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Butein is a flavonoid found in many plants, including dahlia, butea, and coreopsis, and has both antioxidant and sirtuin-activating activities. In light of the postulated role of free radicals in aging, we examined the effects of butein on aging and on genetic or nutritional models of age-related diseases in Caenorhabditis elegans. Butein showed radical scavenging activity and increased resistance to oxidative stress in Caenorhabditis elegans. The mean lifespan of Caenorhabditis elegans was significantly increased by butein, from 22.7 days in the untreated control to 25.0 days in the butein-treated group. However, the lifespan-extending effect of butein was accompanied by reduced production of progeny as a trade-off. Moreover, the age-related decline in motility was delayed by butein supplementation. Genetic analysis showed that the lifespan-extending effect of butein required the autophagic protein BEC-1 and the transcription factor DAF-16 to regulate stress response and aging. At the genetic level, expression of the DAF-16 downstream target genes hsp-16.2 and sod-3 was induced in butein-treated worms. Butein additionally exhibited a preventive effect in models of age-related diseases. In an Alzheimer’s disease model, butein treatment significantly delayed the paralysis caused by accumulation of amyloid-beta in muscle, which requires SKN-1, not DAF-16. In a high-glucose-diet model of diabetes mellitus, butein markedly improved survival, requiring both SKN-1 and DAF-16. In a Parkinson’s disease model, dopaminergic neurodegeneration was completely inhibited by butein supplementation and the accumulation of α-synuclein was significantly reduced. These findings suggest the use of butein as a novel nutraceutical compound for aging and age-related diseases.

Ezetimibe is an approved drug for lowering plasma LDL (low-density lipoprotein) level via inhibition of cholesterol absorption. Derivatives of ezetimibe reduce inflammatory response and oxidative stress. In the present study, we investigated the effect of dietary supplementation with ezetimibe in response to environmental stressors and found that ezetimibe increases resistance to oxidative stress and ultraviolet irradiation. Ezetimibe also significantly extended lifespan accompanying reduced fertility, which is a common trade-off for longevity in C. elegans. Cellular level of reactive oxygen species was increased and the expression of stress-responsive genes, hsp-16.2 and sod-3, was induced by dietary supplementation with ezetimibe, suggesting a hormetic effect on oxidative stress response and lifespan. Ezetimibe also significantly prevented amyloid beta-induced toxicity and completely reversed increased mortality by high-glucose diet. Nuclear localization of DAF-16 required for the prevention of amyloid beta-induced toxicity was enhanced by ezetimibe supplementation. Lifespan assay using known long-lived mutants, age-1, clk-1, and eat-2, revealed that lifespan extension by ezetimibe specifically overlapped with that of eat-2 mutants, which are genetic models of dietary restriction. Effect of ezetimibe on lifespan of worms fed with diluted bacteria suggested that ezetimibe mimics the effect of dietary restriction on lifespan. These findings suggest that ezetimibe exhibits anti-oxidative and anti-aging effects through hormesis and works as a dietary-restriction mimetic on lifespan extension.

Nitric oxide (NO) is a free radical associated with physiological functions such as blood pressure regulation, cardiovascular health, mitochondrial production, calcium transport, oxidative stress, and skeletal muscle repair. This study aimed to isolate Latilactobacillus curvatus strains with enhanced NO production from the traditional Korean fermented food, jangajji, and evaluate their probiotic properties for industrial purposes. When cells were co-cultured with various bacterial stimulants, NO production generally increased, and NO synthesis was observed in the range of 20–40 mg/mL. The selected strains of Lat. curvatus were resistant to acid and bile conditions and with variable effectiveness (1–14%) in adhering to Caco-2 cells. Most bacterial strains can inhibit the growth of various pathogens. In addition, they are capable of reducing cholesterol levels via assimilation of cholesterol at 10–50%. Among the selected NO synthases from Lat. curvatus strains, the strain JBCC38 showed the highest capacity to scavenge ABTS (30.1%) and DPPH radicals (39.4%). Moreover, these strains exhibited immunomodulatory properties. The production of TNF-α and IL-6 in the macrophages treated with various bacterial stimulants was induced in all the selected strains.

