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OBJECTIVE: External environmental stressors and internal factors have a significant impact on the skin, causing inflammation, aging, reduced immunity and other adverse responses. Dead Sea Water (DSW) is well known for its dermatological benefits and has been widely used in dermatological therapy and skin care for conditions such as psoriasis, atopic dermatitis and photoaging. However, the anti-aging and rejuvenating effects of DSW and the related biological pathways involved, which have attracted increasing attention, are not fully understood. The aim of this study is to investigate the anti-aging and rejuvenating effects of DSW and to explore the related potential biological mechanisms of DSW under different environmental conditions. METHODS: The effects of DSW were investigated using in vitro human dermal cells and reconstructed skin models. Extracellular matrix (ECM) components and the morphological changes at the dermal-epidermal junction (DEJ) in a 3D human skin model were evaluated after DSW treatment. RNA sequencing (RNA-seq) analysis of human dermal fibroblast models after DSW treatment was performed to explore the potential mechanisms of action of DSW under normal and UV stress conditions. RESULTS: The novel findings in this work present the biological functions of DSW, including procollagen-1 and elastin secretion, hemidesmosome increase and the epidermal basal cell regeneration. In addition, GO, KEGG and Reactome analyses reveal the activation of pathways related to ion transmembrane transporter activity, ECM component biosynthesis, senescence-associated secretory phenotype (SASP), DNA repair and autophagy, which are associated with the anti-aging activities of DSW. CONCLUSION: Our work provides new perspectives for understanding the anti-aging and rejuvenating effects and mechanisms of DSW. The new findings also provide a theoretical basis for the further development of age-related strategies.
OBJECTIF: Les facteurs de stress environnementaux externes et les facteurs internes ont un impact significatif sur la peau, provoquant une inflammation, le vieillissement, une baisse de l'immunité et d'autres réactions indésirables. L'eau de la mer Morte est bien connue pour ses bienfaits dermatologiques, et a été largement utilisée dans le traitement dermatologique et les soins de la peau pour des affections telles que le psoriasis, la dermatite atopique et le photovieillissement. Cependant, les effets antivieillissement et rajeunissants de l'eau de la mer Morte et les voies biologiques connexes impliquées, qui font l'objet d'une attention croissante, ne sont pas entièrement compris. L'objectif de cette étude est d'étudier les effets antivieillissement et rajeunissants de l'eau de la mer Morte, et d'étudier les mécanismes biologiques potentiels liés à l'eau de la mer Morte dans différentes conditions environnementales. MÉTHODES: Les effets de l'eau de la mer Morte ont été étudiés à l'aide de cellules dermiques humaines in vitro et de modèles cutanés reconstruits. Les composants de la matrice extracellulaire (MEC) et les changements morphologiques au niveau de la jonction dermoépidermique (JDE) dans un modèle 3D de peau humaine ont été évalués après le traitement avec de l'eau de la mer Morte. Une analyse de séquençage de l'ARN (ARNseq) de modèles de fibroblastes dermiques humains après un traitement avec de l'eau de la mer Morte a été réalisée pour étudier les mécanismes d'action potentiels de l'eau de la mer Morte dans des conditions de stress normales et par UV. RÉSULTATS: Les nouveaux résultats de ce travail présentent les fonctions biologiques de l'eau de la mer Morte, y compris la sécrétion de procollagène1 et d'élastine, l'augmentation des hémidesmosomes et la régénération des cellules basales épidermiques. En outre, les analyses GO, KEGG et Réactome révèlent l'activation de voies liées à l'activité des transporteurs transmembranaires d'ions, à la biosynthèse des composants de la MEC, au phénotype sécrétoire associé à la sénescence (SenescenceAssociated Secretory Phenotype, SASP), à la réparation de l'ADN et à l'autophagie, qui sont associés aux activités antivieillissement de l'eau de la mer Morte. CONCLUSION: Notre travail apporte de nouvelles perspectives pour comprendre les effets et les mécanismes antivieillissement et rajeunissants de l'eau de la mer Morte. Les nouveaux résultats fournissent également une base théorique pour le développement ultérieur de stratégies liées à l'âge.
