RESUMO
The beekeeping industry plays a crucial role in local economies, contributing significantly to their growth. However, bee colonies often face the threat of American foulbrood (AFB), a dangerous disease caused by the Gram-positive bacterium Paenibacillus larvae (P. l.). While the antibiotic Tylosin has been suggested as a treatment, its bacterial resistance necessitates the search for more effective alternatives. This investigation focused on evaluating the potential of bee venom (BV) and silver nanoparticles (Ag NPs) as antibacterial agents against AFB. In vitro treatments were conducted using isolated AFB bacterial samples, with various concentrations of BV and Ag NPs (average size: 25nm) applied individually and in combination. The treatments were administered under both light and dark conditions. The viability of the treatments was assessed by monitoring the lifespans of treated bees and evaluating the treatment's efficiency within bee populations. Promising results were obtained with the use of Ag NPs, which effectively inhibited the progression of AFB. Moreover, the combination of BV and Ag NPs, known as bee venom/silver nanocomposites (BV/Ag NCs), significantly extended the natural lifespan of bees from 27 to 40 days. Notably, oral administration of BV in varying concentrations (1.53, 3.12, and 6.25 mg/mL) through sugary syrup doubled the bees' lifespan compared to the control group. The study established a significant correlation between the concentration of each treatment and the extent of bacterial inhibition. BV/Ag NCs demonstrated 1.4 times greater bactericidal efficiency under photo-stimulation with visible light compared to darkness, suggesting that light exposure enhances the effectiveness of BV/Ag NCs. The combination of BV and Ag NPs demonstrated enhanced antibacterial efficacy and prolonged honeybee lifespan. These results offer insights that can contribute to the development of safer and more efficient antibacterial agents for maintaining honeybee health.
Assuntos
Antibacterianos , Venenos de Abelha , Nanopartículas Metálicas , Paenibacillus larvae , Prata , Animais , Abelhas/microbiologia , Venenos de Abelha/farmacologia , Nanopartículas Metálicas/química , Prata/farmacologia , Prata/química , Antibacterianos/farmacologia , Paenibacillus larvae/efeitos dos fármacos , Longevidade/efeitos dos fármacosRESUMO
Given the unprecedented rate of global aging, advancing aging research and drug discovery to support healthy and productive longevity is a pressing socioeconomic need. Holistic models of human and population aging that account for biomedical background, environmental context, and lifestyle choices are fundamental to address these needs, but integration of diverse data sources and large data sets into comprehensive models is challenging using traditional approaches. Recent advances in artificial intelligence and machine learning, and specifically multimodal transformer-based neural networks, have enabled the development of highly capable systems that can generalize across multiple data types. As such, multimodal transformers can generate systemic models of aging that can predict health status and disease risks, identify drivers, or breaks of physiological aging, and aid in target discovery against age-related disease. The unprecedented capacity of transformers to extract and integrate information from large and diverse data modalities, combined with the ever-increasing availability of biological and medical data, has the potential to revolutionize healthcare, promoting healthy longevity and mitigating the societal and economic impacts of global aging.
Assuntos
Envelhecimento , Descoberta de Drogas , Humanos , Envelhecimento/fisiologia , Descoberta de Drogas/métodos , Inteligência Artificial , Longevidade/efeitos dos fármacos , Aprendizado de Máquina , Redes Neurais de ComputaçãoRESUMO
For healthspan and lifespan, ERK, AMPK and mTORC1 represent critical pathways and inflammation is a centrally important hallmark1-7. Here we examined whether IL-11, a pro-inflammatory cytokine of the IL-6 family, has a negative effect on age-associated disease and lifespan. As mice age, IL-11 is upregulated across cell types and tissues to regulate an ERK-AMPK-mTORC1 axis to modulate cellular, tissue- and organismal-level ageing pathologies. Deletion of Il11 or Il11ra1 protects against metabolic decline, multi-morbidity and frailty in old age. Administration of anti-IL-11 to 75-week-old mice for 25 weeks improves metabolism and muscle function, and reduces ageing biomarkers and frailty across sexes. In lifespan studies, genetic deletion of Il11 extended the lives of mice of both sexes, by 24.9% on average. Treatment with anti-IL-11 from 75 weeks of age until death extends the median lifespan of male mice by 22.5% and of female mice by 25%. Together, these results demonstrate a role for the pro-inflammatory factor IL-11 in mammalian healthspan and lifespan. We suggest that anti-IL-11 therapy, which is currently in early-stage clinical trials for fibrotic lung disease, may provide a translational opportunity to determine the effects of IL-11 inhibition on ageing pathologies in older people.