To understand the biological roles of Pediococcus pentosaceus strains as probiotics isolated from the traditional Korean fermented food, Jangajji, Pediococcus pentosaceus was selected based on its high cinnamoyl esterase (CE) and antioxidant activities. The acid and bile stability, intestinal adhesion, antagonistic activity against human pathogens, cholesterol-lowering effects, and immune system stimulation without inflammatory effects were evaluated. Nitric oxide (NO) levels were measured in co-culture with various bacterial stimulants. Fermentation ability was measured by using a broccoli matrix and the sulforaphane levels were measured. Resistance to acidic and bilious conditions and 8% adherence to Caco-2 cells were observed. Cholesterol levels were lowered by 51% by assimilation. Moreover, these strains exhibited immunomodulatory properties with induction of macrophage TNF-α and IL-6 and had microstatic effects on various pathogens. Co-culture with various bacterial stimulants resulted in increased NO production. Fermentation activity was increased with the strains, and higher sulforaphane levels were observed. Therefore, in the future, the applicability of the selected strain to broccoli matrix-based fermented functional foods should be confirmed.

Fisetin (3,3′,4′,7-tetrahydroxyflavone), a flavonoid abundant in various fruits and vegetables, including apple, strawberry, and onion, shows several beneficial effects such as anti-oxidant, anti-inflammatory, and anti-tumor effects. The free radical theory of aging suggests that age-related accumulation of oxidative damage is the major cause of aging and that decreasing cellular oxidative stress can regulate aging. Here, we investigated the effects of dietary supplementation with fisetin on the stress response, aging, and age-related diseases. Fisetin reduced the cellular ROS levels and increased the resistance to oxidative stress. However, the response to UV irradiation was not affected by fisetin. Both the mean and maximum lifespans were significantly extended by fisetin; lifespan extension by fisetin was accompanied by reduced fertility as a trade-off. Age-related decline in motility was also delayed by supplementation with fisetin. Amyloid beta-induced toxicity was markedly decreased by fisetin, which required DAF-16 and SKN-1. Reduced motility induced by a high-glucose diet was completely recovered by supplementation with fisetin, which was dependent on SKN-1. Using a Parkinson’s disease model, we showed that degeneration of dopaminergic neurons was significantly inhibited by treatment with fisetin. Genetic analysis revealed that lifespan extension by fisetin was mediated by DAF-16-induced stress response and autophagy. These findings support the free radical theory of aging and suggest that fisetin can be a strong candidate for use in novel anti-aging anti-oxidant nutraceuticals.

Given the worldwide burden of neglected tropical diseases, there is ongoing need to develop novel anthelmintic agents to strengthen the pipeline of drugs to combat these burdensome infections. Many diseases caused by parasitic flatworms are treated using the anthelmintic drug praziquantel (PZQ), employed for decades as the key clinical agent to treat schistosomiasis. PZQ activates a flatworm transient receptor potential (TRP) channel within the melastatin family (TRPMPZQ) to mediate sustained Ca2+ influx and worm paralysis. As a druggable target present in many parasitic flatworms, TRPMPZQ is a promising target for a target-based screening campaign with the goal of discovering novel regulators of this channel complex. Here, we have optimized methods to miniaturize a Ca2+-based reporter assay for Schistosoma mansoni TRPMPZQ (Sm.TRPMPZQ) activity enabling a high throughput screening (HTS) approach. This methodology will enable further HTS efforts against Sm.TRPMPZQ as well as other flatworm ion channels. A pilot screen of ~16,000 compounds yielded a novel activator of Sm.TRPMPZQ, and numerous potential blockers. The new activator of Sm.TRPMPZQ represented a distinct chemotype to PZQ, but is a known chemical entity previously identified by phenotypic screening. The fact that a compound prioritized from a phenotypic screening campaign is revealed to act, like PZQ, as an Sm.TRPMPZQ agonist underscores the validity of TRPMPZQ as a druggable target for antischistosomal ligands. Author summary The drug praziquantel is used to treat diseases caused by parasitic flatworms. Praziquantel is an old drug, and there is a need to identify novel treatments that retain desirable features and improve weaknesses in the mode of PZQ action. One way to do this is to identify new drugs that exploit vulnerabilities in the same drug target but work in slightly differently ways. Here, we have optimized high throughput screening methods to pharmacologically profile a parasitic flatworm ion channel targeted by PZQ. We have identified several new chemical structures that interact with this channel complex. These ligands provide new opportunity for developing tools to manipulate flatworm biology and potentially new trajectories for anthelmintic drug development.