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Dermatitis Atópica , Envejecimiento de la Piel , Humanos , Piel , Epidermis , Agua de Mar , EnvejecimientoRESUMEN
Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive impairment. The main hypotheses about the pathogenesis of AD include the hypothesis of ß-amyloid protein, the hypothesis of abnormal phosphorylation of Tau protein, and the hypothesis of neuroinflammation. In recent years, environmental pollutants have been considered as an important factor in causing neurological dysfunction. Common environmental pollutants include heavy metals, pesticides, polychlorinated biphenyls, microplastics, and air pollutants, all of which have been proven to have neurotoxicity. In this review, we not only discussed epidemiological and animal experimental studies that link environmental pollution with AD, but also summarized the mechanisms of action of relevant toxins, providing insights for studying the interrelationships between environmental pollutants and AD.
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Enfermedad de Alzheimer , Contaminantes Ambientales , Enfermedades Neurodegenerativas , Animales , Enfermedad de Alzheimer/inducido químicamente , Contaminantes Ambientales/toxicidad , Plásticos , Péptidos beta-Amiloides/metabolismoRESUMEN
The history of long-term environmental exposure to heavy metals can be recorded in the genome as sporadic and specific mutations. Variable environments introduce diverse and adaptive mutations to organisms. To reveal the information hidden in genomes about environmental exposure to heavy metals, we performed long-term mutation accumulation (MA) experiments with Escherichia coli, analyzed genomes from 36 populations across 1650 generations with 6 heavy metal exposure regimes (arsenic, cadmium, chromium, copper, nickel, and lead), and inferred metal-specific evolution modes at the genomic level. All heavy metals induced genetic mutations with a mean rate of 3.459 × 10-9 per nucleotide per generation. The mutational spectrum exhibited distinct signatures; however, heavy metals also shared common mutation signatures prominently associated with all cancer types. The mutated genes showed an average similarity of 54.4% within the same exposure regime, whereas only 38.8% between exposure regimes. In terms of biological insights, mutated genes were enriched to fundamental cellular processes such as metabolism, motility, and transport. Our study elucidates the mutagenic commonality and specificity of environmental heavy metals, which are highly specific at mutational features and locus, but conserved at gene and functional levels, and may play crucial roles in the convergence of adaptation to heavy metals.
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Arsénico , Metales Pesados , Cadmio , Cromo , Cobre , Escherichia coli/genética , Mutágenos , Níquel , NucleótidosRESUMEN
Helicobacter pylori infection induces gastric cancer (GC) development through a progressive cascade; however, the roles of the microRNAs that are involved in the cascade and the underlying mechanisms are still unclear. Here, we found that microRNA-204 was suppressed in gastric mucosal cells in response to H.pylori infection and downregulated in GC tissues due to aberrant methylation of the promoter of its host gene, TRPM3. Helicobacter pylori induced a progressive downregulation of microRNA-204 from superficial gastritis to intestinal metaplasia, with an accompanying increment of the methylated levels of CpG sites in the TRPM3 promoter. With the GC cellular models of AGS, MGC-803 or BGC-823, we found that microRNA-204 suppressed the tumor necrosis factor (TNF)-α-induced activation of NF-κB signaling pathways and, in animal models, inhibited tumor growth and metastasis. The conditional supernatant of microRNA-204 overexpression GC cells led to reduced tube formation of human umbilical vein endothelial cells. A target gene for microRNA-204 was BIRC2, and in GC cells, BIRC2 knockdown recapitulated the biological phenotype of microRNA-204 overexpression. BIRC2 overexpression promoted the metastasis of GC cells and rescued the inhibition activities of microRNA-204 on cell migration and the NF-κB signaling pathway. Moreover, lower microRNA-204 and higher BIRC2 expression levels were associated with a poorer prognosis of GC patients. These results demonstrate that epigenetic silencing of microRNA-204 induced by H.pylori infection augments the NF-κB signaling pathway in H.pylori-induced gastritis and GC, potentially providing novel intervention targets for these diseases. MicroRNA-204 was epigenetically down-regulated by H. pylori infection in gastric mucosal cells. It led to enhanced BIRC2 expression level and BIRC2/TNF-a/NF-kB signaling pathway activities, which promoted angiogenesis and metastasis of gastric cancer cells.
