKN-1. However, we discovered that SKN-1A is not activated by pathogen exposure in marked contrast to the cytoplasmic associated isoform, SKN-1C. Rather, loss of CDC-48 blocks the antioxidant response normally orchestrated by SKN-1C by strongly inducing the unfolded protein response (UPRER). The data is consistent with the model of these two pathways being mutually inhibitory and support the emerging paradigm in the field of coordinated cooperation between different stress responses.

Research on the anti-oxidant and anti-aging effects of Polygonatum kingianum saponins in Caenorhabditis elegans.

Oxidative stress and its impact on aging are critical areas of research. Natural anti-oxidants, such as saponins found in Polygonatum sibiricum, hold promise as potential clinical interventions against aging. In this study, we utilized the nematode model organism, Caenorhabditis elegans, to investigate the pharmacological effects of Polygonatum sibiricum saponins (PKS) on antioxidation and anti-aging. The results demonstrated a significant anti-aging biological activity associated with PKS. Through experiments involving lifespan and stress, lipofuscin, q-PCR, and ROS measurement, we found that PKS effectively mitigated aging-related processes. Furthermore, the mechanism underlying these anti-aging effects was linked to the SKN-1 signaling pathway. PKS increased the nuclear localization of the SKN-1 transcription factor, leading to the up-regulation of downstream anti-oxidant genes, such as gst-4 and sod-3, and a substantial reduction in intracellular ROS levels within the nematode. In conclusion, our study sheds light on the anti-oxidant and anti-aging properties of PKS in C. elegans. This research not only contributes to understanding the biological mechanisms involved but also highlights the potential therapeutic applications of these natural compounds in combating aging-related processes.

Cornus officinalis Extract Enriched with Ursolic Acid Ameliorates UVB-Induced Photoaging in Caenorhabditis elegans.

Ultraviolet B (UVB) exposure can contribute to photoaging of skin. Cornus officinalis is rich in ursolic acid (UA), which is beneficial to the prevention of photoaging. Because UA is hardly soluble in water, the Cornus officinalis extract (COE) was obtained using water as the antisolvent to separate the components containing UA from the crude extract of Cornus officinalis. The effect of COE on UVB damage was assessed using Caenorhabditis elegans. The results showed that COE could increase the lifespan and enhance the antioxidant enzyme activity of C. elegans exposed to UVB while decreasing the reactive oxygen species (ROS) level. At the same time, COE upregulated the expression of antioxidant-related genes and promoted the migration of SKN-1 to the nucleus. Moreover, COE inhibited the expression of the skn-1 downstream gene and the extension of the lifespan in skn-1 mutants exposed to UVB, indicating that SKN-1 was required for COE to function. Our findings indicate that COE mainly ameliorates the oxidative stress caused by UVB in C. elegans via the SKN-1/Nrf2 pathway.

Age-dependent heat shock hormesis to HSF-1 deficiency suggests a compensatory mechanism mediated by the unfolded protein response and innate immunity in young Caenorhabditis elegans.

The transcription factor HSF-1 (heat shock factor 1) acts as a master regulator of heat shock response in eukaryotic cells to maintain cellular proteostasis. The protein has a protective role in preventing cells from undergoing ageing, and neurodegeneration, and also mediates tumorigenesis. Thus, modulating HSF-1 activity in humans has a promising therapeutic potential for treating these pathologies. Loss of HSF-1 function is usually associated with impaired stress tolerance. Contrary to this conventional knowledge, we show here that inactivation of HSF-1 in the nematode Caenorhabditis elegans results in increased thermotolerance at young adult stages, whereas HSF-1 deficiency in animals passing early adult stages indeed leads to decreased thermotolerance, as compared to wild-type. Furthermore, a gene expression analysis supports that in young adults, distinct cellular stress response and immunity-related signaling pathways become induced upon HSF-1 deficiency. We also demonstrate that increased tolerance to proteotoxic stress in HSF-1-depleted young worms requires the activity of the unfolded protein response of the endoplasmic reticulum and the SKN-1/Nrf2-mediated oxidative stress response pathway, as well as an innate immunity-related pathway, suggesting a mutual compensatory interaction between HSF-1 and these conserved stress response systems. A similar compensatory molecular network is likely to also operate in higher animal taxa, raising the possibility of an unexpected outcome when HSF-1 activity is manipulated in humans.

