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In recent years, carbonized silicon nanoparticles (SiC NPs) have found widespread scientific and engineering applications, raising concerns about potential human health risks. SiC NPs may induce pulmonary damage through sustained inflammatory responses and oxidative stress, with unclear toxicity mechanisms. This study uses an in vitro co-culture model of alveolar macrophages (NR8383) and alveolar epithelial cells (RLE-6TN) to simulate the interaction between airway epithelial cells and immune cells, providing initial insights into SiC NP-triggered inflammatory responses. The research reveals that increasing SiC NP exposure prompts NR8383 cells to release high mobility group box 1 protein (HMGB1), which migrates into RLE-6TN cells and activates the receptor for advanced glycation end-products (RAGE) and Toll-like receptor 4 (TLR4). RAGE and TLR4 synergistically activate the MyD88/NF-κB inflammatory pathway, ultimately inducing inflammatory responses and oxidative stress in RLE-6TN cells, characterized by excessive ROS generation and altered cytokine levels. Pretreatment with RAGE and TLR4 inhibitors attenuates SiC-induced HMGB1 expression and downstream pathway proteins, reducing inflammatory responses and oxidative damage. This highlights the pivotal role of RAGE-TLR4 crosstalk in SiC NP-induced pulmonary inflammation, providing insights into SiC NP cytotoxicity and nanomaterial safety guidelines.
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Células Epiteliales , Proteína HMGB1 , Pulmón , Macrófagos Alveolares , Nanopartículas , Compuestos de Silicona , Animales , Humanos , Ratas , Compuestos Inorgánicos de Carbono/toxicidad , Línea Celular , Técnicas de Cocultivo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Proteína HMGB1/metabolismo , Inflamación/inducido químicamente , Inflamación/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Macrófagos Alveolares/efectos de los fármacos , Macrófagos Alveolares/metabolismo , Nanopartículas/toxicidad , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Compuestos de Silicona/toxicidad , Receptor Toll-Like 4/metabolismoRESUMEN
S-adenosylmethionine (SAM) was a methyl donor for modifying histones, which had crucial roles in lipid accumulation, tissue injury, and immune responses. SAM fluctuation might be linked to variations in histone methylation. However, the underlying molecular mechanisms of whether the SAM diet influenced the immune response via histone modification remained obscure. In this study, we utilized the Caenorhabditis elegans as a model to investigate the role of SAM diet in innate immunity. We found that 50 µM SAM increased resistance to Gram-negative pathogen Pseudomonas aeruginosa PA14 by reducing the bacterial burden in the intestine. Furthermore, through the genetic screening in C. elegans, we found that SAM functioned in germline to enhance innate immunity via an H3K4 methyltransferase complex to upregulate the immune response genes, including irg-1 and T24B8.5. Intriguingly, SAM also protected mice from P. aeruginosa PA14 infection by reducing the bacterial burden in lung. These findings provided insight into the mechanisms of molecular connections among SAM diet, histone modifications and innate immunity.
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Proteínas de Caenorhabditis elegans , Histonas , Animales , Ratones , Caenorhabditis elegans/genética , Caenorhabditis elegans/microbiología , S-Adenosilmetionina , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Inmunidad Innata , DietaRESUMEN
The evolutionarily conserved insulin/IGF-1 signaling pathway plays a central role in aging and aging related diseases such as neurodegeneration diseases. Inhibition of insulin/IGF-1 signaling pathway has been proposed as an effective way to extend lifespan and delay neurodegeneration diseases in different organisms. Cynaroside (Cyn), a flavonoid contained in many medical plants and in vegetables, had been shown to exhibit pharmacological properties such as anti-inflammatory, anti-tumor, and anti-oxidant effects. The study demonstrated that lifespan extension and neurodegeneration diseases improving could be achieved by targeting evolutionarily conserved insulin/IGF-1 pathway through using pharmacological interventions. Via using this approach in tractable model Caenorhabditis elegans, we found that 10 µM Cynaroside significantly promoted the healthy lifespan in wild-type animals. Furthermore, via genetic screen, we showed that Cynaroside acted on IGF-1-R /DAF-2, which was followed by the activation of transcription factor DAF-16/FOXO to extend the healthy lifespan. Intriguingly, Cynaroside also improved neurodegeneration diseases such as Alzheimer's and polyglutamine disease by suppressing insulin/IGF-1 signaling pathway. Our work suggests that Cynaroside may be a promising candidate for the prevention and treatment of aging and neurodegeneration diseases.