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Biomarcadores de Tumor/metabolismo , Infecciones por Helicobacter/complicaciones , Helicobacter pylori/aislamiento & purificación , Proteínas Inhibidoras de la Apoptosis/metabolismo , MicroARNs/genética , FN-kappa B/metabolismo , Neoplasias Gástricas/patología , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Progresión de la Enfermedad , Epigénesis Genética , Femenino , Regulación Neoplásica de la Expresión Génica , Infecciones por Helicobacter/microbiología , Humanos , Proteínas Inhibidoras de la Apoptosis/genética , Ratones , Ratones Desnudos , FN-kappa B/genética , Pronóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/microbiología , Tasa de Supervivencia , Células Tumorales Cultivadas , Ubiquitina-Proteína Ligasas/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Rotaxane-based molecular shuttles are often operated using low-symmetry axles and changing the states of the binding stations. A molecular shuttle capable of directional shuttling of an acid-responsive cone-like macrocycle on a single-state symmetric dumbbell axle is now presented. The axle contains three binding stations: one symmetric di(quaternary ammonium) station and two nonsymmetric phenyl triazole stations arranged in opposite orientations. Upon addition of an acid, the protonated macrocycle shuttles from the di(quaternary ammonium) station to the phenyl triazole binding station closer to its butyl groups. This directional shuttling presumably originates from charge repulsion and an orientational binding preference between the cone-like cavity and the nonsymmetric phenyl triazole station. This mechanism for achieving directional shuttling by manipulating only the wheels instead of the tracks is new for artificial molecular machines.
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Cadmium has been defined as type I carcinogen for humans, but the underlying mechanisms of its carcinogenic activity and its influence on protein-protein interactions in cells are not fully elucidated. The aim of the current study was to evaluate, systematically, the carcinogenic activity of cadmium with systems biology approaches. From a literature search of 209 studies that performed with cellular models, 208 proteins influenced by cadmium exposure were identified. All of these were assessed by Western blotting and were recognized as key nodes in network analyses. The protein-protein functional interaction networks were constructed with NetBox software and visualized with Cytoscape software. These cadmium-rewired genes were used to construct a scale-free, highly connected biological protein interaction network with 850 nodes and 8770 edges. Of the network, nine key modules were identified and 60 key signaling pathways, including the estrogen, RAS, PI3K-Akt, NF-κB, HIF-1α, Jak-STAT, and TGF-ß signaling pathways, were significantly enriched. With breast cancer, colorectal and prostate cancer cellular models, we validated the key node genes in the network that had been previously reported or inferred form the network by Western blotting methods, including STAT3, JNK, p38, SMAD2/3, P65, AKT1, and HIF-1α. These results suggested the established network was robust and provided a systematic view of the carcinogenic activities of cadmium in human.
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Cadmio/toxicidad , Carcinógenos/toxicidad , Femenino , Humanos , Masculino , Biología de SistemasRESUMEN
Benzo(a)pyrene is a common environmental and foodborne pollutant that has been identified as a human carcinogen. Although the carcinogenicity of benzo(a)pyrene has been extensively reported, its precise molecular mechanisms and the influence on system-level protein networks are not well understood. To investigate the system-level influence of benzo(a)pyrene on protein interactions and regulatory networks, a benzo(a)pyrene-rewired protein interaction network was constructed based on 769 key proteins derived from more than 500 literature reports. The protein interaction network rewired by benzo(a)pyrene was a scale-free, highly-connected biological system. Ten modules were identified, and 25 signaling pathways were enriched, most of which belong to the human diseases category, especially cancer and infectious disease. In addition, two lung-specific and two liver-specific pathways were identified. Three pathways were specific in short and medium-term networks (<48h), and five pathways were enriched only in the medium-term network (6h-48h). Finally, the expression of linker genes in the network was validated by Western blotting. These findings establish the overall, tissue- and time-specific benzo(a)pyrene-rewired protein interaction networks and provide insights into the biological effects and molecular mechanisms of action of benzo(a)pyrene.