Assuntos
Envelhecimento , Interleucina-11 , Longevidade , Transdução de Sinais , Animais , Feminino , Masculino , Camundongos , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Envelhecimento/metabolismo , Envelhecimento/patologia , Proteínas Quinases Ativadas por AMP/metabolismo , Fragilidade/genética , Fragilidade/metabolismo , Fragilidade/prevenção & controle , Inflamação/metabolismo , Inflamação/tratamento farmacológico , Interleucina-11/antagonistas & inibidores , Interleucina-11/deficiência , Interleucina-11/genética , Interleucina-11/metabolismo , Subunidade alfa de Receptor de Interleucina-11/metabolismo , Subunidade alfa de Receptor de Interleucina-11/deficiência , Longevidade/efeitos dos fármacos , Longevidade/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Humanos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiologiaRESUMO
Investigations into human longevity are increasingly focusing on healthspan enhancement, not just lifespan extension. Lifestyle modifications and nutritional choices, including food supplements, can significantly affect aging and general health. Phytochemicals in centenarians' diets, such as those found in Timut pepper, a Nepalese spice with various medicinal properties, may contribute to their longevity. Similarly, Sichuan pepper, a related species, has demonstrated anti-inflammatory and neuroprotective activities. With the broader purpose of uncovering a novel treatment to address aging and its comorbidities, this study aims to investigate the potential lifespan- and healthspan-promoting effects of Timut pepper using the model organism Caenorhabditis elegans. We show that Timut pepper extract extends C. elegans' lifespan at different maintenance temperatures and increases the proportion of active nematodes in their early adulthood. In addition, we show that Timut pepper extract enhances speed and distance moved as the nematodes age. Finally, Timut pepper extract assures extracellular matrix homeostasis by slowing the age-dependent decline of collagen expression.
Assuntos
Caenorhabditis elegans , Capsicum , Colágeno , Longevidade , Extratos Vegetais , Caenorhabditis elegans/efeitos dos fármacos , Longevidade/efeitos dos fármacos , Animais , Extratos Vegetais/farmacologia , Colágeno/metabolismo , Capsicum/química , Envelhecimento/efeitos dos fármacos , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismoRESUMO
Mating in female Drosophila melanogaster causes midgut hypertrophy and reduced lifespan, and these effects are blocked by the drug mifepristone. Eip75B is a transcription factor previously reported to have pleiotropic effects on Drosophila lifespan. Because Eip75B null mutations are lethal, conditional systems and/or partial knock-down are needed to study Eip75B effects in adults. Previous studies showed that Eip75B is required for adult midgut cell proliferation in response to mating. To test the possible role of Eip75B in mediating the lifespan effects of mating and mifepristone, a tripartite FLP-recombinase-based conditional system was employed that provides controls for genetic background. Expression of a Hsp70-FLP transgene was induced in third instar larvae by a brief heat pulse. The FLP recombinase catalyzed the recombination and activation of an Actin5C-GAL4 transgene. The GAL4 transcription factor in turn activated expression of a UAS-Eip75B-RNAi transgene. Inhibition of Eip75B activity was confirmed by loss of midgut hypertrophy upon mating, and the lifespan effects of both mating and mifepristone were eliminated. In addition, the negative effects of mifepristone on egg production were eliminated. The data indicate that Eip75B mediates the effects of mating and mifepristone on female midgut hypertrophy, egg production, and lifespan.
