RESUMEN
BACKGROUND: Numerous metabolic illnesses have obesity as a risk factor. The composition of the gut microbiota and endogenous metabolism are important factors in the onset and progression of obesity. Recent research indicates that cordycepin (CRD), derived from fungi, exhibits anti-inflammatory and antioxidant properties, showing potential in combating obesity. However, further investigation is required to delineate its precise impacts on endogenous metabolism and gut microbiota. METHODS: In this work, male C57BL/6J mice were used as models of obesity caused by a high-fat diet (HFD) and given CRD. Mice's colon, liver, and adipose tissues were stained with H&E. Serum metabolome analysis and 16S rRNA sequencing elucidated the effects of CRD on HFD-induced obese mice and identified potential mediators for its anti-obesity effects. RESULTS: CRD intervention alleviated HFD-induced intestinal inflammation, improved blood glucose levels, and reduced fat accumulation. Furthermore, CRD supplementation demonstrated the ability to modulate endogenous metabolic disorders by regulating the levels of key metabolites, including DL-2-aminooctanoic acid, inositol, and 6-deoxyfagomine. CRD influenced the abundance of important microbiota such as Parasutterella, Alloprevotella, Prevotellaceae_NK3B31_group, Alistipes, unclassified_Clostridia_vadinBB60_group, and unclassified_Muribaculaceae, ultimately leading to the modulation of endogenous metabolism and the amelioration of gut microbiota disorders. CONCLUSIONS: According to our research, CRD therapies show promise in regulating fat accumulation and stabilizing blood glucose levels. Furthermore, through the modulation of gut microbiota composition and key metabolites, CRD interventions have the dual capacity to prevent and ameliorate obesity.
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Desoxiadenosinas , Dieta Alta en Grasa , Disbiosis , Microbioma Gastrointestinal , Ratones Endogámicos C57BL , Obesidad , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Obesidad/metabolismo , Obesidad/microbiología , Masculino , Ratones , Desoxiadenosinas/farmacología , Fármacos Antiobesidad/farmacología , Modelos Animales de Enfermedad , Hígado/metabolismo , Hígado/efectos de los fármacos , Tejido Adiposo/metabolismo , Tejido Adiposo/efectos de los fármacosRESUMEN
A disintegrin and metalloproteinase domain 10 (ADAM10), a member of the ADAM family, is a cellular surface protein with potential adhesion and protease/convertase functions. The expression regulations in cancers by natural products [adenosine (AD) and its analogs, cordycepin (CD), and N6, N6-dimethyladenosine (m6 2A)], and immune regulation are unclear. As results, AD, CD, and m6 2A inhibited ADAM10 expression in various cancer cell lines, indicating their roles in anti-cancer agents. Further molecular docking with ADAM10 protein found the binding energies of all docking groups were <-7 kcal/mol for all small-molecules (AD, CD and m6 2A), suggesting very good binding activities. In addition, analysis of the immunomodulatory roles in cancer showed that ADAM10 was negatively correlated with immunomodulatory genes such as CCL27, CCL14, CCL25, CXCR5, HLA-B, HLA-DOB1, LAG3, TNFRSF18, and TNFRSF4 in bladder urothelial carcinoma, thymoma, breast invasive carcinoma, TGCT, kidney renal papillary cell carcinoma, SKCM and thyroid carcinoma, indicating the immune-promoting roles for ADAM10. LAG3 mRNA levels were reduced by both AD and CD in vivo. ADAM10 is also negatively associated with tumor immunosuppression and interrelated with the immune infiltration of tumors. Overall, the present study determined ADAM10 expression by AD, CD and m6 2A, and in AD or CD/ADAM10/LAG3 signaling in cancers, and suggested a potential method for immunotherapy of cancers by targeting ADAM10 using the small molecules AD, CD and m6 2A.
Asunto(s)
Proteína ADAM10 , Adenosina , Desoxiadenosinas , Neoplasias , Humanos , Proteína ADAM10/metabolismo , Proteína ADAM10/genética , Adenosina/análogos & derivados , Adenosina/metabolismo , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Desoxiadenosinas/farmacología , Ratones , Animales , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Simulación del Acoplamiento Molecular , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Inmunomodulación/efectos de los fármacos , FemeninoRESUMEN
With the escalating incidence and mortality rates of cancer, there is an ever-growing emphasis on the research of anticancer drugs. Cordycepin, the primary nucleoside antibiotic isolated from Cordyceps militaris, has emerged as a remarkable agent for cancer prevention and treatment. Functioning as a natural targeted antitumor drug, cordycepin assumes an increasingly pivotal role in cancer therapy. This review elucidates the mechanisms of cordycepin in inhibiting tumor cell proliferation, inducing apoptosis, as well as its capabilities in suppressing angiogenesis and metastasis. Moreover, the immunomodulatory effects of cordycepin in cancer treatment are explored. Additionally, the current status, challenges, and future prospects of cordycepin application in clinical trials are briefly discussed. The objective is to provide a valuable reference for the utilization of cordycepin in cancer treatment.