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Benzo(a)pireno/toxicidad , Mapas de Interacción de Proteínas/efectos de los fármacos , Mapas de Interacción de Proteínas/fisiología , Línea Celular Tumoral , HumanosRESUMEN
Mitochondria-targeting theranostic probes that enable the simultaneously reporting of and triggering of mitochondrial dysfunctions in cancer cells are highly attractive for cancer diagnosis and therapy. Three fluorescent mitochondria-targeting theranostic probes have been developed by linking a mitochondrial dye, coumarin-3-carboximide, with a widely used traditional Chinese medicine, artemisinin, to kill cancer cells. Fluorescence images showed that the designed coumarin-artemisinin conjugates localized mainly in mitochondria, leading to enhanced anticancer activities over artemisinin. High cytotoxicity against cancer cells correlated with the strong ability to accumulate in mitochondria, which could efficiently increase the intracellular reactive oxygen species level and induce cell apoptosis. This study highlights the potential of using mitochondria-targeting fluorophores to selectively trigger and directly visualize subcellular drug delivery in living cells.
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Artemisininas/farmacología , Cumarinas/farmacología , Colorantes Fluorescentes/farmacología , Mitocondrias/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Artemisininas/química , Sistemas de Liberación de Medicamentos , Humanos , Especies Reactivas de Oxígeno , Nanomedicina TeranósticaRESUMEN
Benzo(a)pyrene (BaP) is a prevalent food and environmental carcinogen. Chronic low-dose BaP exposure can promote the migratory and invasive capacities of human hepatocellular carcinoma (HCC) cells, yet its intricate molecular mechanisms remain elusive. Utilizing the established BaP-exposed HCC cell model, we analyzed the gene expression alteration, exosomal RNA cargo, and genetic variants induced by BaP through transcriptomic and whole-genome sequencing. Transcriptomic analysis revealed significant dysregulation in genes and pathways associated with tumor metastasis, particularly those involved in steroidal lipid metabolism and cell migration. BaP exposure enriched PI3K-AKT, mTOR, and NF-κB signaling pathways and disrupted genes implicated in cellular secretory processes, suggesting the potential involvement of exosomes in metastasis. Exosome analysis depicted the RNA profiling in exosomes of HCC cells altered by BaP, and the exosomal circRNA-miRNA-mRNA interaction network was constructed. Finally, whole-genome sequencing delineated BaP-induced gene mutations and genomic instability in HCC cells. In summary, prolonged low-dose BaP exposure induces intricate molecular alterations in gene mutation and expression profiles in HCC cells, notably those secreted in exosomes, which may potentially remodel the tumor microenvironment and foster HCC metastasis. Our findings offer new insights into the molecular underpinnings of BaP-induced HCC metastasis, thereby advancing the comprehensive understanding of BaP toxicity.
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BACKGROUND: Cadmium (Cd) is an environmental contaminant that poses risks to human and animal health. Selenium (Se), a beneficial element, alleviates the detrimental consequences of colitis and Cd toxicity. Se is found in food products as both inorganic Se (sodium selenite) and organic Se (typically Se-enriched yeast). Nano-selenium (nano-Se; a novel form of Se produced through the bioreduction of Se species) has recently garnered considerable interest, although its effects against Cd-induced enterotoxicity are poorly understood. The aim of this study was to investigate the impact of nano-selenium on mitigating cadmium toxicity and safeguarding the integrity of the intestinal barrier. METHODS: For a total of two cycles, we subjected 6-week-old C57 mice to chronic colitis by exposing them to Cd and nano-selenium for two weeks, followed by DSS water for one week. RESULTS: The application of nano-selenium mitigated the intensity of colitis and alleviated inflammation in the colon. Nano-selenium enhanced the diversity of the intestinal flora, elevated the concentration of short-chain fatty acids (SCFAs) in feces, and improved the integrity of the intestinal barrier. CONCLUSIONS: In summary, nano-Se may reduce intestinal inflammation by regulating the growth of intestinal microorganisms and protecting the intestinal barrier.