Differential impacts of nonsteroidal anti-inflammatory drugs on lifespan and healthspan in aged Caenorhabditis elegans.

Aging and age-related diseases are intricately associated with oxidative stress and inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown their promise in mitigating age-related conditions and potentially extending lifespan in various model organisms. However, the efficacy of NSAIDs in older individuals may be influenced by age-related changes in drug metabolism and tolerance, which could result in age-dependent toxicities. This study aimed to evaluate the potential risks of toxicities associated with commonly used NSAIDs (aspirin, ibuprofen, acetaminophen, and indomethacin) on lifespan, healthspan, and oxidative stress levels in both young and old Caenorhabditis elegans. The results revealed that aspirin and ibuprofen were able to extend lifespan in both young and old worms by suppressing ROS generation and enhancing the expression of antioxidant SOD genes. In contrast, acetaminophen and indomeacin accelerated aging process in old worms, leading to oxidative stress damage and reduced resistance to heat stress through the pmk-1/skn-1 pathway. Notably, the harmful effects of acetaminophen and indomeacin were mitigated when pmk-1 was knocked out in the pmk-1(km25) strain. These results underscore the potential lack of benefit from acetaminophen and indomeacin in elderly individuals due to their increased susceptibility to toxicity. Further research is essential to elucidate the underlying mechanisms driving these age-dependent responses and to evaluate the potential risks associated with NSAID use in the elderly population.

Ovalbumin promotes innate immune response of Caenorhabditis elegans through DAF-16 and SKN-1 pathways in insulin/IGF-1 signaling.

Ovalbumin (OVA) is a major allergen in eggs and could induce severe allergic reactions in sensitive individuals, where the innate immune system works as a regulator. The mechanism of how innate immunity adjusts to food allergy is relatively well-studied, however, the effects of allergen uptake on the innate immune system remain unclear. Therefore, the Caenorhabditis elegans (C. elegans) model was utilized to assess the effects of OVA on its innate immune system. OVA enhanced the immune response of C. elegans with higher survival rates under Pseudomonas aeruginosa infection. Moreover, sustaining OVA treatment improved the health states that were reflected in the prolonged lifespan, alleviated oxidative stress, accelerated growth, and promoted motility. RNA-sequencing analysis and the slow-killing assays in the mutants of insulin/IGF-1 signaling (IIS)-related genes confirmed that IIS was necessary for OVA to regulate innate immunity. Besides, OVA activated SKN-1 temporarily and facilitated the nuclear localization of DAF-16 for improving immunity and health status in C. elegans. Together, OVA could enhance the innate immune responses via DAF-16 and SKN-1 pathways in the IIS of C. elegans, and this work will provide novel insights into the regulation of innate immunity by OVA in higher organisms.

In Vitro and In Vivo Insights into a Broccoli Byproduct as a Healthy Ingredient for the Management of Alzheimer's Disease and Aging through Redox Biology.

Broccoli has gained popularity as a highly consumed vegetable due to its nutritional and health properties. This study aimed to evaluate the composition profile and the antioxidant capacity of a hydrophilic extract derived from broccoli byproducts, as well as its influence on redox biology, Alzheimer's disease markers, and aging in the Caenorhabditis elegans model. The presence of glucosinolate was observed and antioxidant capacity was demonstrated both in vitro and in vivo. The in vitro acetylcholinesterase inhibitory capacity was quantified, and the treatment ameliorated the amyloid-ß- and tau-induced proteotoxicity in transgenic strains via SOD-3 and SKN-1, respectively, and HSP-16.2 for both parameters. Furthermore, a preliminary study on aging indicated that the extract effectively reduced reactive oxygen species levels in aged worms and extended their lifespan. Utilizing broccoli byproducts for nutraceutical or functional foods could manage vegetable processing waste, enhancing productivity and sustainability while providing significant health benefits.