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Apoptosis , Proliferación Celular , Desoxiadenosinas , Neoplasias , Desoxiadenosinas/farmacología , Desoxiadenosinas/uso terapéutico , Humanos , Neoplasias/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neovascularización Patológica/tratamiento farmacológicoRESUMEN
Plastic pollution is an emerging environmental issue, with microplastics and nanoplastics raising health concerns due to bioaccumulation. This work explored the impact of polystyrene nanoparticle (PS-NPs) exposure during prepuberty on male reproductive function post maturation in rats. Rats were gavaged with PS-NPs (80 nm) at 0, 3, 6, 12 mg/kg/day from postnatal day 21 to 95. PS-NPs accumulated in the testes and reduced sperm quality, serum reproductive hormones, and testicular coefficients. HE staining showed impaired spermatogenesis. PS-NPs disrupted the blood-testis barrier (BTB) by decreasing junction proteins, inducing inflammation and apoptosis. Transcriptomics identified differentially expressed genes related to metabolism, lysosome, apoptosis, and TLR4 signaling. Molecular docking revealed Cordycepin could compete with polystyrene for binding to TLR4. Cordycepin alleviated oxidative stress and improved barrier function in PS-NPs treated Sertoli cells. In conclusion, prepubertal PS-NPs exposure induces long-term reproductive toxicity in male rats, likely by disrupting spermatogenesis through oxidative stress and BTB damage. Cordycepin could potentially antagonize this effect by targeting TLR4 and warrants further study as a protective agent. This study elucidates the mechanisms underlying reproductive toxicity of PS-NPs and explores therapeutic strategies.
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Barrera Hematotesticular , Desoxiadenosinas , Nanopartículas , Poliestirenos , Espermatogénesis , Testículo , Animales , Masculino , Desoxiadenosinas/farmacología , Barrera Hematotesticular/efectos de los fármacos , Poliestirenos/toxicidad , Nanopartículas/toxicidad , Espermatogénesis/efectos de los fármacos , Testículo/efectos de los fármacos , Testículo/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Células de Sertoli/efectos de los fármacos , Células de Sertoli/metabolismo , Simulación del Acoplamiento Molecular , Microplásticos/toxicidad , Receptor Toll-Like 4/metabolismo , Apoptosis/efectos de los fármacos , Maduración Sexual/efectos de los fármacos , Sustancias Protectoras/farmacologíaRESUMEN
Neospora caninum (N. caninum) is an obligate intracellular Apicomplexa parasite that causes abortions in dairy cows and incurs substantial to significant economic losses in the global dairy farming industry. Cordycepin, a nucleoside antibiotic derived from Chinese medicine Cordyceps militaries, exhibits diverse biological activities. However, it remains unclear whether cordycepin possesses inhibitory effects against N. caninum infection. Therefore, this study aimed to establish both in vivo and in vitro models of N. caninum to investigate the potential impact of cordycepin against N. caninum infection. We successfully established an in vitro model of N. caninum infection in RAW264.7 cells, followed by qRT- PCR analysis to detect the content of N. caninum DNA within the cells. The effects of cordycepin on N. caninum was observed using the Giemsa method on RAW264.7, and the rate of cell infection was calculated. Cordycepin exhibited inhibitory effects on N. caninum tachyzoites in vitro, preserving cellular integrity and reducing the rate of cell infection. In mice, we established an in vivo model of N. caninum infection and detected N. caninum presence in tissues using. Real-time fluorescence quantitative PCR. Histopathological changes were observed through Hematoxylin-eosin staining. Liver function was assessed by using glutamic acid aminotransferase (ALT) and aspartic acid aminotransferase (AST) kits. Oxidative stress status was measured using catalase (CAT), malondialdehyde (MDA), and glutathione (GSH) kits. Compared with the model group, mice treated with cordycepin showed reduced clinical symptoms, increased food intake, and their body weight (P=0.0143, P=0.0068) was significantly higher than those in the model group. Furthermore, cordycepin treatment significantly alleviated hepatic cord disorders, hepatocellular swelling, detachment, and vacuolization; duodenal epithelial detachment and shortening of villi caused by N. caninum infection. Cordycepin administration reduced the increase in ALT (P=0.01, P=0.008) and AST (P<0.001) levels caused by N. caninum infection, while ameliorating hepatocyte swelling, necrosis, and detachment as well as inflammatory cell infiltration within mice liver; it also led to shortened or even disappeared duodenal villi along with and oedema of the submucosa. Analysis of oxidative stress showed that cordycepin ameliorated the damage caused by N. caninum by reducing MDA (P=0.03, P=0.02, P=0.005) and increasing CAT (P=0.004, P<0.001) and GSH (P=0.004, P<0.001) levels. In conclusion, this study reports for the first time on cordycepin's efficacy against N. caninum infection providing a potential candidate drug for neosporosis treatment.