Assuntos
Proteínas de Drosophila , Drosophila melanogaster , Longevidade , Mifepristona , Fatores de Transcrição , Animais , Mifepristona/farmacologia , Feminino , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/genética , Drosophila melanogaster/fisiologia , Longevidade/efeitos dos fármacos , Longevidade/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Masculino , Comportamento Sexual Animal/efeitos dos fármacosRESUMO
BACKGROUND: Restraining or slowing ageing hallmarks at the cellular level have been proposed as a route to increased organismal lifespan and healthspan. Consequently, there is great interest in anti-ageing drug discovery. However, this currently requires laborious and lengthy longevity analysis. Here, we present a novel screening readout for the expedited discovery of compounds that restrain ageing of cell populations in vitro and enable extension of in vivo lifespan. METHODS: Using Illumina methylation arrays, we monitored DNA methylation changes accompanying long-term passaging of adult primary human cells in culture. This enabled us to develop, test, and validate the CellPopAge Clock, an epigenetic clock with underlying algorithm, unique among existing epigenetic clocks for its design to detect anti-ageing compounds in vitro. Additionally, we measured markers of senescence and performed longevity experiments in vivo in Drosophila, to further validate our approach to discover novel anti-ageing compounds. Finally, we bench mark our epigenetic clock with other available epigenetic clocks to consolidate its usefulness and specialisation for primary cells in culture. RESULTS: We developed a novel epigenetic clock, the CellPopAge Clock, to accurately monitor the age of a population of adult human primary cells. We find that the CellPopAge Clock can detect decelerated passage-based ageing of human primary cells treated with rapamycin or trametinib, well-established longevity drugs. We then utilise the CellPopAge Clock as a screening tool for the identification of compounds which decelerate ageing of cell populations, uncovering novel anti-ageing drugs, torin2 and dactolisib (BEZ-235). We demonstrate that delayed epigenetic ageing in human primary cells treated with anti-ageing compounds is accompanied by a reduction in senescence and ageing biomarkers. Finally, we extend our screening platform in vivo by taking advantage of a specially formulated holidic medium for increased drug bioavailability in Drosophila. We show that the novel anti-ageing drugs, torin2 and dactolisib (BEZ-235), increase longevity in vivo. CONCLUSIONS: Our method expands the scope of CpG methylation profiling to accurately and rapidly detecting anti-ageing potential of drugs using human cells in vitro, and in vivo, providing a novel accelerated discovery platform to test sought after anti-ageing compounds and geroprotectors.
Assuntos
Envelhecimento , Metilação de DNA , Longevidade , Humanos , Animais , Metilação de DNA/efeitos dos fármacos , Longevidade/efeitos dos fármacos , Envelhecimento/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Descoberta de Drogas/métodos , Senescência Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Drosophila , Células Cultivadas , Sirolimo/farmacologiaRESUMO
Macauba (Acrocomia aculeata) is a Brazilian palm tree whose oil in the pulp is rich in oleic acid and carotenoids. However, its physiological function remains unknown. This study aimed to investigate the effects of macauba pulp oil (MPO) on the metabolic link between lipid metabolism and lifespan using Caenorhabditis elegans (C. elegans). C. elegans were treated with 5.0 mg/mL of MPO for analyzing triglyceride and glycerol accumulation, fatty acid profile, gene expression of lipid and oxidative metabolism proteins under cold (4°C) stress conditions, and lifespan analysis under stress conditions such as cold (4°C), heat (37°C), and oxidative (paraquat) stress. MPO significantly suppressed fat accumulation and increased glycerol (a lipolysis index) and the lifespan of C. elegans at low temperature (4°C). This was accompanied by decreased mRNA levels of the genes involved in lipogenesis (spb-1 and pod-2) and increased levels of the genes involved in fatty acid ß-oxidation (acs-2 and nhr-49) and fat mobilization genes (hosl-1 and aak-2). Additionally, MPO treatment modulated fatty acid pools in C. elegans at low temperatures in that MPO treatment decreased saturated fatty acid levels and shifted the fatty acid profile to long-chain fatty acids. Moreover, the effect of MPO on fat accumulation at low temperatures was abolished in fat-7 mutants, whereas both fat-1 and fat-7 contribute, at least in part, to MPO-elevated survival of C. elegans under cold conditions. PRACTICAL APPLICATION: The results obtained in the present study may contribute to the understanding of the health benefits of consuming macauba pulp oil and consequently stimulate economic growth and the industrial application of this new type of oil, which may result in the creation of new jobs and increased value of small producers.
Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Temperatura Baixa , Metabolismo dos Lipídeos , Longevidade , Animais , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/fisiologia , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Longevidade/efeitos dos fármacos , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Óleos de Plantas/farmacologia , Arecaceae/química , Ácidos Graxos/metabolismo , Triglicerídeos/metabolismo , Glicerol/metabolismo , Glicerol/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Óleo de Palmeira/farmacologiaRESUMO
Imiqualines are analogues of the immunomodulatory drug imiquimod. EAPB02303, the lead of the second-generation imiqualines, is characterized by significant anti-tumor effects with IC50s in the nanomolar range. We used Caenorhabditis elegans transgenic and mutant strains of two key signaling pathways (PI3K-Akt and Ras-MAPK) disrupted in human cancers to investigate the mode of action of EAPB02303. The ability of this imiqualine to inhibit the insulin/IGF1 signaling (IIS) pathway via the PI3K-Akt kinase cascade was explored through assessing the lifespan of wild-type worms. Micromolar doses of EAPB02303 significantly enhanced longevity of N2 strain and led to the nuclear translocation and subsequent activation of transcription factor DAF-16, the only forkhead box transcription factor class O (Fox O) homolog in C. elegans. Moreover, EAPB02303 significantly reduced the multivulva phenotype in let-60/Ras mutant strains MT2124 and MT4698, indicative of its mode of action through the Ras pathway. In summary, we showed that EAPB02303 potently reduced the activity of IIS and Ras-MAPK signaling in C. elegans. Our results revealed the mechanism of action of EAPB02303 against human cancers associated with hyperactivated IIS pathway and oncogenic Ras mutations.
Assuntos
Antineoplásicos , Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Fatores de Transcrição Forkhead , Quinoxalinas , Transdução de Sinais , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/genética , Animais , Quinoxalinas/farmacologia , Quinoxalinas/química , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Antineoplásicos/farmacologia , Antineoplásicos/química , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição Forkhead/metabolismo , Fatores de Transcrição Forkhead/genética , Longevidade/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Humanos , Imidazóis/farmacologia , Imidazóis/química , Animais Geneticamente ModificadosRESUMO
Today, plastic pollution is one of the biggest threats to the environment and public health. In the tissues of exposed species, micro- and nano-fragments accumulate, leading to genotoxicity, altered metabolism, and decreased lifespan. A model to investigate the genotoxic and tumor-promoting potential of nanoplastics (NPs) is Drosophila melanogaster. Here we tested polystyrene, which is commonly used in food packaging, is not well recycled, and makes up at least 30% of landfills. In order to investigate the biological effects and carcinogenic potential of 100 µm polystyrene nanoparticles (PSNPs), we raised Oregon [R] wild-type flies on contaminated food. After prolonged exposure, fluorescent PSNPs accumulated in the gut and fat bodies. Furthermore, PSNP-fed flies showed considerable alterations in weight, developmental time, and lifespan, as well as a compromised ability to recover from starvation. Additionally, we noticed a decrease in motor activity in DNAlig4 mutants fed with PSNPs, which are known to be susceptible to dietary stressors. A qPCR molecular investigation of the larval intestines revealed a markedly elevated expression of the genes drice and p53, suggesting a response to cell damage. Lastly, we used warts-defective mutants to assess the carcinogenic potential of PSNPs and discovered that exposed flies had more aberrant masses than untreated ones. In summary, our findings support the notion that ingested nanopolystyrene triggers metabolic and genetic modifications in the exposed organisms, eventually delaying development and accelerating death and disease.