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Caenorhabditis elegans , Factor I del Crecimiento Similar a la Insulina , Insulina , Longevidad , Transducción de Señal , Animales , Caenorhabditis elegans/efectos de los fármacos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Transducción de Señal/efectos de los fármacos , Longevidad/efectos de los fármacos , Insulina/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/prevención & control , Envejecimiento/efectos de los fármacos , Envejecimiento/fisiología , Luteolina/farmacología , Factores de Transcripción Forkhead/metabolismo , Factores de Transcripción Forkhead/genéticaRESUMEN
Background: Immune checkpoint inhibitors (ICIs), either as monotherapy or in combination with chemotherapy, have improved the therapeutic outcome for non-small cell lung cancer (NSCLC). However, the efficacy of combination therapies, such as programmed cell death 1(PD-1)/its ligand (PD-L1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors, in targeting different pathways remains unclear. We performed a meta-analysis to determine whether the addition of a CTLA-4 inhibitor to PD-1/PD-L1 therapy improves the efficacy of PD-1/PD-L1 monotherapy in NSCLC. Methods: We systematically searched various electronic databases for suitable trials. Only randomized controlled trials (RCTs) comparing the clinical efficacy of PD-1/PD-L1 with and without CTLA-4 were included in the analyses. The meta-analysis software RevMan 5.3 was used for statistical analyses. Results: A total of seven RCTs were retrieved. The results suggested that the combination of CTLA-4 and PD-1/PDL-1 inhibitors did not show enhanced efficacy over PD1/PDL-1 inhibitor monotherapy as determined by overall survival (OS) (HR = 0.98, 95% CI = 0.84-1.14, p = 0.79), progression-free survival (PFS) (HR = 0.92, 95% CI = 0.81-1.06, p = 0.25), and objective response rate (ORR) (HR = 1.08, 95% CI = 0.96-1.21, p = 0.19). Furthermore, the combination immunotherapy was associated increased toxicity as evidenced by increased incidence of any type adverse events (AEs) (RR = 1.06, 95% CI = 1.00-1.13, p = 0.03), grade ≥3 immune-mediated AEs (RR = 1.58, 95% CI = 1.36-1.82, p < 0.05), and treatment discontinuation (RR = 1.83, 95% CI = 1.46-2.28, p < 0.05). Conclusion: Combining anti-CTLA-4 with anti-PD-1/PD-L1 therapy did not improve the therapeutic efficacy, and was associated with greater toxicity than anti-PD-1/PD-L1 monotherapy in patients with advanced NSCLC. Further investigation of the combination immunotherapy in specific subsets of patients is warranted to identify and define the patient-specific benefits of this combination. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023435399.
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Constitutive activation of STAT3 plays important role in the pathogenesis of colorectal cancer (CRC). Inhibition of STAT3 has been proposed as a reasonable strategy to suppress CRC. Gamabufotalin (Gam), an effective bioactive compound of ChanChu, has been used for cancer therapy due to its desirable metabolic stability and less adverse effect. However, its effect on CRC is still unclear. In this study, we found that Gam significantly inhibited the CRC in vitro and vivo. Furthermore, Gam induced apoptosis to inhibit the viability of HCT-116 and HT-29 cell lines in dose-dependent manner by suppressing the transcription factor STAT3. In addition, Gam was also found to inhibit carcinogenesis of colitis-associated cancer (CAC) in AOM/DSS mice model by inhibiting STAT3. Our findings suggest that Gam may be an effective way to prevent occurrence and development of CRC and CAC.