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Coccidiosis , Desoxiadenosinas , Neospora , Animales , Neospora/efectos de los fármacos , Coccidiosis/tratamiento farmacológico , Coccidiosis/veterinaria , Coccidiosis/parasitología , Ratones , Desoxiadenosinas/farmacología , Desoxiadenosinas/uso terapéutico , Femenino , Células RAW 264.7 , Hígado/parasitología , Hígado/efectos de los fármacos , Ratones Endogámicos BALB C , Coccidiostáticos/farmacología , Coccidiostáticos/uso terapéuticoRESUMEN
To explain the effect and mechanism of cordycepin (COR) in resisting acute kidney injury (AKI). Network pharmacology was employed to analyze the correlations between COR, AKI, and pyroptosis, as well as the action target of COR. A mouse model of AKI was established by ischemia reperfusion injury (IRI), and after treatment with COR, the renal function, tissue inflammatory cytokine levels, and pyroptosis-related signals were detected in mice. In in-vitro experiments, damage of renal macrophages was caused by the oxygen-glucose deprivation model, and pyroptosis indicators and inflammatory cytokine levels were assayed after COR treatment. Network pharmacological analysis revealed that nuclear factor kappa-B (NF-κB) was the primary action target of COR and that COR could inhibit kidney injury and tissue inflammation during IRI by inhibiting NF-κB-mediated gasdermin D cleavage. When NF-κB was inhibited, the effect of COR was weakened. COR in renal macrophages could inhibit pyroptosis and lower the levels of inflammatory cytokines, whose effect was associated with NF-κB. Our study finds that COR can play an anti-inflammatory role and inhibit the progression of AKI through the NF-κB-mediated pyroptosis, which represents its nephroprotective mechanism.
Asunto(s)
Lesión Renal Aguda , Desoxiadenosinas , Péptidos y Proteínas de Señalización Intracelular , Macrófagos , FN-kappa B , Proteínas de Unión a Fosfato , Piroptosis , Animales , Piroptosis/efectos de los fármacos , Ratones , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/patología , Lesión Renal Aguda/prevención & control , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , FN-kappa B/metabolismo , Desoxiadenosinas/farmacología , Proteínas de Unión a Fosfato/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Riñón/metabolismo , Riñón/efectos de los fármacos , Riñón/patología , Ratones Endogámicos C57BL , Daño por Reperfusión/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/patología , Daño por Reperfusión/prevención & control , GasderminasRESUMEN
Glioma is a serious primary malignant tumor of the human central nervous system with a poor prognosis and a high recurrence rate; however, inhibition of immune checkpoints can greatly improve the survival rate of patients. The purpose of this study was to investigate the regulation of PD-L1 by cordycepin and the mechanism of its anti-tumor action. The results of previous studies indicate that cordycepin has good anti-proliferative and anti-migratory activities and can induce apoptosis in U251 and T98G cells in vitro. Here, transcriptome sequencing showed that cordycepin may exert anti-tumor effects through the NOD-like receptor signaling pathway. Further intervention with BMS-1, a small molecule inhibitor of PD-L1, was used to explore whether inhibition of PD-L1 affected the regulation of the NOD-like receptor signaling pathway by cordycepin. Mechanistically, on the one hand, cordycepin regulated the expression of NFKB1 and STAT1 through the NOD-like receptor signaling pathway, thereby inhibiting the expression of PD-L1. In addition, inhibition of PD-L1 enhanced the regulation by cordycepin of the NOD-like receptor signaling pathway. On the other hand, cordycepin directly upregulated expression of STAT1 and downregulated that of PD-L1. In vivo studies further showed that cordycepin could downregulate expression of PD-L1 and NFKB1 and upregulate that of STAT1 in glioma xenograft tumor tissues, consistent with the results of in vitro studies. The results suggest that cordycepin may down-regulate the expression of PD-L1 through NOD-like receptor signaling pathway and NFKB signaling pathway, thereby inhibiting the immune escape of glioma, and can be developed as a PD-L1 inhibitor. Our results therefore provide a theoretical foundation for the use of cordycepin in treatment of glioma and enrich our understanding of its pharmacological mechanism.
Asunto(s)
Antígeno B7-H1 , Desoxiadenosinas , Glioma , Subunidad p50 de NF-kappa B , Factor de Transcripción STAT1 , Transducción de Señal , Animales , Humanos , Ratones , Antineoplásicos/farmacología , Antígeno B7-H1/metabolismo , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Desoxiadenosinas/farmacología , Regulación hacia Abajo , Glioma/tratamiento farmacológico , Glioma/metabolismo , Ratones Endogámicos BALB C , Ratones Desnudos , Subunidad p50 de NF-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Factor de Transcripción STAT1/metabolismoRESUMEN
In this study, we first screened and evaluated the inhibitory effects of seven medicinal fungi on diseases such as hyperuricemia (HUA). Then, using metabolomics and gut microbiome methods, the focus was on analyzing and evaluating the effects of the aqueous extract of Cordyceps. militaris (CME) and cordycepin on potassium oxyzinate induced HUA mice. It was found that CME exhibits good uric acid lowering activity in both in vivo and in vitro experiments. It can relieve hyperuricemia by inhibiting xanthine oxidase enzyme activity, reducing the production of xanthine precursors, and inhibiting insulin resistance. The uric acid-lowering efficacy of cordycepin in vivo is comparable to that of CME. The species abundance of Oscillibacter, Alistipes, Prevotellaaceae_NK3B31, Lachnospiraceae_NK4A136 were decreased after treatment with CME and cordycepin. The metabolomics analysis of cecal contents and fecal samples elucidated the mechanism of intervention of CME on hyperuricemia from different perspectives. This suggests that we should consider carefully when selecting samples. This current research provides the scientific foundation for the medicinal research of C. militaris and the maintenance of human health.