Assuntos
Drosophila melanogaster , Nanopartículas , Poliestirenos , Animais , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/genética , Poliestirenos/toxicidade , Nanopartículas/toxicidade , Nanopartículas/química , Carcinógenos/toxicidade , Larva/efeitos dos fármacos , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Longevidade/efeitos dos fármacos , Corpo Adiposo/metabolismo , Corpo Adiposo/efeitos dos fármacosRESUMO
The mutations in Caenorhabditis elegans (C. elegans) that extend lifespan slow down aging by interfering with several signaling pathways, including the insulin/IGF-1 signaling (IIS) pathway, AMP-activated protein kinase (AMPK), and mechanistic target of rapamycin (mTOR). The tumor suppressor pRb (retinoblastoma protein) is believed to be involved in almost all human cancers. Lin-35, the C. elegans orthologue of the tumor suppressor pRb, was included in the study to explore the effects of insulin and IGF-1 because it has been linked to cancer-related pRb function in mammals and exhibits a tumor suppressor effect by inhibiting mTOR or IIS signaling. According to our results, IGF-1 or insulin increased the lifespan of lin-35 worms compared to N2 worms by increasing fertilization efficiency, also causing a significant increase in body size. It was concluded that the expression of daf-2 and rsks-1 decreased after insulin or IGF-1 administration, thus extending the lifespan of C. elegans lin-35 worms through both IIS and mTOR-dependent mechanisms. This suggests that it was mediated by the combined effect of the TOR and IIS pathways. These results, especially obtained in cancer-associated mutant lin-35 worms, will be useful in elucidating the C. elegans cancer model in the future.
Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Fator de Crescimento Insulin-Like I , Insulina , Longevidade , Transdução de Sinais , Serina-Treonina Quinases TOR , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Animais , Longevidade/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like I/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Insulina/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/genética , Receptor de Insulina/metabolismo , Receptor de Insulina/genética , Humanos , Proteínas Quinases S6 Ribossômicas 70-kDaRESUMO
Milk-derived peptides and milk fat globule membrane (MFGM) have gained interest as health-promoting food ingredients. However, the mechanisms by which these nutraceuticals modulate the function of biological systems often remain unclear. We utilized Caenorhabditis elegans to elucidate how MFGM-containing protein powder (MProPow), previously used in a clinical trial, affect the physiology of this model organism. Our results demonstrate that MProPow does not affect lifespan but promotes the fitness of the animals. Surprisingly, gene expression analysis revealed that MProPow decreases the expression of genes functioning on innate immunity, which also translates into reduced survival on pathogenic bacteria. One of the innate immunity-associated genes showing reduced expression upon MProPow supplementation is cpr-3, the homolog of human cathepsin B. Interestingly, knockdown of cpr-3 enhances fitness, but not in MProPow-treated animals, suggesting that MProPow contributes to fitness by downregulating the expression of this gene. In summary, this research highlights the value of C. elegans in testing the biological activity of food supplements and nutraceuticals. Furthermore, this study should encourage investigations into whether milk-derived peptides and MFGM mediate their beneficial effects through the modulation of cathepsin B expression in humans.
Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Suplementos Nutricionais , Glicolipídeos , Glicoproteínas , Gotículas Lipídicas , Animais , Caenorhabditis elegans/efeitos dos fármacos , Glicolipídeos/farmacologia , Glicoproteínas/farmacologia , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Imunidade Inata/efeitos dos fármacos , Catepsina B/metabolismo , Pós , Proteínas do Leite/farmacologia , Longevidade/efeitos dos fármacosRESUMO
Parkinson's disease (PD) is a complex multifactorial progressive neurodegenerative disease characterized by locomotor alteration due to the specific deterioration of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc). Mounting evidence shows that human LRRK2 (hLRRK2) kinase activity is involved in oxidative stress (OS)-induced neurodegeneration, suggesting LRRK2 inhibition as a potential therapeutic target. We report that the hLRRK2 inhibitor PF-06447475 (PF-475) prolonged lifespan, increased locomotor activity, maintained DAergic neuronal integrity, and reduced lipid peroxidation (LPO) in female Drosophila melanogaster flies chronically exposed to paraquat (PQ), a redox cycling compound, compared to flies treated with vehicle only. Since LRRK2 is an evolutionary conserved kinase, the present findings reinforce the idea that either reduction or inhibition of the LRRK2 kinase might decrease OS and locomotor alterations associated with PD. Our observations highlight the importance of uncovering the function of the hLRRK2 orthologue dLrrk2 in D. melanogaster as an excellent model for pharmacological screenings.