Disrupting the SKN-1 homeostat: mechanistic insights and phenotypic outcomes.

The mechanisms that govern maintenance of cellular homeostasis are crucial to the lifespan and healthspan of all living systems. As an organism ages, there is a gradual decline in cellular homeostasis that leads to senescence and death. As an organism lives into advanced age, the cells within will attempt to abate age-related decline by enhancing the activity of cellular stress pathways. The regulation of cellular stress responses by transcription factors SKN-1/Nrf2 is a well characterized pathway in which cellular stress, particularly xenobiotic stress, is abated by SKN-1/Nrf2-mediated transcriptional activation of the Phase II detoxification pathway. However, SKN-1/Nrf2 also regulates a multitude of other processes including development, pathogenic stress responses, proteostasis, and lipid metabolism. While this process is typically tightly regulated, constitutive activation of SKN-1/Nrf2 is detrimental to organismal health, this raises interesting questions surrounding the tradeoff between SKN-1/Nrf2 cryoprotection and cellular health and the ability of cells to deactivate stress response pathways post stress. Recent work has determined that transcriptional programs of SKN-1 can be redirected or suppressed to abate negative health outcomes of constitutive activation. Here we will detail the mechanisms by which SKN-1 is controlled, which are important for our understanding of SKN-1/Nrf2 cytoprotection across the lifespan.

SKN-1 is indispensable for protection against Aß-induced proteotoxicity by a selenopeptide derived from Cordyceps militaris.

Oxidative stress (OS) and disruption of proteostasis caused by aggregated proteins are the primary causes of cell death in various diseases. Selenopeptides have shown the potential to control OS and alleviate inflammatory damage, suggesting promising therapeutic applications. However, their potential function in inhibiting proteotoxicity is not yet fully understood. To address this gap in knowledge, this study aimed to investigate the effects and underlying mechanisms of the selenopeptide VPRKL(Se)M on amyloid ß protein (Aß) toxicity in transgenic Caenorhabditis elegans. The results revealed that supplementation with VPRKL(Se)M can alleviate Aß-induced toxic effects in the transgenic C. elegans model. Moreover, the addition of VPRKL(Se)M inhibited the Aß aggregates formation, reduced the reactive oxygen species (ROS) levels, and ameliorated the overall proteostasis. Importantly, we found that the inhibitory effects of VPRKL(Se)M on Aß toxicity and activation of the unfolded protein are dependent on skinhead-1 (SKN-1). These findings suggested that VPRKL(Se)M is a potential bioactive agent for modulating SKN-1, which subsequently improves proteostasis and reduces OS. Collectively, the findings from the current study suggests VPRKL(Se)M may play a critical role in preventing protein disorder and related diseases.

Abalone peptide increases stress resilience and cost-free longevity via SKN-1-governed transcriptional metabolic reprogramming in C. elegans.