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Cadmio , Colitis , Microbioma Gastrointestinal , Ratones Endogámicos C57BL , Selenio , Animales , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Selenio/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Ratones , Colon/efectos de los fármacos , Colon/metabolismo , Colon/microbiología , Masculino , Enfermedad Crónica , Modelos Animales de Enfermedad , Nanopartículas , Ácidos Grasos Volátiles/metabolismo , Heces/microbiología , Sulfato de Dextran , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologíaRESUMEN
AIM: To investigate the embryotoxicity of dihydroartemisinin (DHA), the main active metabolite of artemisinin, in zebrafish, and explore the corresponding mechanisms. METHODS: The embryos of wild type and TG (flk1:GFP) transgenic zebrafish were exposed to DHA. Developmental phenotypes of the embryos were observed. Development of blood vessels was directly observed in living embryos of TG (flk1:GFP) transgenic zebrafish under fluorescence microscope. The expression of angiogenesis marker genes vegfa, flk1, and flt1 in the embryos was detected using real-time PCR and RNA in situ hybridization assays. RESULTS: Exposure to DHA (1-10 mg/L) dose-dependently caused abnormal zebrafish embryonic phenotypes in the early developmental stage. Furthermore, exposure to DHA (10 mg/L) resulted in more pronounced embryonic angiogenesis in TG (flk1:GFP) zebrafish line. Exposure to DHA (10 mg/L) significantly increased the mRNA expression of vegfa, flk1, and flt1 in the embryos. Knockdown of the flk1 protein partially blocked the effects of DHA on embryogenesis. CONCLUSION: DHA causes abnormal embryonic phenotypes and promotes angiogenesis in zebrafish early embryonic development, demonstrating the potential embryotoxicity of DHA.
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Artemisia/toxicidad , Artemisininas/toxicidad , Embrión no Mamífero/efectos de los fármacos , Embrión no Mamífero/embriología , Neovascularización Patológica/inducido químicamente , Pez Cebra/embriología , Animales , Animales Modificados Genéticamente , Embrión no Mamífero/patología , Desarrollo Embrionario/efectos de los fármacos , Desarrollo Embrionario/fisiología , Neovascularización Patológica/patología , Pez Cebra/genéticaRESUMEN
Selenium is an essential microelement involved in various biological processes. Selenium deficiency increases the risk of human immunodeficiency virus infection, cancer, cardiovascular disease, and inflammatory bowel disease. Selenium possesses anti-oxidant, anti-cancer, immunomodulatory, hypoglycemic, and intestinal microbiota-regulating properties. The non-linear dose-response relationship between selenium status and health effects is U-shaped; individuals with low baseline selenium levels may benefit from supplementation, whereas those with acceptable or high selenium levels may face possible health hazards. Selenium supplementation is beneficial in various populations and conditions; however, given its small safety window, the safety of selenium supplementation is still a subject of debate. This review summarizes the current understanding of the health-promoting effects of selenium on the human body, the dietary reference intake, and evidence of the association between selenium deficiency and disease.
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Phosphorylation is one of the most important post-translational modifications (PTMs) of proteins, governing critical protein functions. Most human proteins have been shown to undergo phosphorylation, and phosphoproteomic studies have been widely applied due to recent advancements in high-resolution mass spectrometry technology. Although the experimental workflow for phosphoproteomics has been well-established, it would be useful to optimize and summarize a detailed, feasible protocol that combines phosphoproteomics and data-independent acquisition (DIA), along with follow-up data analysis procedures due to the recent instrumental and bioinformatic advances in measuring and understanding tens of thousands of site-specific phosphorylation events in a single experiment. Here, we describe an optimized Phos-DIA protocol, from sample preparation to bioinformatic analysis, along with practical considerations and experimental configurations for each step. The protocol is designed to be robust and applicable for both small-scale phosphoproteomic analysis and large-scale quantification of hundreds of samples for studies in systems biology and systems medicine.