Asunto(s)
Cordyceps , Desoxiadenosinas , Microbioma Gastrointestinal , Hiperuricemia , Animales , Desoxiadenosinas/farmacología , Hiperuricemia/tratamiento farmacológico , Microbioma Gastrointestinal/efectos de los fármacos , Ratones , Cordyceps/química , Masculino , Metabolómica/métodos , Ácido Úrico/metabolismo , Metaboloma/efectos de los fármacos , Xantina Oxidasa/metabolismo , Xantina Oxidasa/antagonistas & inhibidores , Modelos Animales de Enfermedad , Ácido OxónicoRESUMEN
Elevated homocysteine (Hcy) levels are detrimental to neuronal cells and contribute to cognitive dysfunction in rats. Mitochondria plays a crucial role in cellular energy metabolism. Interestingly, the damaging effects of Hcy in vivo and in vitro conditions exhibit distinct results. Herein, we aimed to investigate the effects of Hcy on mitochondrial function in primary neurons and PC12 cells and explore the underlying mechanisms involved. The metabolic intermediates of Hcy act as methyl donors and play important epigenetic regulatory roles. N6-methyldeoxyadenosine (6 mA) modification, which is enriched in mitochondrial DNA (mtDNA), can be mediated by methylase METTL4. Our study suggested that mitochondrial perturbation caused by Hcy in primary neurons and PC12 cells may be attributable to mtDNA 6 mA modification difference. Hcy could activate the expression of METTL4 within mitochondria to facilitate mtDNA 6 mA status, and repress mtDNA transcription, then result in mitochondrial dysfunction.
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Desoxiadenosinas , Hipocampo , Homocisteína , Mitocondrias , Neuronas , Animales , Ratas , Células PC12 , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Homocisteína/farmacología , Homocisteína/análogos & derivados , Homocisteína/metabolismo , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Desoxiadenosinas/farmacología , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Ratas Sprague-Dawley , ADN Mitocondrial/metabolismo , ADN Mitocondrial/genética , Células Cultivadas , Metiltransferasas/metabolismo , Metiltransferasas/genéticaRESUMEN
Cordycepin is a nucleoside molecule found in Cordyceps sinensis and can be obtained through chemical synthesis and biotransformation. Cordycepin has been extensively studied and has been shown to have antitumour activity. This activity includes effects on the autophagy process and inhibition of the MAPK/ERK and Hedgehog pathways. Ultimately, the inhibitory effect of cordycepin on tumour cells is due to the interplay of these effects. Cordycepin was shown to enhance the therapeutic effects of radiotherapy. There is increasing evidence indicating that cordycepin plays an anticancer role in the treatment of various cancers. The present review aims to provide a clear understanding of the antitumour mechanisms of cordycepin and discuss its present application in the treatment of tumours. This information can be an important theoretical basis and provide clinical guidance for the further development of cordycepin as an antitumour drug.
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Desoxiadenosinas , Neoplasias , Humanos , Desoxiadenosinas/uso terapéutico , Desoxiadenosinas/farmacología , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Animales , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Autofagia/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
Triple-negative breast cancer (TNBC) is a subtype of breast cancer with high mortality and poor prognosis. Meanwhile, doxorubicin, a chemotherapeutic agent for triple-negative breast cancer, has poor sensitivity. The objective of this study was to examine the effect of cordycepin on doxorubicin sensitivity and efficacy in the TNBC xenograft model and explore the relevant molecular pathways. The combination of the drugs in nude mice carrying MDA-MB-231 xenografts significantly reduced the volume, size, and weight of xenografts and improved the tumor inhibition rate. The drug combination was significantly more effective than cordycepin or doxorubicin alone, reflecting the fact that cordycepin enhanced the anti-tumor effects of doxorubicin in MDA-MB-231 xenografts. At the same time, the monitoring of several biological parameters failed to detect any obvious side effects associated with this treatment. After predicting the importance of the TNF pathway in inhibiting tumor growth using network pharmacology methods, we verified the expression of TNF pathway targets via immunohistochemistry and quantitative PCR. Furthermore, a TNF-α inhibitor was able to abrogate the beneficial effects of cordycepin and doxorubicin treatment in MDA-MB-231 cells. This clearly indicates the role of TNF-α, or related molecules, in mediating the therapeutic benefits of the combined treatment in animals carrying TNBC xenografts. The observations reported here may present a new direction for the clinical treatment of TNBC.