Assuntos
Proteínas de Drosophila , Drosophila melanogaster , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Locomoção , Longevidade , Estresse Oxidativo , Paraquat , Animais , Estresse Oxidativo/efeitos dos fármacos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/antagonistas & inibidores , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Paraquat/toxicidade , Longevidade/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Feminino , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Herbicidas/toxicidadeRESUMO
Aging is one of the main risk factors for neurodegenerative disorders, which represent a global burden on healthcare systems. Therefore, identifying new strategies to slow the progression of brain aging is a compelling challenge. In this article, we first assessed the potential anti-aging effects of the Citrus flavanone naringenin (NAR), an activator of the enzyme sirtuin-1 (SIRT1), in a 3R-compliant and short-lived aging model (i.e., the nematode C. elegans). Then, we investigated the preventive effects of a 6-month treatment with NAR (100 mg/kg, orally) against brain aging and studied its mechanism of action in middle-aged mice. We demonstrated that NAR (100 µM) extends lifespan and improves healthspan in C. elegans. In the brain of middle-aged mice, NAR promotes the activity of metabolic enzymes (citrate synthase, cytochrome C oxidase) and increases the expression of the SIRT1 enzyme. Consistently, NAR up-regulates the expression of downstream antioxidant (Foxo3, Nrf2, Ho-1), anti-senescence (p16), and anti-inflammatory (Il-6, Il-18) markers. Our findings support NAR supplementation to slow the signs of brain aging.
Assuntos
Envelhecimento , Encéfalo , Caenorhabditis elegans , Citrus , Flavanonas , Longevidade , Sirtuína 1 , Animais , Flavanonas/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Envelhecimento/efeitos dos fármacos , Longevidade/efeitos dos fármacos , Caenorhabditis elegans/efeitos dos fármacos , Sirtuína 1/metabolismo , Camundongos , Citrus/química , Antioxidantes/farmacologia , Masculino , Camundongos Endogâmicos C57BLRESUMO
The fading efficacy of antibiotics is a growing global health concern due to its life-threatening consequences and increased healthcare costs. Non-genetic mechanisms of antimicrobial resistance, such as those employed by Chlamydia pneumoniae and Chlamydia trachomatis, complicate treatment as these bacteria can enter a non-replicative, persistent state under stress, evading antibiotics and linking to inflammatory conditions. Understanding chlamydial persistence at the molecular level is challenging, and new models for studying Chlamydia-host interactions in vivo are urgently needed. Caenorhabditis elegans offers an alternative given its immune system and numerous orthologues of human genes. This study established C. elegans as an in vivo model for chlamydial infection. Both Chlamydia species reduced the worm's lifespan, their DNA being detectable at three- and six-days post-infection. Azithromycin at its MIC (25â¯nM) failed to prevent the infection-induced lifespan reduction, indicating a persister phenotype. In contrast, the methanolic extract of Schisandra chinensis berries showed anti-chlamydial activity both in vitro (in THP-1 macrophages) and in vivo, significantly extending the lifespan of infected C. elegans and reducing the bacterial load. Moreover, S. chinensis increased the transcriptional activity of SKN-1 in the worms, but was unable to impact the bacterial load or lifespan in a sek-1 defective C. elegans strain. In summary, this study validated C. elegans as a chlamydial infection model and showcased S. chinensis berries' in vivo anti-chlamydial potential, possibly through SEK/SKN-1 signaling modulation.