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Cadmium (Cd) is a hazardous environmental heavy metal with a prolonged biological half-life. Due to the main route of foodborne exposure, the intestinal tract is particularly vulnerable to Cd-induced toxicity. However, the chronic toxicity and underlying mechanisms of Cd in intestinal diseases, including colorectal cancer (CRC), still remain vague. Herein, we aim to investigate the long-term effects of Cd exposure on CRC development and the key signaling event. Our findings indicate that chronic and low-dose exposure to Cd promoted the invasion and metastasis capability of CRC cells in vitro and in mice, with a marginal increase in cell growth. The expression of cell junction-related genes was down-regulated while those molecules that facilitate cell mobility were significantly increased by Cd exposure. Epidermal growth factor receptor (EGFR) signaling was identified to play the dominant role in Cd-promoted CRC metastasis. Interestingly, Cd activated EGFR in a non-canonical manner that exhibited distinct signaling dynamics from the canonical ligand. In contrast to EGF, which induced transient EGFR signaling and ERK activation, Cd promoted sustained EGFR signaling to trigger Akt/mTOR cascade. The unique signaling dynamics of EGFR induced by Cd provoked responses that preferably enhanced the metastatic capacity rather than the growth. Furthermore, blockade of EGFR abrogated the promoting effects of Cd on the liver metastasis of CRC cells. In conclusion, this study provides a better understanding of the long-term influences of environmental Cd on CRC metastasis and reveals the unique EGFR signaling dynamics induced by Cd exposure.
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Cadmio , Neoplasias Colorrectales , Animales , Ratones , Cadmio/toxicidad , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Serina-Treonina Quinasas TOR , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Línea Celular TumoralRESUMEN
BACKGROUND: The bark of Eucommia ulmoides (a perennial deciduous tree termed eucommia hereafter) has anti-hyperlipidemia effects due to its bioactive components. However, the slow growth of eucommia bark leads to a deficit in this resource. Studies have shown that eucommia leaf has bioactive components similar to those of eucommia bark and anti-hyperlipidemia effects. At present, the strength of the anti-hyperlipidemia effect of eucommia bark and eucommia leaf has not been reported. Their interaction with the gut microbiota and the mechanism by which the gut microbiota exerts anti-hyperlipidemia effects are unclear. PURPOSES: Through fecal microbiota transplantation (FMT) experiments, this study aimed to investigate the mechanism by which fecal bacteria suspensions containing chlorogenic acid (CGA), eucommia bark extract (EBE), and eucommia leaves extract (ELE) improve high-fat diet (HFD)-induced lipid metabolism disorders. Difference in anti-hyperlipidemia effects between EBE and ELE and exploring an eucommia bark substitute to improve the sustainable utilization of eucommia were also evaluated. RESULTS: EBE and ELE contain eight identical bioactive ingredients, and fecal bacteria suspensions containing EBE and ELE significantly improved HFD-induced lipid metabolism disorders and elevated blood glucose levels. The fecal bacteria suspension of healthy mice containing CGA, EBE, and ELE significantly reduced the relative abundance of Erysipelothrichaceae and Ruminococcaceae and promoted short chain fatty acids (SCFAs) production thereby activating the expression of the SCFA. G protein-coupled receptor 43 (GPR43) gene in colon and epididymal fat tissues. In addition, fecal bacteria suspensions of healthy mice containing CGA, EBE, or ELE significantly activated fasting-induced adipose factor (Fiaf) gene expression in colon tissue and inhibited the secretion of lipoprotein lipase (LPL) in liver tissue, thereby inhibiting the synthesis of triglycerides (TG). Changed in the Erysipelotrichaceae and Ruminococcaceae relative abundances were significantly correlated with these target genes. Thus, regulating the abundance of the Erysipelotrichaceae and Ruminococcaceae could serve as a potential target for the role of fecal bacteria suspensions of healthy mice containing CGA, EBE, or ELE in the Fiaf-LPL gut-liver axis and SCFAs-GPR43 gut-fat axis. In addition, regarding HFD-induced lipid metabolism disorders and gut microbiota structural disorders, we found no significant difference between ELE and EBE. CONCLUSIONS: Our FMT experiments evidenced that EBE and ELE improve lipid metabolism disorders by regulating the gut microbiota, providing a new pathway for treating hyperlipidemia using eucommia dietary therapy. There was no significant difference in the anti-hyperlipidemia effects of ELE and EBE; thus, eucommia leaf could replace eucommia bark in traditional Chinese medicine, so as to achieve a sustainable utilization of eucommia resources.