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Bufanólidos , Neoplasias Asociadas a Colitis , Colitis , Neoplasias Colorrectales , Animales , Ratones , Colitis/complicaciones , Colitis/tratamiento farmacológico , Colitis/metabolismo , Factores de Transcripción/metabolismo , Transducción de Señal , Proliferación Celular , Neoplasias Colorrectales/metabolismo , Factor de Transcripción STAT3/metabolismo , Sulfato de Dextran/farmacología , Modelos Animales de Enfermedad , Ratones Endogámicos C57BLRESUMEN
Mitochondria play roles in the resistance of Caenorhabditis elegans against pathogenic bacteria by regulating mitochondrial unfolded protein response (UPRmt). Caffeic acid (CA) (3,4-dihydroxy cinnamic acid) is a major phenolic compound present in several plant species, which exhibits biological activities such as antioxidant, anti-fibrosis, anti-inflammatory, and anti-tumor properties. However, whether caffeic acid influences the innate immune response and the underlying molecular mechanisms remains unknown. In this study, we find that 20 µM caffeic acid enhances innate immunity to resist the Gram-negative pathogen Pseudomonas aeruginosa infection in C. elegans. Meanwhile, caffeic acid also inhibits the growth of pathogenic bacteria. Furthermore, caffeic acid promotes host immune response by reducing the bacterial burden in the intestine. Through genetic screening in C. elegans, we find that caffeic acid promotes innate immunity via the transcription factor ATFS-1. In addition, caffeic acid activates the UPRmt and immune response genes for innate immune response through ATFS-1. Our work suggests that caffeic acid has the potential to protect patients from pathogen infection.
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Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Ácidos Cafeicos , Animales , Humanos , Caenorhabditis elegans/microbiología , Proteínas de Caenorhabditis elegans/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Mitocondrias/metabolismoRESUMEN
Schizandrin A (SA), also known as deoxyschizandrin, is one of the most biologically active lignans isolated from the traditional Chinese medicine Fructus schisandrae chinensis. Schisandrin A has proven benefits for anti-cancer, anti-inflammation, hepatoprotection, anti-oxidation, neuroprotection, anti-diabetes. But the influence of Schisandrin A to the innate immune response and its molecular mechanisms remain obscure. In this study, we found that Schisandrin A increased resistance to not only the Gram-negative pathogens Pseudomonas aeruginosa and Salmonella enterica but also the Gram-positive pathogen Listeria monocytogenes. Meanwhile, Schisandrin A protected the animals from the infection by enhancing the tolerance to the pathogens infection rather than by reducing the bacterial burden. Through the screening of the conserved immune pathways in Caenorhabditis elegans, we found that Schisandrin A enhanced innate immunity via p38 MAPK pathway. Furthermore, Schisandrin A increased the expression of antibacterial peptide genes, such as K08D8.5, lys-2, F35E12.5, T24B8.5, and C32H11.12 by activation PMK-1/p38 MAPK. Importantly, Schisandrin A-treated mice also enhanced resistance to P. aeruginosa PA14 infection and significantly increased the levels of active PMK-1. Thus, promoted PMK-1/p38 MAPK-mediated innate immunity by Schisandrin A is conserved from worms to mammals. Our work provides a conserved mechanism by which Schisandrin A enhances innate immune response and boosts its therapeutic application in the treatment of infectious diseases.