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Desoxiadenosinas , Doxorrubicina , Ratones Desnudos , Neoplasias de la Mama Triple Negativas , Ensayos Antitumor por Modelo de Xenoinjerto , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Desoxiadenosinas/farmacología , Desoxiadenosinas/uso terapéutico , Animales , Humanos , Femenino , Ratones , Línea Celular Tumoral , Sinergismo Farmacológico , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/genética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proliferación Celular/efectos de los fármacos , Ratones Endogámicos BALB CRESUMEN
The microenvironment mediated by the microglia (MG) M1/M2 phenotypic switch plays a decisive role in the neuronal fate and cognitive function of Alzheimer's disease (AD). However, the impact of metabolic reprogramming on microglial polarization and its underlying mechanism remains elusive. This study reveals that cordycepin improved cognitive function and memory in APP/PS1 mice, as well as attenuated neuronal damage by triggering MG-M2 polarization and metabolic reprogramming characterized by increased OXPHOS and glycolysis, rather than directly protecting neurons. Simultaneously, cordycepin partially alleviates mitochondrial damage in microglia induced by inhibitors of OXPHOS and glycolysis, further promoting MG-M2 transformation and increasing neuronal survival. Through confirmation of cordycepin distribution in the microglial mitochondria via mitochondrial isolation followed by HPLC-MS/MS techniques, HKII and PDK2 are further identified as potential targets of cordycepin. By investigating the effects of HKII and PDK2 inhibitors, the mechanism through which cordycepin targeted HKII to elevate ECAR levels in the glycolysis pathway while targeting PDK2 to enhance OCR levels in PDH-mediated OXPHOS pathway, thereby inducing MG-M2 polarization, promoting neuronal survival and exerting an anti-AD role is elucidated.
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Desoxiadenosinas , Modelos Animales de Enfermedad , Microglía , Mitocondrias , Animales , Microglía/metabolismo , Microglía/efectos de los fármacos , Desoxiadenosinas/farmacología , Desoxiadenosinas/metabolismo , Ratones , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Hexoquinasa/metabolismo , Hexoquinasa/genética , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/metabolismo , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Glucólisis/efectos de los fármacos , Reprogramación MetabólicaRESUMEN
Cordycepin, or 3'-deoxyadenosine, is an adenosine analog with a broad spectrum of biological activity. The key structural difference between cordycepin and adenosine lies in the absence of a hydroxyl group at the 3' position of the ribose ring. Upon administration, cordycepin can undergo an enzymatic transformation in specific tissues, forming cordycepin triphosphate. In this study, we conducted a comprehensive analysis of the structural features of cordycepin and its derivatives, contrasting them with endogenous purine-based metabolites using chemoinformatics and bioinformatics tools in addition to molecular dynamics simulations. We tested the hypothesis that cordycepin triphosphate could bind to the active site of the adenylate cyclase enzyme. The outcomes of our molecular dynamics simulations revealed scores that are comparable to, and superior to, those of adenosine triphosphate (ATP), the endogenous ligand. This interaction could reduce the production of cyclic adenosine monophosphate (cAMP) by acting as a pseudo-ATP that lacks a hydroxyl group at the 3' position, essential to carry out nucleotide cyclization. We discuss the implications in the context of the plasticity of cancer and other cells within the tumor microenvironment, such as cancer-associated fibroblast, endothelial, and immune cells. This interaction could awaken antitumor immunity by preventing phenotypic changes in the immune cells driven by sustained cAMP signaling. The last could be an unreported molecular mechanism that helps to explain more details about cordycepin's mechanism of action.
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AMP Cíclico , Desoxiadenosinas , Simulación de Dinámica Molecular , Neoplasias , Desoxiadenosinas/metabolismo , Desoxiadenosinas/farmacología , Desoxiadenosinas/química , Humanos , Neoplasias/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/patología , AMP Cíclico/metabolismo , Adenosina Trifosfato/metabolismo , Transducción de Señal/efectos de los fármacos , Simulación por Computador , Adenilil Ciclasas/metabolismoRESUMEN
Islatravir (ISL) is a deoxyadenosine analog that inhibits HIV-1 reverse transcription by multiple mechanisms. Lenacapavir (LEN) is a novel capsid inhibitor that inhibits HIV-1 at multiple stages throughout the viral life cycle. ISL and LEN are being investigated as once-weekly combination oral therapy for the treatment of HIV-1. Here, we characterized ISL and LEN in vitro to assess combinatorial antiviral activity, cytotoxicity, and the potential for interactions between the two compounds. Bliss analysis revealed ISL with LEN demonstrated additive inhibition of HIV-1 replication, with no evidence of antagonism across the range of concentrations tested. ISL exhibited potent antiviral activity against variants encoding known LEN resistance-associated mutations (RAMs) with or without the presence of M184V, an ISL RAM in reverse transcriptase (RT) . Static resistance selection experiments were conducted with ISL and LEN alone and in combination, initiating with either wild-type virus or virus containing the M184I RAM in RT to further assess their barrier to the emergence of resistance. The combination of ISL with LEN more effectively suppressed viral breakthrough at lower multiples of the compounds' IC50 (half-maximal inhibitory concentration) values and fewer mutations emerged with the combination compared to either compound on its own. The known pathways for development of resistance with ISL and LEN were not altered, and no novel single mutations emerged that substantially reduced susceptibility to either compound. The lack of antagonism and cross-resistance between ISL and LEN support the ongoing evaluation of the combination for treatment of HIV-1.