A major goal of healthy aging is to prevent declining resilience and increasing frailty, which are associated with many chronic diseases and deterioration of stress response. Here, we propose a loss-or-gain survival model, represented by the ratio of cumulative stress span to life span, to quantify stress resilience at organismal level. As a proof of concept, this is demonstrated by reduced survival resilience in Caenorhabditis elegans exposed to exogenous oxidative stress induced by paraquat or with endogenous proteotoxic stress caused by polyglutamine or amyloid-ß aggregation. Based on this, we reveal that a hidden peptide ("cryptide")-AbaPep#07 (SETYELRK)-derived from abalone hemocyanin not only enhances survival resilience against paraquat-induced oxidative stress but also rescues proteotoxicity-mediated behavioral deficits in C. elegans, indicating its capacity against stress and neurodegeneration. Interestingly, AbaPep#07 is also found to increase cost-free longevity and age-related physical fitness in nematodes. We then demonstrate that AbaPep#07 can promote nuclear localization of SKN-1/Nrf, but not DAF-16/FOXO, transcription factor. In contrast to its effects in wild-type nematodes, AbaPep#07 cannot increase oxidative stress survival and physical motility in loss-of-function skn-1 mutant, suggesting an SKN-1/Nrf-dependent fashion of these effects. Further investigation reveals that AbaPep#07 can induce transcriptional activation of immune defense, lipid metabolism, and metabolic detoxification pathways, including many SKN-1/Nrf target genes. Together, our findings demonstrate that AbaPep#07 is able to boost stress resilience and reduce behavioral frailty via SKN-1/Nrf-governed transcriptional reprogramming, and provide an insight into the health-promoting potential of antioxidant cryptides as geroprotectors in aging and associated conditions.

SKN-1/NRF2 upregulation by vitamin A is conserved from nematodes to mammals and is critical for lifespan extension in Caenorhabditis elegans.

Vitamin A (VA) is a micronutrient essential for the physiology of many organisms, but its role in longevity and age-related diseases remains unclear. In this work, we used Caenorhabditis elegans to study the impact of various bioactive compounds on lifespan. We demonstrate that VA extends lifespan and reduces lipofuscin and fat accumulation while increasing resistance to heat and oxidative stress. This resistance can be attributed to high levels of detoxifying enzymes called glutathione S-transferases, induced by the transcription factor skinhead-1 (SKN-1). Notably, VA upregulated the transcript levels of skn-1 or its mammalian ortholog NRF2 in both C. elegans, human cells, and liver tissues of mice. Moreover, the loss-of-function genetic models demonstrated a critical involvement of the SKN-1 pathway in longevity extension by VA. Our study thus provides novel insights into the molecular mechanism of anti-aging and anti-oxidative effects of VA, suggesting that this micronutrient could be used for the prevention and/or treatment of age-related disorders.

NFE2L1/Nrf1 serves as a potential therapeutical target for neurodegenerative diseases.

The failure of the proper protein turnover in the nervous system is mainly linked to a variety of neurodegenerative disorders. Therefore, a better understanding of key protein degradation through the ubiquitin-proteasome system is critical for effective prevention and treatment of those disorders. The proteasome expression is tightly regulated by a CNC (cap'n'collar) family of transcription factors, amongst which the nuclear factor-erythroid 2-like bZIP factor 1 (NFE2L1, also known as Nrf1, with its long isoform TCF11 and short isoform LCR-F1) has been identified as an indispensable regulator of the transcriptional expression of the ubiquitin-proteasome system. However, much less is known about how the pivotal role of NFE2L1/Nrf1, as compared to its homologous NFE2L2 (also called Nrf2), is translated to its physiological and pathophysiological functions in the nervous system insomuch as to yield its proper cytoprotective effects against neurodegenerative diseases. The potential of NFE2L1 to fulfill its unique neuronal function to serve as a novel therapeutic target for neurodegenerative diseases is explored by evaluating the hitherto established preclinical and clinical studies of Alzheimer's and Parkinson's diseases. In this review, we have also showcased a group of currently available activators of NFE2L1, along with an additional putative requirement of this CNC-bZIP factor for healthy longevity based on the experimental evidence obtained from its orthologous SKN1-A in Caenorhabditis elegans.

Comparative analysis of the molecular and physiological consequences of constitutive SKN-1 activation.