Phlorizin (phloridzin) is a polyphenolic phytochemical primarily found in unripe Malus (apple). It is a glucoside of phloretin and acts as an inhibitor of renal glucose transport, thus lowering blood glucose. The objective of this study was to determine effects of dietary supplementation with phlorizin on stress response, aging, and age-related diseases using Caenorhabditis elegans as a model system. Survival after oxidative stress or ultraviolet irradiation was significantly increased by pre-treatment of phlorizin. Dietary supplementation with phlorizin also significantly extended lifespans without reducing fertility. Age-related decline of muscle function was delayed by supplementation with phlorizin. Phlorizin induced the expression of stress-responsive genes hsp-16.2 and sod-3 and nuclear localization of DAF-16, a FOXO transcription factor modulating stress response and lifespan in C. elegans. Amyloid-beta-induced toxicity was significantly reduced by phlorizin. This effect was dependent on DAF-16 and SKN-1. Increased mortality induced with a high-glucose diet was partially prevented by phlorizin via SKN-1. Inactivation of dopaminergic neurons observed in a Parkinson’s disease model was completely recovered by supplementation with phlorizin. Genetic analysis suggests that lifespan extension by phlorizin is mediated through oxidative stress response and autophagy. Taken together, these data suggest that phlorizin has strong anti-oxidant and anti-aging activities with potential to be developed as a novel anti-oxidant nutraceutical against aging and age-related diseases.

Cestodes are platyhelminth parasites with a wide range of hosts that cause neglected diseases. Neurotransmitter signaling is of critical importance for these parasites which lack circulatory, respiratory and digestive systems. For example, serotonin (5-HT) and serotonergic G-protein coupled receptors (5-HT GPCRs) play major roles in cestode motility, development and reproduction. In previous work, we deorphanized a group of 5-HT7 type GPCRs from cestodes. However, little is known about another type of 5-HT GPCR, the 5-HT1 clade, which has been studied in several invertebrate phyla but not in platyhelminthes. Three putative 5-HT GPCRs from Echinococcus canadensis, Mesocestoides vogae (syn. M. corti) and Hymenolepis microstoma were cloned, sequenced and bioinformatically analyzed. Evidence grouped these new sequences within the 5-HT1 clade of GPCRs but differences in highly conserved GPCR motifs were observed. Transcriptomic analysis, heterologous expression and immunolocalization studies were performed to characterize the E. canadensis receptor, called Eca-5-HT1a. Functional heterologous expression studies showed that Eca-5-HT1a is highly specific for serotonin. 5-Methoxytryptamine and α-methylserotonin, both known 5-HT GPCR agonists, give stimulatory responses whereas methysergide, a known 5-HT GPCR ligand, give an antagonist response in Eca-5-HT1a. Mutants obtained by the substitution of key predicted residues resulted in severe impairment of receptor activity, confirming that indeed, these residues have important roles in receptor function. Immunolocalization studies on the protoscolex stage from E. canadensis, showed that Eca-5-HT1a is localized in branched fibers which correspond to the nervous system of the parasite. The patterns of immunoreactive fibers for Eca-5-HT1a and for serotonin were intimately intertwined but not identical, suggesting that they are two separate groups of fibers. These data provide the first functional, pharmacological and localization report of a serotonergic receptor that putatively belongs to the 5-HT1 type of GPCRs in cestodes. The serotonergic GPCR characterized here may represent a new target for antiparasitic intervention.