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Fármacos Anti-VIH , Farmacorresistencia Viral , VIH-1 , Replicación Viral , VIH-1/efectos de los fármacos , VIH-1/genética , Farmacorresistencia Viral/efectos de los fármacos , Farmacorresistencia Viral/genética , Humanos , Fármacos Anti-VIH/farmacología , Replicación Viral/efectos de los fármacos , Desoxiadenosinas/farmacología , Mutación , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/genética , Inhibidores de la Transcriptasa Inversa/farmacología , Pruebas de Sensibilidad Microbiana , Línea Celular , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virologíaRESUMEN
Cholangiocarcinoma (CCA) is an aggressive cancer originating from bile duct epithelium, particularly prevalent in Asian countries with liver fluke infections. Current chemotherapy for CCA often fails due to drug resistance, necessitating novel anticancer agents. This study investigates the potential of 5'-deoxy-5'-methylthioadenosine (MTA), a naturally occurring nucleoside, against CCA. While MTA has shown promise against various cancers, its effects on CCA remain unexplored. We evaluated MTA's anticancer activity in CCA cell lines and drug-resistant sub-lines, assessing cell viability, migration, invasion, and apoptosis. The potential anticancer mechanisms of MTA were explored through proteomic analysis using LC-MS/MS and bioinformatic analysis. The results show a dose-dependent reduction in CCA cell viability, with enhanced effects on cancer cells compared to normal cells. Moreover, MTA inhibits growth, induces apoptosis, and suppresses cell migration and invasion. Additionally, MTA enhanced the anticancer effects of gemcitabine on drug-resistant CCA cells. Proteomics revealed the down-regulation of multiple proteins by MTA, affecting various molecular functions, biological processes, and cellular components. Network analysis highlighted MTA's role in inhibiting proteins related to mitochondrial function and energy derivation, crucial for cell growth and survival. Additionally, MTA suppressed proteins involved in cell morphology and cytoskeleton organization, important for cancer cell motility and metastasis. Six candidate genes, including ZNF860, KLC1, GRAMD1C, MAMSTR, TANC1, and TTC13, were selected from the top 10 most down-regulated proteins identified in the proteomics results and were subsequently verified through RT-qPCR. Further, KLC1 protein suppression by MTA treatment was confirmed through Western blotting. Additionally, based on TCGA data, KLC1 mRNA was found to be upregulated in the tissue of CCA patients compared to that of normal adjacent tissues. In summary, MTA shows promising anticancer potential against CCA by inhibiting growth, inducing apoptosis, and suppressing migration and invasion, while enhancing gemcitabine's effects. Proteomic analysis elucidates possible molecular mechanisms underlying MTA's anticancer activity, laying the groundwork for future research and development of MTA as a treatment for advanced CCA.
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Apoptosis , Neoplasias de los Conductos Biliares , Movimiento Celular , Colangiocarcinoma , Desoxiadenosinas , Proteómica , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patología , Humanos , Proteómica/métodos , Línea Celular Tumoral , Desoxiadenosinas/farmacología , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/metabolismo , Apoptosis/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Tionucleósidos/farmacología , Antineoplásicos/farmacología , Gemcitabina , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Supervivencia Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacosRESUMEN
Many liqueurs, including spirits infused with botanicals, are crafted not only for their taste and flavor but also for potential medicinal benefits. However, the scientific evidence supporting their medicinal effects remains limited. This study aims to verify in vitro anticancer activity and bioactive compounds in shochu spirits infused with Cordyceps militaris, a Chinese medicine. The results revealed that a bioactive fraction was eluted from the spirit extract with 40% ethanol. The infusion time impacted the inhibitory effect of the spirit extract on the proliferation of colon cancer-derived cell line HCT-116 cells, and a 21-day infusion showed the strongest inhibitory effect. Furthermore, the spirit extract was separated into four fractions, A-D, by high-performance liquid chromatography (HPLC), and Fractions B, C, and D, but not A, exerted the effects of proliferation inhibition and apoptotic induction of HCT-116 cells and HL-60 cells. Furthermore, Fractions B, C, and D were, respectively, identified as adenosine, cordycepin, and N6-(2-hydroxyethyl)-adenosine (HEA) by comprehensive chemical analyses, including proton nuclear magnetic resonance (1H-NMR), Fourier transform infrared spectroscopy (FT-IR), and electrospray ionization mass spectrometry (ESI-MS). To better understand the bioactivity mechanisms of cordycepin and HEA, the agonist and antagonist tests of the A3 adenosine receptor (A3AR) were performed. Cell viability was suppressed by cordycepin, and HEA was restored by the A3AR antagonist MR1523, suggesting that cordycepin and HEA possibly acted as agonists to activate A3ARs to inhibit cell proliferation. Molecular docking simulations revealed that both adenosine and cordycepin bound to the same pocket site of A3ARs, while HEA exhibited a different binding pattern, supporting a possible explanation for the difference in their bioactivity. Taken together, the present study demonstrated that cordycepin and HEA were major bioactive ingredients in Cordyceps militaries-infused sweet potato shochu spirits, which contributed to the in vitro anticancer activity.