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Proteínas de Caenorhabditis elegans , Ciclooctanos , Lignanos , Compuestos Policíclicos , Animales , Ratones , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/microbiología , Inmunidad Innata , MamíferosRESUMEN
The unfolded protein response (UPR) is an evolutionarily conserved pathway that senses and responds to the accumulation of misfolded proteins in the endoplasmic reticulum (ER) lumen during bacterial infection. The IRE-1/XBP-1 pathway is a major branch of the UPRER that has been conserved from yeast to human. Dioscin, a steroidal saponin exhibits a broad spectrum of properties. However, whether dioscin influences the immune response and the underlying molecular mechanisms remain obscure. We find that dioscin increases resistance to Gram-negative pathogen Pseudomonas aeruginosa. Furthermore, dioscin also inhibits the growth of pathogenic bacteria. Meanwhile, dioscin enhances the resistance to pathogens by reducing bacterial burden in the intestine. Through genetic screening, we find that dioscin activates the UPRER to promote innate immunity via IRE-1/XBP-1 pathway. Intriguingly, dioscin requires the neural XBP-1 for immune response. Our findings suggest that dioscin may be a viable candidate for the treatment of infectious diseases.
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Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Diosgenina/análogos & derivados , Animales , Humanos , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Respuesta de Proteína Desplegada , Inmunidad Innata , Bacterias , Retículo Endoplásmico/genética , Retículo Endoplásmico/metabolismo , Proteínas Portadoras/metabolismoRESUMEN
BACKGROUND: Several studies have provided evidence about adverse pregnancy outcomes of nurses involved in occupational exposure. However, the pregnancy outcomes among nurses in middle-income countries are not well demonstrated. The main aim of this study is to present the prevalence and influencing factors of pregnancy outcomes among female nurses in China. METHODS: We included 2243 non-nurse health care workers, and 4230 nurses in this national cross-sectional study in China. Information on occupational exposures and pregnancy outcomes was collected using a face-to-face investigation. Odds ratios (ORs) were estimated through logistic regression. RESULTS: The proportion of threatened abortion, spontaneous abortion, and stillbirth of female nurses was 2.6%, 7%, and 2.1%, respectively. We found an increased risk of threatened abortion among nurses with overtime work (OR = 1.719, 95% CI 1.158-2.550). The risk of threatened abortion and spontaneous abortion was elevated among nurses handling disinfectant (OR = 2.293 and 1.63, respectively). We found a nearly twofold increased risk of premature birth (OR = 2.169, 95% CI 1.36-3.459) among nurses handling anti-cancer drugs. CONCLUSIONS: Our findings suggested that maternal occupational exposures might be associated with the risk of adverse pregnancy outcomes among female nurses in China. We recommend that policy-markers and hospital managers work together to reduce exposure to occupational hazards and improve pregnancy outcomes among female nurses.
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Exposición Materna , Enfermería , Exposición Profesional , Femenino , Humanos , Embarazo , Aborto Espontáneo/epidemiología , Aborto Espontáneo/etiología , Amenaza de Aborto , Estudios Transversales , Pueblos del Este de Asia/estadística & datos numéricos , Exposición Profesional/efectos adversos , Exposición Profesional/estadística & datos numéricos , Resultado del Embarazo/epidemiología , China , Enfermería/estadística & datos numéricos , Exposición Materna/efectos adversos , Exposición Materna/estadística & datos numéricosRESUMEN
Increasing evidence indicate that the expression of defense genes at the right place and the right time are regulated by host-defense transcription factors. However, the precise mechanisms of this regulation are not well understood. Homeodomain transcription factors, encoded by homeobox genes, play crucial role for the development of multicellular eukaryotes. In this study, we demonstrated that homeodomain transcription factor CEH-37 (known as OTX2 in mammals) was a key transcription factor for host defense in Caenorhabditis elegans. Meanwhile, CEH-37 acted in the intestine to protect C. elegans against pathogen infection. We further showed that the homeodomain transcription factor CEH-37 positively regulated PMK-1/ p38 MAPK activity to promote the intestinal immunity via suppression phosphatase VHP-1. Furthermore, we demonstrated that this function was conserved, because the human homeodomain transcription factor OTX2 also exhibited protective function in lung epithelial cells during Pseudomonas aeruginosa infection. Thus, our work reveal that CEH-37/OTX2 is a evolutionarily conserved transcription factor for defense against pathogen infection. The finding provides a model in which CEH-37 decreases VHP-1 phosphatase activity, allowing increased stimulation of PMK-1/p38 MAPK phosphorylation cascade in the intestine for pathogen resistance.