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Eucommiaceae , Microbioma Gastrointestinal , Trastornos del Metabolismo de los Lípidos , Ratones , Animales , Dieta Alta en Grasa/efectos adversos , Metabolismo de los Lípidos , Eucommiaceae/química , Lipoproteína Lipasa , Corteza de la Planta , Hígado , Ácidos Grasos Volátiles/metabolismo , Extractos Vegetales/uso terapéutico , Trastornos del Metabolismo de los Lípidos/tratamiento farmacológico , Trastornos del Metabolismo de los Lípidos/metabolismoRESUMEN
Eucommia bark contains many bioactive compounds and has anti-hyperlipidemic effects. However, due to the slow growth rate of the plant, there is a limited supply of this resource. Studies have demonstrated that Eucommia leaves contain active ingredients similar to those of Eucommia bark and also have anti-hyperlipidemic effects. It is not currently clear whether Eucommia leaf can be used as a substitute for Eucommia bark. Furthermore, their mechanism of action for anti-hyperlipidemia by improving the structure of the gut microbiota is also unclear. We aimed to determine the composition of the active ingredients in EBE and ELE by HPLC, establish an HFD-induced hyperlipidemia model, and combine fecal microbiota transplantation (FMT) experiments to investigate the mechanism of EBE/ELE anti-hyperlipidemia by modifying the structure of intestinal microbiota, as well as to compare the effects of EBE and ELE. Our results showed that EBE and ELE contained similar active ingredients and significantly alleviated lipid metabolism disorders and blood glucose levels in the HFD-induced hyperlipidemia model. In this study, EBE and ELE significantly reduced the relative abundance of Desulfovibrionaceae and Erysipelotrichaceae and significantly increased the relative abundance of Ruminococcaceae. They also promoted the production of short-chain fatty acids (SCFAs) and activated the gene expression of the SCFA receptors G protein-coupled receptor 41 (GPR41) and GPR43. In addition, EBE and ELE can significantly increase the expression of the fasting-induced adipose factor (Fiaf) gene in the colon and inhibit the secretion of lipoprotein lipase (LPL) in the liver, thereby inhibiting triglyceride (TG) synthesis. They also significantly activate the expression of GPR41 and GPR43 genes in the epididymal fat tissue, leading to reduced lipid accumulation in adipocytes. These effects on the target genes were associated with changes in the abundance of Desulfovibrionaceae, Erysipelotrichaceae, and Ruminococcaceae bacteria in the intestinal microbiota. Thus, regulating the relative abundance of these microbes may serve as prospective targets for EBE/ELE to influence the Fiaf-LPL gut-liver axis and the SCFAs-GPR41/GPR43 gut-fat axis. In addition, there was no significant difference in the anti-hyperlipidemic effects of ELE and EBE, suggesting that Eucommia leaf may be a suitable alternative to Eucommia bark for managing hyperlipidemia by regulating the structure of the intestinal microbiota. These findings suggest that Eucommia leaves have great potential for development as a functional food with lipid-lowering properties.
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Necroptosis, a programmed cell death with necrotic-like morphology, has been recognized as an important driver in various inflammatory diseases. Inhibition of necroptosis has shown potential promise in the therapy of multiple human diseases. However, very few necroptosis inhibitors are available for clinical use as yet. Here, we identified an FDA-approved anti-cancer drug, Vemurafenib, as a potent inhibitor of necroptosis. Through direct binding, Vemurafenib blocked the kinase activity of receptor-interacting protein kinases 1 (RIPK1), impeded the downstream signaling and necrosome complex assembly, and inhibited necroptosis. Compared with Necrostain-1, Vemurafenib stabilized RIPK1 in an inactive DLG-out conformation by occupying a distinct allosteric hydrophobic pocket. Furthermore, pretreatment with Vemurafenib provided strong protection against necroptosis-associated diseases in vivo. Altogether, our results demonstrate that Vemurafenib is an effective RIPK1 antagonist and provide rationale and preclinical evidence for the potential application of approved drug in necroptosis-related diseases.