Asunto(s)
Apoptosis , Proliferación Celular , Cordyceps , Humanos , Cordyceps/química , Proliferación Celular/efectos de los fármacos , Células HCT116 , Apoptosis/efectos de los fármacos , Adenosina/farmacología , Adenosina/análogos & derivados , Adenosina/química , Desoxiadenosinas/farmacología , Desoxiadenosinas/química , Antineoplásicos/farmacología , Antineoplásicos/química , Simulación del Acoplamiento Molecular , Células HL-60 , Cromatografía Líquida de Alta Presión , Extractos Vegetales/farmacología , Extractos Vegetales/química , Línea Celular TumoralRESUMEN
Pulmonary arterial hypertension (PAH) is a fatal disease featured by high morbidity and mortality. Although Cordycepin is known for its anti-inflammatory, antioxidant and immune-enhancing effects, its role in PAH treatment and the underlying mechanisms remain unclear. The therapeutic effects of Cordycepin on rats with PAH were investigated using a monocrotaline (MCT)-induced rat model. The metabolic effects of Cordycepin were assessed based on the plasma metabolome. The potential mechanisms of Cordycepin in PAH treatment were investigated through transcriptome sequencing and validated in pulmonary artery smooth muscle cells (PASMC). Evaluations included hematoxylin and eosin staining for pulmonary vascular remodeling, CCK-8 assay, EDU, and TUNEL kits for cell viability, proliferation, and apoptosis, respectively, and western blot for protein expression. Cordycepin significantly reduced right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVHI) in PAH rats, and mitigated pulmonary vascular remodeling. Plasma metabolomics showed that Cordycepin could reverse the metabolic disorders in the lungs of MCT-induced PAH rats, particularly impacting linoleic acid and alpha-linolenic acid metabolism pathways. Transcriptomics revealed that the P53 pathway might be the primary pathway involved, and western blot results showed that Cordycepin significantly increased P53 and P21 protein levels in lung tissues. Integrated analysis of transcriptomics and metabolomics suggested that these pathways were mainly enriched in linoleic acid metabolism and alpha-linolenic acid metabolism pathway. In vitro experiments demonstrated that Cordycepin significantly inhibited the PDGFBB (PD)-induced abnormal proliferation and migration of PASMC and promoted PD-induced apoptosis. Meanwhile, Cordycepin enhanced the expression levels of P53 and P21 proteins in PD-insulted PASMC. However, inhibitors of P53 and P21 eliminated these effects of Cordycepin. Cordycepin may activate the P53-P21 pathway to inhibit abnormal proliferation and migration of PASMC and promote apoptosis, offering a potential approach for PAH treatment.
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Apoptosis , Proliferación Celular , Desoxiadenosinas , Hipertensión Arterial Pulmonar , Animales , Desoxiadenosinas/farmacología , Desoxiadenosinas/uso terapéutico , Ratas , Masculino , Apoptosis/efectos de los fármacos , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Hipertensión Arterial Pulmonar/metabolismo , Hipertensión Arterial Pulmonar/patología , Proliferación Celular/efectos de los fármacos , Transcriptoma/efectos de los fármacos , Metabolómica , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , Monocrotalina , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , Ratas Sprague-Dawley , Modelos Animales de Enfermedad , Remodelación Vascular/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Ácido Linoleico/farmacología , Hipertrofia Ventricular Derecha/tratamiento farmacológico , Hipertrofia Ventricular Derecha/metabolismo , Perfilación de la Expresión GénicaRESUMEN
Cordycepin (CRD) is an active component derived from Cordyceps militaris, which possesses multiple biological activities and uses in liver disease. However, whether CRD improves liver fibrosis by regulating hepatic stellate cell (HSC) activation has remained unknown. The study aims further to clarify the activities of CRD on liver fibrosis and elucidate the possible mechanism. Our results demonstrated that CRD significantly relieved hepatocyte injury and inhibited HSC activation, alleviating hepatic fibrogenesis in the Diethyl 1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate (DDC)-induced mice model. In vitro, CRD exhibited dose-dependent repress effects on HSC proliferation, migration, and pro-fibrotic function in TGF-ß1-activated LX-2 and JS-1 cells. The functional enrichment analysis of RNA-seq data indicated that the pathway through which CRD alleviates HSC activation involves cellular senescence and cell cycle-related pathways. Furthermore, it was observed that CRD accumulated the number of senescence-associated a-galactosidase positive cells and the levels of senescencemarker p21, and provoked S phasearrestof activated HSC. Remarkably, CRD treatment abolished TGF-ß-induced yes-associated protein (YAP) nuclear translocation that acts upstream of glutaminolysis in activated HSC. On the whole, CRD significantly inhibited glutaminolysis of activated-HSC and induced cell senescence through the YAP signaling pathway, consequently alleviating liver fibrosis, which may be a valuable supplement for treating liver fibrosis.