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Proteínas de Caenorhabditis elegans , Factores de Transcripción , Animales , Humanos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Monoéster Fosfórico Hidrolasas/metabolismo , Inmunidad Innata , Proteínas de Unión al ADN/metabolismo , Mamíferos/metabolismo , Fosfatasas de Especificidad DualRESUMEN
The endophytic fungus Cladosporium sphaerospermum WBS017 exhibits broad-spectrum activity against plant pathogens, with particular effectiveness against Botrytis cinerea. Subsequently, a compound is isolated from strain WBS017 as the main active ingredient against B. cinerea using activity-guided separation and identified as hybrid polyketide (namely cladodionen, CLD) using UV, MS, NMR, etc. In vitro and in vivo antifungal activity tests demonstrate that CLD effectively inhibits the mycelial growth and spore germination, with an IC50 value of 1.13 and 0.095 mM, respectively, and exerts antifungal and fresh-keeping effects on both strawberry and tomato. Microscopy analysis reveals that the inhibitory effects of CLD on hyphae and spore germination are attributed to a decrease in structural stability of mycelia cells as well as the accumulation of reactive oxygen species (ROS). Furthermore, transcriptome analysis further indicates that spore germination is inhibited by suppressing the transcription levels of membrane or membrane-related genes, disturbing the balance of ROS metabolism, altering the primary metabolic pathways, genetic information processing, and cellular processes. Importantly, CLD demonstrates no significant toxicity on zebrafish embryos even at a concentration of 0.226 mM, indicating its potential as a safe biological-control agent. In summary, CLD would be a novel potential biological-control agent and can be considered as a promising fungicide to control B. cinerea.
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Antifúngicos , Policétidos , Animales , Antifúngicos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Policétidos/farmacología , Policétidos/metabolismo , Pez Cebra , Botrytis , Agentes de Control Biológico/metabolismo , Enfermedades de las Plantas/prevención & control , Enfermedades de las Plantas/microbiologíaRESUMEN
Delay aging, especially in healthy life extension, brought the most interest to the medical field. Searching for anti-aging drugs with relative safety profiles bring natural products in hotspot. In this study, we find that dioscin promotes the health span extension in wild-type Caenorhabditis elegans. Through the genetic screening in C. elegans, we further reveal that dioscin activates the transcription factor SBP-1/SREBP by the UPRER transcription factor XBP-1 to upregulate transcription of the Δ9 desaturase FAT-5 and FAT-7, resulting in increased monounsaturated fatty acid content which requires for healthy life span extension. Intriguingly, through tissue-specific knockdown, we find that dioscin modulates the health span by activating SBP-1 in the intestine. Unexpectedly, dietary supplementation of POA and OA rescues XBP-1, SBP-1 mutants-induced shortened life span phenotype. Considering the conservation of MUFAs metabolism, dioscin may promote health span in other species, including mammals. Our work suggests that dioscin might be a promising candidate for developing anti-aging agent.
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The DAF-2/DAF-16 insulin-like signaling pathway was an evolutionarily conserved pathway, which regulated many aspects of organismal physiology, such as pathogen resistance, metabolism, stress response, longevity. Luteolin, a flavone contained in many medical plants and in vegetables, had been shown to exhibit activities such as anti-tumor, anti-oxidant and neuroprotective effects. However, whether the Luteolin influenced the immune response and the underlying molecular mechanisms remained obscure. We found that Luteolin increased resistance to not only the Gram-negative pathogens Pseudomonas aeruginosa and Salmonella enterica but also the Gram-positive pathogens Enterococcus faecalis and Staphylococcus aureus in dose dependent manner. Meanwhile, Luteolin promoted host immune response via inhibiting the growth of pathogenic bacteria. Through the genetic screening in C. elegans, we found that Luteolin promoted innate immunity via DAF-2/DAF-16 insulin-like signaling pathway rather than p38 MAPK pathway and SKN-1. Furthermore, Luteolin activated the DAF-16/FOXO transcription factor for innate immune response. Our work suggested that Luteolin had the potential of improving the patients with pathogen infection.