Molecular homeostats play essential roles across all levels of biological organization to ensure a return to normal function after responding to abnormal internal and environmental events. SKN-1 is an evolutionarily conserved cytoprotective transcription factor that is integral for the maintenance of cellular homeostasis upon exposure to a variety of stress conditions. Despite the essentiality of turning on SKN-1/NRF2 in response to exogenous and endogenous stress, animals with chronic activation of SKN-1 display premature loss of health with age, and ultimately, diminished lifespan. Previous genetic models of constitutive SKN-1 activation include gain-of-function alleles of skn-1 and loss-of-function alleles of wdr-23 that impede the turnover of SKN-1 by the ubiquitin proteasome. Here, we define a novel gain-of-function mutation in the xrep-4 locus that results in constitutive activation of SKN-1 in the absence of stress. Although each of these genetic mutations results in continuously unregulated transcriptional output from SKN-1, the physiological consequences of each model on development, stress resistance, reproduction, lipid homeostasis, and lifespan are distinct. Here, we provide a comprehensive assessment of the differential healthspan impacts across multiple models of constitutive SKN-1 activation. Although our results reveal the universal need to reign in the uncontrolled activity of cytoprotective transcription factors, we also define the unique signatures of each model of constitutive SKN-1 activation, which provides innovative solutions for the design of molecular "off-switches" of unregulated transcriptional homeostats.

A fruit extract of Styphnolobium japonicum (L.) counteracts oxidative stress and mediates neuroprotection in Caenorhabditis elegans.

BACKGROUND: Despite its widespread uses in Chinese and European medicine, Styphnolobium japonicum (Chinese scholar tree, formerly Sophora japonicum) has not been extensively investigated for its potential to protect against neurodegenerative processes and to promote resistance to oxidative stress. In this study, we evaluated the neuroprotective activities of a hydroalcoholic extract from Chinese scholar tree fruits that could be possibly linked to its antioxidant properties using Caenorhabditis elegans as a well-established in vivo model. METHODS: Survival rate in mutant daf-16 and skn-1 worms, stressed by the pro-oxidant juglone and treated with the extract, was tested. Localization of the transcription factors SKN-1 and DAF-16, and expression of gst-4 were measured. For evaluation of neuroprotective effects, formation of polyglutamine (polyQ40) clusters, α-synuclein aggregates, loss of amphid sensilla (ASH) neuronal function, and amyloid ß (Aß) accumulation (as markers for Huntington's, Parkinson's, and Alzheimer's) was examined. RESULTS: The extract, which contains substantial amounts of phenolic phytochemicals, showed an increase in the survival rate of worms challenged with juglone in daf-16 mutants but not in skn-1 mutants. The transcription factor SKN-1 was activated by the extract, while DAF-16 was not affected. Upon application of the extract, a significant decline in GST-4 levels, polyQ40 cluster formation, number of lost ASH sensory neurons, α-synuclein aggregation, and paralysis resulting from Aß accumulation was observed. CONCLUSIONS: Styphnolobium japonicum fruit extract activated the SKN-1/Nrf2 pathway, resulting in oxidative stress resistance. It revealed promising pharmacological activities towards treatment of Huntington's, Parkinson's, and Alzheimer's diseases. Polyphenolics from Styphnolobium japonicum may be a promising route towards treatment of CNS disorders, but need to be tested in other in vivo systems.

Vitexin and isovitexin delayed ageing and enhanced stress-resistance through the activation of the SKN-1/Nrf2 signaling pathway.

Vitexin and isovitexin, as potential SKN-1/Nrf2 (SKN-1 is a homologous protein of mammalian Nrf2) activators, extended lifespan and promoted healthspan in Caenorhabditis elegans. This study aims to elucidate the role of SKN-1/Nrf2 in vitexin and isovitexin-induced anti-aging and stress-resistance. Vitexin and isovitexin upregulated antioxidant gene and protein expressions, reduced ROS accumulation, and increased SKN-1 accumulation in the nucleus. They prolonged lifespan and clear ROS during stressful conditions in a skn-1-dependent manner. skn-1 was also found to be necessary for these compounds-induced longevity under normal conditions. They were also witnessed to retard cellular senescence and scavenge ROS in senescent cells by directly binding to the pocket of Keap1 to promote the dissociation and activation of Nrf2. This study showed that SKN-1/Nrf2 signaling was vital to delaying ageing and enhancing anti-stress capacity with vitexin and isovitexin. The findings provide new insights into apigenin C-glycosides activating the SKN-1/Nrf2 pathway and demonstrate their potential as candidates for innovative strategies in chemoprophylaxis against ageing and oxidative-related diseases.