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Necroptosis , Proteína Serina-Treonina Quinasas de Interacción con Receptores , Vemurafenib , Humanos , Necrosis , Fosforilación , Proteína Serina-Treonina Quinasas de Interacción con Receptores/antagonistas & inhibidores , Vemurafenib/farmacologíaRESUMEN
Environmental cadmium, with a high dietary intake and long biological half-life, is a severe health risk by harming physiological function directly or through gut microbiota. However, the toxicity mechanisms of environmental cadmium on microbes and host systems remain unclear. Herein, we established three C. elegans and E. coli cultivated systems to investigate the vital role of microorganisms in cadmium-induced lipid toxicity and depict the interaction between environmental cadmium, bacteria, and the host. We found that only nematodes in the system with live bacteria, rather than UV-killed bacteria or no bacteria, could be induced to fat accumulation by cadmium exposure, suggesting that bacteria mediated the effect of environmental cadmium on body fat. Cadmium caused perturbation of metabolite in bacteria, most notably oleic acid, elevated the synthesis genes expression, and enhanced the bacterial oleic acid production, which further promoted the expression of lipid metabolism-related genes and fat deposition in C. elegans regardless of the cultivated system. Finally, we showed the potential protective effect of Vitamin D3 which prevented cadmium- or oleic acid-induced fat storage significantly. In conclusion, this study illustrates the mechanism underlying cadmium-induced lipid accumulation in body through bacterial metabolites and reveals the interplay between environmental cadmium, microorganisms, and the host.
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Cadmio , Caenorhabditis elegans , Animales , Bacterias/genética , Cadmio/toxicidad , Escherichia coli , Ácido OléicoRESUMEN
Evolutionary profiling has been largely limited to the nucleotide level. Using consistent proteomic methods, we quantified proteomic and phosphoproteomic layers in fibroblasts from 11 common mammalian species, with transcriptomes as reference. Covariation analysis indicates that transcript and protein expression levels and variabilities across mammals remarkably follow functional role, with extracellular matrix-associated expression being the most variable, demonstrating strong transcriptome-proteome coevolution. The biological variability of gene expression is universal at both interindividual and interspecies scales but to a different extent. RNA metabolic processes particularly show higher interspecies versus interindividual variation. Our results further indicate that while the ubiquitin-proteasome system is strongly conserved in mammals, lysosome-mediated protein degradation exhibits remarkable variation between mammalian lineages. In addition, the phosphosite profiles reveal a phosphorylation coevolution network independent of protein abundance.
Asunto(s)
Mamíferos , Proteómica , Animales , Evolución Biológica , Perfilación de la Expresión Génica , Mamíferos/genética , Mamíferos/metabolismo , Proteoma/metabolismo , TranscriptomaRESUMEN
Population-based studies to identify disease-associated risk alleles typically require samples from a large number of individuals. Here, we report a human-induced pluripotent stem cell (hiPSC)-based screening strategy to link human genetics with viral infectivity. A genome-wide association study (GWAS) identified a cluster of single-nucleotide polymorphisms (SNPs) in a cis-regulatory region of the NDUFA4 gene, which was associated with susceptibility to Zika virus (ZIKV) infection. Loss of NDUFA4 led to decreased sensitivity to ZIKV, dengue virus, and SARS-CoV-2 infection. Isogenic hiPSC lines carrying non-risk alleles of SNPs or deletion of the cis-regulatory region lower sensitivity to viral infection. Mechanistic studies indicated that loss/reduction of NDUFA4 causes mitochondrial stress, which leads to the leakage of mtDNA and thereby upregulation of type I interferon signaling. This study provides proof-of-principle for the application of iPSC arrays in GWAS and identifies NDUFA4 as a previously unknown susceptibility locus for viral infection.