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Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animales , Humanos , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Insulina/metabolismo , Luteolina/farmacología , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Transducción de Señal , Inmunidad Innata/genética , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Receptor de Insulina/farmacologíaRESUMEN
The conserved p38/PMK-1 pathway that is an evolutionarily conserved module used by mammals and nematodes in immune response against bacterial infections. Brevilin A (BA), a sesquiterpene lactone compound of Centipeda minima has been shown to exhibit activities such as anti-tumor, anti-bacterial and anti-protozoal. However, whether the Brevilin A influences the immune response and the underlying molecular mechanisms remain obscure. We find that 10 µM Brevilin A increases resistance to not only the Gram-negative pathogens Pseudomonas aeruginosa and Salmonella enterica but also the Gram-positive pathogens Enterococcusfaecalis and Staphylococcus aureus. Meanwhile, Brevilin A enhances the resistance to pathogens by reducing the bacterial burden in the intestine. Through the genetic screening in C. elegans, we find that Brevilin A promotes innate immunity via p38 MAPK pathway. Furthermore, Brevilin A activates the p38/PMK-1 in the intestine for innate immune response. In addition, we also find that Brevilin A increases the resistance of oxidative stress and extends lifespan through p38 MAPK pathway. Our work suggests that Brevilin A may be a viable candidate for the treatment of infectious diseases.
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Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animales , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Inmunidad Innata , Estrés Oxidativo , MamíferosRESUMEN
The Mammalian/mechanistic target of rapamycin (mTOR) played a central role in cellular survival and aging. Inhibition of mTOR had been proposed as a reasonable strategy to promote lifespan and delay age-related diseases in evolutionarily diverse organisms. The study showed that lifespan extension and age-related diseases improvement could be achieved by targeting evolutionarily conserved mTOR pathways and mechanisms using pharmacological interventions. Using this approach in Caenorhabditis elegans, We found that 2 µM Usnic Acid significantly extended the healthy lifespan in wild-type animals. Furthermore, via genetic screen, we showed that Usnic Acid acted on mTOR, which was followed by the activation of PHA-4/Foxa to extend the healthy lifespan. Intriguingly, Usnic Acid also delayed neurodegeneration diseases such as Alzheimer's and polyglutamine disease through mTOR-dependent manner. Our work suggested that Usnic Acid might be a viable candidate for the prevention and treatment of aging and age-related diseases.
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Three new coumarin derivatives named maytenucoums A-C (1-3), along with six known analogs (4-9), were isolated from the branches of Maytenus hookeri. Their structures were determined by comprehensive spectroscopic data analysis, including NMR and HR-ESIMS. In the preliminary assays, compound 4 showed cytotoxic activity against the A549, SK-Hep1 and HCT116 cells with IC50 values of 29.0, 28.6 and 54.4 µM, respectively.
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The longevity of an organism is influenced by both genetic and environmental factors. With respect to genetic factors, a significant effort is being made to identify pharmacological agents that extend lifespan by targeting pathways with a defined role in the aging process. Sanguinarine (San) is a benzophenanthridine alkaloid that exerts a broad spectrum of properties. In this study, we utilized Caenorhabditis elegans to examine the mechanisms by which sanguinarine influences aging and innate immunity. We find that 0.2 µM sanguinarine extends healthspan in C. elegans. We further show that sanguinarine generates reactive oxygen species (ROS), which is followed by the activation of PMK-1/SKN-1pathway to extend healthspan. Intriguingly, sanguinarine increases resistance to pathogens by reducing the bacterial burden in the intestine. In addition, we also find that sanguinarine enhances innate immunity through PMK-1/SKN-1 pathway. Our data suggest that sanguinarine may be a viable candidate for the treatment of age-related disorders.