Assuntos
Antibacterianos , Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Infecções por Chlamydia , Caenorhabditis elegans/microbiologia , Caenorhabditis elegans/efeitos dos fármacos , Animais , Humanos , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Infecções por Chlamydia/microbiologia , Infecções por Chlamydia/tratamento farmacológico , Antibacterianos/farmacologia , Chlamydia trachomatis/efeitos dos fármacos , Interações Hospedeiro-Patógeno , Extratos Vegetais/farmacologia , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Células THP-1 , Azitromicina/farmacologia , Longevidade/efeitos dos fármacos , Chlamydophila pneumoniae/efeitos dos fármacosRESUMO
The amount of dietary sugars and the administration of lithium both impact the lifespan of the fruit fly Drosophila melanogaster. It is noteworthy that lithium is attributed with insulin-like activity as it stimulates protein kinase B/Akt and suppresses the activity of glycogen synthase kinase-3 (GSK-3). However, its interaction with dietary sugar has largely remained unexplored. Therefore, we investigated the effects of lithium supplementation on known lithium-sensitive parameters in fruit flies, such as lifespan, body composition, GSK-3 phosphorylation, and the transcriptome, while varying the dietary sugar concentration. For all these parameters, we observed that the efficacy of lithium was significantly influenced by the sucrose content in the diet. Overall, we found that lithium was most effective in enhancing longevity and altering body composition when added to a low-sucrose diet. Whole-body RNA sequencing revealed a remarkably similar transcriptional response when either increasing dietary sucrose from 1% to 10% or adding 1 mM LiCl to a 1% sucrose diet, characterized by a substantial overlap of nearly 500 differentially expressed genes. Hence, dietary sugar supply is suggested as a key factor in understanding lithium bioactivity, which could hold relevance for its therapeutic applications.
Assuntos
Sacarose Alimentar , Drosophila melanogaster , Longevidade , Animais , Drosophila melanogaster/genética , Drosophila melanogaster/efeitos dos fármacos , Longevidade/efeitos dos fármacos , Longevidade/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Quinase 3 da Glicogênio Sintase/genética , Quinase 3 da Glicogênio Sintase/metabolismo , Lítio/farmacologia , Cloreto de Lítio/farmacologia , Fosforilação/efeitos dos fármacos , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismoRESUMO
Acrylamide (ACR) is a known carcinogen and neurotoxin. It is chronically consumed in carbohydrate-rich snacks processed at high temperatures. This calls for systematic research into the effects of ACR intake, best performed in an experimental model capable of detecting symptoms of its neurotoxicity at both high and low doses. Here, we study the influence of 10 µg/g (corresponding to the concentrations found in food products) and, for comparison, 60, 80 and 110 µg/g dietary ACR, on the fruit fly Drosophila melanogaster. We show that chronic administration of ACR affects lifespan, activity level and, most importantly, the daily and circadian pattern of locomotor activity of Drosophila. ACR-treated flies show well-defined and concentration-dependent symptoms of ACR neurotoxicity; a reduced anticipation of upcoming changes in light conditions and increased arrhythmicity in constant darkness. The results suggest that the rhythm-generating neural circuits of their circadian oscillator (biological clock) are sensitive to ACR even at low concentrations if the exposure time is sufficiently long. This makes the behavioural readout of the clock, the rhythm of locomotor activity, a useful tool for studying the adverse effects of ACR and probably other compounds.
Assuntos
Acrilamida , Drosophila melanogaster , Animais , Acrilamida/toxicidade , Drosophila melanogaster/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Relógios Biológicos/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Masculino , Dieta , Feminino , Longevidade/efeitos dos fármacosRESUMO
This investigation explores the combined influence of SCD Probiotics and tauroursodeoxycholic acid (TUDCA) on liver health in elderly male Sprague-Dawley rats. Through the administration of intravenous TUDCA (300 mg/kg) and oral SCD Probiotics (3 mL at 1 × 10^8 CFU) daily for one week, this study evaluates the biomolecular composition, histopathological alterations, and inflammasome activity in the liver. Analytical methods encompassed ATR-FTIR spectroscopy integrated with machine learning for the assessment of biomolecular structures, RT-qPCR for quantifying inflammasome markers (NLRP3, ASC, Caspase-1, IL18, IL1ß), and histological examinations to assess liver pathology. The findings reveal that TUDCA prominently enhanced lipid metabolism by reducing cholesterol esters, while SCD Probiotics modulated both lipid and protein profiles, notably affecting fatty acid chain lengths and protein configurations. Histological analysis showed significant reductions in cellular degeneration, lymphatic infiltration, and hepatic fibrosis. Furthermore, the study noted a decrease in the immunoreactivity for NLRP3 and ASC, suggesting suppressed inflammasome activity. While SCD Probiotics reduced the expression of certain inflammasome-related genes, they also paradoxically increased AST and LDH levels. Conversely, an exclusive elevation in albumin levels was observed in the group treated with SCD Probiotics, implying a protective role against liver damage. These results underscore the therapeutic potential of TUDCA and SCD Probiotics for managing age-associated liver disorders, illustrating their individual and synergistic effects on liver health and pathology. This study provides insights into the complex interactions of these agents, advocating for customized therapeutic approaches to combat liver fibrosis, enhance liver functionality, and decrease inflammation in aging populations.