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Senescencia Celular , Desoxiadenosinas , Células Estrelladas Hepáticas , Cirrosis Hepática , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Animales , Senescencia Celular/efectos de los fármacos , Desoxiadenosinas/farmacología , Desoxiadenosinas/uso terapéutico , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/patología , Cirrosis Hepática/metabolismo , Ratones , Masculino , Humanos , Ratones Endogámicos C57BL , Proliferación Celular/efectos de los fármacos , Línea Celular , Proteínas Señalizadoras YAP/metabolismo , Modelos Animales de Enfermedad , Factor de Crecimiento Transformador beta1/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismoRESUMEN
Neoadjuvant radiotherapy, a preoperative intervention regimen for reducing the stage of primary tumors and surgical margins, has gained increasing attention in the past decade. However, radiation-induced skin damage during neoadjuvant radiotherapy exacerbates surgical injury, remarkably increasing the risk of refractory wounds and compromising the therapeutic effects. Radiation impedes wound healing by increasing the production of reactive oxygen species and inducing cell apoptosis and senescence. Here, a self-assembling peptide (R-peptide) and hyaluronic-acid (HA)-based and cordycepin-loaded superstructure hydrogel is prepared for surgical incision healing after neoadjuvant radiotherapy. Results show that i) R-peptide coassembles with HA to form biomimetic fiber bundle microstructure, in which R-peptide drives the assembly of single fiber through π-π stacking and other forces and HA, as a single fiber adhesive, facilitates bunching through electrostatic interactions. ii) The biomimetic superstructure contributes to the adhesion and proliferation of cells in the surgical wound. iii) Aldehyde-modified HA provides dynamic covalent binding sites for cordycepin to achieve responsive release, inhibiting radiation-induced cellular senescence. iv) Arginine in the peptides provides antioxidant capacity and a substrate for the endogenous production of nitric oxide to promote wound healing and angiogenesis of surgical wounds after neoadjuvant radiotherapy.
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Senescencia Celular , Hidrogeles , Óxido Nítrico , Cicatrización de Heridas , Cicatrización de Heridas/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Senescencia Celular/efectos de la radiación , Animales , Hidrogeles/química , Hidrogeles/farmacología , Humanos , Óxido Nítrico/metabolismo , Péptidos/química , Péptidos/farmacología , Terapia Neoadyuvante , Ratones , Ácido Hialurónico/química , Ácido Hialurónico/farmacología , Desoxiadenosinas/química , Desoxiadenosinas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiaciónRESUMEN
Cordyceps militaris (L.) Link (C. militaris) contains various beneficial substances, including polysaccharides (galactomannan), nucleotides (adenosine and cordycepin), cordycepic acid, amino acids, and sterols (ergosterol and beta-sitosterol). It also contains other essential nutrients, such as protein, vitamins (E, K, B1, B2, and B12), and minerals (potassium, sodium, calcium, magnesium, iron, zinc, and selenium). Due to the numerous health benefits of supplements and products containing C. militaris extract, their popularity has increased. However, the immunostimulant effect of C. militaris remains unclear. Therefore, this study developed a functional beverage from the submerged fermentation of C. militaris (FCM) and aimed to investigate the potential of FCM in healthy male and female volunteers in Phayao Province, Thailand. This study provides essential information for the development of healthy drink products. Healthy men and women were provided either FCM containing 2.85 mg of cordycepin or placebo for 8 weeks (n = 10 for each gender). The immune cell markers, immunoglobulins, and safety parameters were assessed initially at baseline and at 4 and 8 weeks. The NK cell activity markedly increased in the male FCM group from baseline (p = 0.049) to 4 weeks after receiving FCM. Compared with those in the placebo group, the NK activity in women who received FCM for 8 weeks significantly increased (p = 0.023) from baseline. Within-group analysis revealed that the IL-1ß levels were markedly reduced in the male FCM group (p = 0.049). Furthermore, the IL-6 levels decreased from baseline in the female FCM group (p = 0.047). The blood sugar, lipid, and safety indices were not different between the experimental groups. FCM can potentially be developed as an immune-boosting supplement without liver, kidney, or blood component toxicity.