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Metformin, a widely prescribed first-line drug for the treatment of type II diabetes mellitus, has been shown to extend lifespan and delay the onset of age-related diseases. The precisely mechanisms by which these effects are realized remain elusive. We find that metformin exposure is restricted to adults, which is sufficient to extend lifespan. However, limiting metformin exposure to the larvae has no significant effect on Caenorhabditis elegans longevity. Here, we show that after metformin treatment, the level of S-adenosylmethionine (SAM) is reduced in adults but not in the larvae. Potential mechanisms by which reduced SAM might increase lifespan include altering the histone methylation. However, the molecular connections between metformin, SAM limitation, methyltransferases, and healthspan-associated phenotypes are unclear. Through genetic screening of C. elegans, we find that metformin promotes the healthspan through an H3K4 methyltransferase/demethylase complex to downregulate the targets, including mTOR and S6 kinase. Thus, our studies provide molecular links between meformin, SAM limitation, histone methylation, and healthspan and elucidate the mode action of metformin-regulated healthspan extension will boost its therapeutic application in the treatment of human aging and age-related diseases.
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Proteínas de Caenorhabditis elegans , Diabetes Mellitus Tipo 2 , Metformina , Animales , Caenorhabditis elegans/fisiología , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Histonas , Longevidad/genética , Metformina/farmacología , Metformina/uso terapéutico , S-Adenosilmetionina/farmacología , S-Adenosilmetionina/uso terapéuticoRESUMEN
A new N-containing phenolic glycoside (1) and seven known compounds were isolated from the fruits of Capsicum annuum L. Their structures were elucidated by extensive spectroscopic methods including MS, 1D and 2D NMR (HSQC, HMBC, 1H-1H COSY, etc.). The stereo configuration of the new compound was determined by comparison of the experimental and calculated electronic circular dichroism (ECD) spectra. Compounds 1-8 were evaluated in vitro for their cytotoxic activities against HCT-116 cell line using Sulforhodamine B (SRB) assay, and the result showed only compound 6 displayed a weak inhibitory activity against HCT-116 (IC50 = 22.5 ± 3.3 mmol/mL).
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Capsicum , Glicósidos Cardíacos , Frutas , Glicósidos/farmacología , Estructura Molecular , Fenoles/farmacologíaRESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) is the most aggressive and frequently diagnosed malignancy of the liver. Despite aggressive therapy, life expectancy of many patients in these cases is extended by only a few months. Hepatocellular carcinoma (HCC) has a particularly poor prognosis and would greatly benefit from more effective therapies. METHODS: The CCK-8 assay and colony formation assays were used to test the cell proliferation and viability. The effects of combination Biochanin A and SB590885 on apoptosis and cell cycle arrest of HCC cells were analysed by flow cytometry. The expression of ERK MAPK and PI3K/AKT/mTOR signalling as well as apoptosis and cell cycle-related proteins in HCC cells were tested by western blotting. The HCC cell xenograft model was established to test the tumor proliferation. Serum and plasma were tested for liver and kidney safety markers (ALP, ALT, AST, total bilirubin, creatinine, urea nitrogen) by using SpectraMax i3X. RESULTS: The combination of natural product Biochanin A with the BRAF inhibitor SB590885 synergistically suppressed proliferation, and promoted cell cycle arrest and apoptosis in vitro. Furthermore, we demonstrated that the combination of Biochanin A and SB590885 led to increased impairment of proliferation and HCC tumour inhibition through disrupting of the ERK MAPK and the PI3K/AKT pathways in vitro. The volumes tumors and the weights of tumours were significantly reduced by the combination treatment compared to the control or single treatments in vivo. In addition, we found that there was no significant hepatorenal toxicity with the drug combination, as indicated by the hepatorenal toxicity test. CONCLUSION: The results identify an effective combination therapy for the most aggressive form of HCC and provide the possibility of therapeutic improvement for patients with advanced HCC.