Dopaminergic neurons are important for regulating energy homeostasis. Here, the authors show the transcription factor FoxO1 negatively regulates tyrosine hydroxylase expression in midbrain dopaminergic neurons, and plays an important role in regulation of glucose homeostasis, energy expenditure, and resistance to diet-induced obesity.

OBJECTIVE: This study was performed to determine the effect of N-acetyl-L-cysteine, a modified sulfur-containing amino acid that acts as a strong cellular antioxidant, on the response to environmental stressors and on aging in C. elegans. METHOD: The survival of worms under oxidative stress conditions induced by paraquat was evaluated with and without in vivo N-acetyl-L-cysteine treatment. The effect of N-acetyl-L-cysteine on the response to other environmental stressors, including heat stress and ultraviolet irradiation (UV), was also monitored. To investigate the effect on aging, we examined changes in lifespan, fertility, and expression of age-related biomarkers in C. elegans after N-acetyl-L-cysteine treatment. RESULTS: Dietary N-acetyl-L-cysteine supplementation significantly increased resistance to oxidative stress, heat stress, and UV irradiation in C. elegans. In addition, N-acetyl-L-cysteine supplementation significantly extended both the mean and maximum lifespan of C. elegans. The mean lifespan was extended by up to 30.5% with 5 mM N-acetyl-L-cysteine treatment, and the maximum lifespan was increased by 8 days. N-acetyl-L-cysteine supplementation also increased the total number of progeny produced and extended the gravid period of C. elegans. The green fluorescent protein reporter assay revealed that expression of the stress-responsive genes, sod-3 and hsp-16.2, increased significantly following N-acetyl-L-cysteine treatment. CONCLUSION: N-acetyl-L-cysteine supplementation confers a longevity phenotype in C. elegans, possibly through increased resistance to environmental stressors.

Previous studies show that nutritional interventions with anti-oxidants have various health-promoting effects in several model organisms. Here, we examine the effects of S-allyl cysteine on resistance to environmental stressors and age-related physiological changes using C. elegans as a model system. S-allyl cysteine is a modified amino acid found in aged garlic extracts and known to have strong antioxidant activity. The survival of worms under oxidative-stress conditions significantly increased with supplementation of S-allyl cysteine. In addition, pre-treatment of S-allyl cysteine significantly increased resistance to both heat stress and ultraviolet irradiation. However, lifespan was not affected by S-allyl cysteine treatment. We also examined the effect of S-allyl cysteine on motility of C. elegans and found that S-allyl cysteine can retard the age-related decline of muscle tissue locomotive activity. S-allyl cysteine also significantly suppressed amyloid β-induced paralysis in Alzheimer's disease model animals. Taken together, our study indicates that dietary supplementation of S-allyl cysteine can improve health span and suggests that S-allyl cysteine can be used to develop novel health-promoting pharmaceuticals.

Electrolyzed-reduced water (ERW) scavenges reactive oxygen species and is a powerful anti-oxidant. A positive correlation between oxidative stress and aging has been proved in many model organisms. In Caenorhabditis elegans, many long-lived mutants showed reduced fertility as a trade off against longevity phenotype. We aimed to study the effect of ERW on oxidative stress, fertility and lifespan of C. elegans. We also investigated the genetic pathway involved in the effect of ERW on resistance to oxidative stress and lifespan. We compared lifespan and fertility of worms in media prepared with distilled water and ERW. ERW significantly extended lifespan and increased the number of progeny produced. Then the effect of ERW on resistance to oxidative stress and lifespan of long-lived mutants was determined. ERW increased resistance to oxidative stress and lifespan of eat-2, a genetic model of dietary restriction, but had no effect on those of age-1, which is involved in insulin/insulin-like growth factor (IGF)-1-like signal. In addition, knockdown of daf-16, the downstream mediator of insulin/IGF-1-like signal, completely prevented the effect of ERW on lifespan. These findings suggest that ERW can extend lifespan without accompanying reduced fertility and modulate resistance to oxidative stress and lifespan via insulin/IGF-1-like signal in C. elegans.