Baicalein mitigates oxidative stress and enhances lifespan through modulation of Wnt ligands and GATA factor: ELT-3 in Caenorhabditis elegans.

AIMS: Age predispose individual to major diseases, and the biological processes contributing to aging are currently under intense investigation. Hence, plant-based natural compounds could be a potential target to counteract aging and age-associated diseases. So, the present study aims to investigate the antiaging properties of a natural compound Baicalein (BAI) on C. elegans and to elucidate the pathways or signaling molecules involved. METHODS: Herein, we investigated the inhibitory effects of BAI on different Wnt ligands of C. elegans and its underlying mechanisms. Moreover, we monitored BAI's antiaging effect on the worms' lifespan and its different aging parameters. We employed different mutant and transgenic C. elegans strains to identify the pathways and transcription factors involved. KEY FINDINGS: We first showed that BAI could downregulate different Wnt ligands mRNA expressions in C. elegans, resulting in enhanced expression of GATA transcription factor ELT-3 and antiaging gene Klotho. On further evaluation, it was observed that BAI could enhance the worm's lifespan via ELT-3 and SKN-1 transcription factors, whereas, for the protection of worms against external oxidative stress, both ELT-3 and DAF-16 transcription factors were involved. Moreover, sensitive aging parameters of worms, including lipofuscin and ROS accumulation, and the declined physiological and mechanical functions observed in aged worms were ameliorated by BAI. SIGNIFICANCE: This study highlighted BAI as a promising antiaging compound. This study also revealed the Wnt inhibitory potential of BAI with future implications for pharmacological target of age-associated diseases with aberrant activation of the Wnt pathway.

SKN-1/Nrf2-dependent regulation of mitochondrial homeostasis modulates transgenerational toxicity induced by nanoplastics with different surface charges in Caenorhabditis elegans.

The toxic effects of nanoplastics on transgenerational toxicity in environmental organisms and the involved mechanisms remain poorly comprehended. This study aimed to identify the role of SKN-1/Nrf2-dependent regulation of mitochondrial homeostasis in response to transgenerational toxicity caused by changes in nanoplastic surface charges in Caenorhabditis elegans (C. elegans). Our results revealed that compared with the wild-type control and PS exposed groups, exposure to PS-NH2 or PS-SOOOH at environmentally relevant concentrations (ERC) of ≥ 1 µg/L caused transgenerational reproductive toxicity, inhibited mitochondrial unfolded protein responses (UPR) by downregulating the transcription levels of hsp-6, ubl-5, dve-1, atfs-1, haf-1, and clpp-1, membrane potential by downregulating phb-1 and phb-2, and promoted mitochondrial apoptosis by downregulating ced-4 and ced-3 and upregulating ced-9, DNA damage by upregulating hus-1, cep-1, egl-1, reactive oxygen species (ROS) by upregulating nduf-7 and nuo-6, ultimately resulting in mitochondrial homeostasis. Additionally, further study indicated that SKN-1/Nrf2 mediated antioxidant response to alleviate PS-induced toxicity in the P0 generation and dysregulated mitochondrial homeostasis to enhance PS-NH2 or PS-SOOOH-induced transgenerational toxicity. Our study highlights the momentous role of SKN-1/Nrf2 mediated mitochondrial homeostasis in the response to nanoplastics caused transgenerational toxicity in environmental organisms.