Assuntos
Inflamassomos , Fígado , Proteína 3 que Contém Domínio de Pirina da Família NLR , Probióticos , Ratos Sprague-Dawley , Ácido Tauroquenodesoxicólico , Animais , Ácido Tauroquenodesoxicólico/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Probióticos/farmacologia , Probióticos/uso terapêutico , Masculino , Ratos , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Fígado/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Longevidade/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Envelhecimento/efeitos dos fármacosRESUMO
The organ-specific toxicity resulting from microplastic (MP) exposure has been extensively explored, particularly concerning the gut, liver, testis, and lung. However, under natural conditions, these effects are not restricted to specific organs or tissues. Investigating whether MP exposure presents a systemic threat to an entire organism, impacting factors such as lifespan, sleep, and fecundity, is essential. In this study, we investigated the effects of dietary exposure to two different doses of MPs (1-5 µm) using the terrestrial model organism Drosophila melanogaster. Results indicated that the particles caused gut damage and remained within the digestive system. Continuous MP exposure significantly shortened the lifespan of adult flies. Even short-term exposure disrupted sleep patterns, increasing the length of daytime sleep episodes. Additionally, one week of MP exposure reduced ovary size, with a trend towards decreased egg-laying in mated females. Although MPs did not penetrate the brain or ovaries, transcriptome analysis revealed altered gene expression in these tissues. In the ovary, Gene Ontology (GO) analysis indicated genotoxic effects impacting inflammation, circadian regulation, and metabolic processes, with significant impacts on extracellular structure-related pathways. In the brain, GO analysis identified changes in pathways associated with proteolysis and carbohydrate metabolism. Overall, this study provides compelling evidence of the systemic negative effects of MP exposure, highlighting the urgent need to address and mitigate environmental MP pollution.
Assuntos
Drosophila melanogaster , Longevidade , Microplásticos , Ovário , Sono , Animais , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/fisiologia , Feminino , Ovário/efeitos dos fármacos , Longevidade/efeitos dos fármacos , Sono/efeitos dos fármacos , Microplásticos/toxicidade , Masculino , Tamanho do Órgão/efeitos dos fármacosRESUMO
Sitobion miscanthi and Schizaphis graminum (Rondani) are the 2 main aphid species that occur simultaneously, causing significant loss to wheat production. Acetamiprid has been used to control a variety of pests, including aphids. In this study, the sublethal effect of acetamiprid on S. miscanthi and S. graminum was evaluated using life-table analyses. The results showed that acetamiprid has a high toxicity to S. miscanthi and S. graminum with a LC50 of 1.90 and 3.58 mg/L at 24 h, respectively. The adult longevity and fecundity of S. miscanthi and S. graminum F0 generation were significantly reduced after being exposed to a sublethal concentration of acetamiprid. Additionally, the sublethal concentration of acetamiprid had negative transgenerational effects on S. miscanthi and S. graminum, which showed a significant decrease in fecundity and population life-table parameters involving age-stage-specific survival rate (sxj), age-specific survival rate (lx), and intrinsic rate of increase (r). Furthermore, the population projections showed that the total population size of S. miscanthi and S. graminum was significantly lower in the aphid group exposed to sublethal concentration of acetamiprid compared to the control group. These results suggest that sublethal concentration of acetamiprid suppresses the population growth of S. miscanthi and S. graminum. This finding is beneficial to the control of wheat aphids, and is important to fully understand the role of acetamiprid in integrated pest management.