OBJECTIVE: The free radical theory of aging suggests that cellular oxidative damage caused by free radicals is a leading cause of aging. In the present study, we examined the effects of a well-known anti-oxidant amino acid derivative, selenocysteine, in response to environmental stress and aging using Caenorhabditis elegans as a model system. METHOD: The response to oxidative stress induced by H2O2 or ultraviolet irradiation was compared between the untreated control and selenocysteine-treated groups. The effect of selenocysteine on lifespan and fertility was then determined. To examine the effect of selenocysteine on muscle aging, we monitored the change in motility with aging in both the untreated control and selenocysteine-treated groups. RESULTS: Dietary supplementation with selenocysteine significantly increased resistance to oxidative stress. Survival after ultraviolet irradiation was also increased by supplementation with selenocysteine. Treatment with selenocysteine confers a longevity phenotype without an accompanying reduction in fertility, which is frequently observed in lifespan-extending interventions as a trade-off in C. elegans. In addition, the age-related decline in motility was significantly delayed by supplementation of selenocysteine. CONCLUSION: These findings suggest that dietary supplementation of selenocysteine can modulate response to stressors and lead to lifespan extension, thus supporting the free radical theory of aging.

Hyperplastic anterior choroidal artery (AchA) is an extremely rare congenital vascular variant that can be mistaken for other cerebral arteries. This case report presents a 38-year-old man who presented with a severe sudden-onset headache and was diagnosed with a ruptured aneurysm originating from a hyperplastic AchA. The aneurysm was successfully treated with coil embolization, but recurrence was detected after eight months, leading to additional surgical intervention. The discussion highlights the classification of hyperplastic AchA and emphasizes the importance of recognizing this anatomical variant to avoid complications during treatment. This case report underscores the need for awareness and understanding of hyperplastic AchA in the management of cerebral aneurysms. [ABSTRACT FROM AUTHOR]

Parasitic flatworms cause various clinical and veterinary infections that impart a huge burden worldwide. The most clinically impactful infection is schistosomiasis, a neglected tropical disease caused by parasitic blood flukes. Schistosomiasis is treated with praziquantel (PZQ), an old drug introduced over 40 years ago. New drugs are urgently needed, as while PZQ is broadly effective it suffers from several limitations including poor efficacy against juvenile worms, which may prevent it from being completely curative. An old compound that retains efficacy against juvenile worms is the benzodiazepine meclonazepam (MCLZ). However, host side effects caused by benzodiazepines preclude development of MCLZ as a drug and MCLZ lacks an identified parasite target to catalyze rational drug design for engineering out human host activity. Here, we identify a transient receptor potential ion channel of the melastatin subfamily, named TRPMMCLZ, as a parasite target of MCLZ. MCLZ potently activates Schistosoma mansoni TRPMMCLZ through engagement of a binding pocket within the voltage-sensor-like domain of the ion channel to cause worm paralysis, tissue depolarization, and surface damage. TRPMMCLZ reproduces all known features of MCLZ action on schistosomes, including a lower activity versus Schistosoma japonicum, which is explained by a polymorphism within this voltage-sensor-like domain-binding pocket. TRPMMCLZ is distinct from the TRP channel targeted by PZQ (TRPMPZQ), with both anthelmintic chemotypes targeting unique parasite TRPM paralogs. This advances TRPMMCLZ as a novel druggable target that could circumvent any target-based resistance emerging in response to current mass drug administration campaigns centered on PZQ. [ABSTRACT FROM AUTHOR]