Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.510
Filtrar
1.
Curr Opin HIV AIDS ; 17(4): 240-246, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35762379

RESUMO

PURPOSE OF REVIEW: To summarize recent updates on the potential role of islatravir for HIV treatment and prevention. RECENT FINDINGS: Islatravir is an investigational antiretroviral agent with unique pharmacologic properties that facilitate flexible dosing regimens. Islatravir has demonstrated potent antiviral activity and a high barrier to resistance when combined with doravirine and lamivudine. A simplified two-drug HIV treatment regimen of islatravir combined with doravirine has also demonstrated comparable efficacy to standard of care three-drug regimens. The long half-life and high potency of islatravir's active metabolite may support its use as a long-acting option for HIV preexposure prophylaxis (PrEP). A once monthly oral dose of islatravir maintains effective concentrations of its active metabolite over the entire dosing interval. Furthermore, an investigational implantable formulation has been projected to provide efficacious concentrations for at least a year and exhibits comparable distribution into vaginal and rectal tissues making it a promising PrEP option for male and female individuals. Islatravir has minimal risks of drug interactions as it is not a substrate, inducer, or inhibitor of major drug metabolizers and transporters. Finally, clinical trials demonstrate islatravir's favorable safety profile revealing only mild and transient adverse events. SUMMARY: Leveraging the unique pharmacological properties of islatravir offers opportunities for simplified HIV treatment regimens and long-acting PrEP making it a valuable addition to the antiretroviral arsenal.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Profilaxia Pré-Exposição , Desoxiadenosinas , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Humanos , Masculino
2.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 38(6): 513-521, 2022 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-35732609

RESUMO

Objective To explore the inhibitory effect of cordycepin on the proliferation and migration of gastric cancer cells and its molecular mechanism. Methods MGC-803 cells were treated with 0, 25, 50, 100 µmol/L of cordycepin and HGC-27 cells with 0, 5, 25, 50 µmol/L of cordycepin for 48 hours. The proliferation ability of MGC-803 and HGC-27 cells was detected by MTT assay and EdU assay; the colony formation ability of cells was detected by colony formation assay; both wound healing assay and cell migration assay were applied to detect the cell migration ability of MGC-803 and HGC-27 cells; the chromatin agglutination was detected by Hoechst 33342 staining; the apoptosis of gastric cancer cells was detected by annexin V-FITC/PI double labeling combined with flow cytometry; Western blot was used to measure the protein expression levels of lipid metabolism-related proteins including sterol regulatory element binding transcription factor 1 (SREBF1), fatty acid synthase (FASN), and acetyl coA carboxylase 1 (ACC1), epithelial-mesenchymal transition (EMT)-related proteins including E-cadherin, vimentin, Snail, Slug, matrix metalloproteinase 2 (MMP2), MMP9, AMPK, and phosphorylated AMPK (p-AMPK), MAPK signaling pathway-related proteins including JNK, phosphorylated JNK (p-JNK), p38 MAPK, and p-p38 MAPK, and apoptosis-related proteins including cleaved caspase-9 (c-caspase-9), c-caspase-3, and cleaved poly (ADP-ribose) polymerase (c-PARP). Results Cordycepin significantly inhibited the proliferation, colony formation, and migration of gastric cancer cells. After cordycepin treatment, the karyopycnosis, karyorrhexis, and apoptosis rate of cancer cells increased, and the expressions of apoptosis-related proteins c-caspase-3, c-caspase-9, and c-PARP increased. The expression of E-cadherin increased, while the expressions of vimentin, Snail, Slug, SREBF1, FASN, ACC1, MMP2, MMP9 significantly decreased; the phosphorylation levels of AMPK, JNK and P38 proteins significantly increased. Conclusion Cordycepin inhibits the proliferation and migration of gastric cancer cells by suppressing the lipid metabolism and EMT process via activating AMPK and MAPK signaling pathway.


Assuntos
Desoxiadenosinas , Neoplasias Gástricas , Proteínas Quinases Ativadas por AMP/metabolismo , Apoptose , Caderinas/metabolismo , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Desoxiadenosinas/farmacologia , Humanos , Metabolismo dos Lipídeos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Vimentina/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
3.
Antimicrob Agents Chemother ; 66(6): e0013322, 2022 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-35546110

RESUMO

Islatravir (ISL) is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) that inhibits human immunodeficiency virus (HIV) reverse transcription by blocking reverse transcriptase (RT) translocation on the primer:template. ISL is being developed for the treatment of HIV-1 infection. To expand our knowledge of viral variants that may confer reduced susceptibility to ISL, resistance selection studies were conducted with wild-type (WT) subtype A, B, and C viruses. RT mutations encoding M184I and M184V were the most frequently observed changes. Selection studies were also initiated with virus containing a single known resistance-associated mutation in RT (K65R, L74I, V90I, M184I, or M184V), and no additional mutations were observed. Antiviral activity assays were performed on variants that emerged in selection studies to determine their impact. M184I and M184V were the only single-codon substitutions that reduced susceptibility >2-fold compared to WT. A114S was an emergent substitution that when combined with other substitutions further reduced susceptibility >2-fold. Viruses containing A114S in combination with M184V did not replicate in primary blood mononuclear cells (PBMCs), consistent with the rare occurrence of the combination in clinical samples. While A114S conferred reduced susceptibility to ISL, it increased susceptibility to approved nucleoside reverse transcriptase inhibitors (NRTIs). This differential impact of A114S on ISL, an NRTTI, compared to NRTIs likely results from the different mechanisms of action. Altogether, the results demonstrate that ISL has a high barrier to resistance and a differentiated mechanism compared to approved NRTIs.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Desoxiadenosinas , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , Transcriptase Reversa do HIV/genética , HIV-1/genética , Humanos , Mutação , Nucleosídeos , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico
4.
Food Chem ; 389: 133070, 2022 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-35490522

RESUMO

Cordyceps militaris is an edible fungus that is widely used as a functional food in many countries. In order to objectively evaluate its nutritional value, free and glycosidic cordycepins need to be analyzed. The cordycepin arabinoside molecule was recognized by the MS2 fragmentation rule, and both cordycepin and its arabinoside were quantitatively analyzed in the fruiting body and pupa of Cordyceps militaris by high-performance liquid chromatography with tandem mass spectrometric (HPLC-MS/MS). The method had good linear regression (R2 = 0.9999), with a detection limit of 0.021 ng/mL. The recovery range was 94.32-103.09% in the fruiting body and pupa. The content of cordycepin and its arabinoside showed an upward trend with growth, and the total contents reached the highest level at the mature stage (60-70th day) without mildew. This study provides a useful reference for the evaluation and application of Cordyceps militaris as a functional food resource.


Assuntos
Cordyceps , Animais , Cordyceps/química , Desoxiadenosinas/análise , Desoxiadenosinas/química , Carpóforos/química , Pupa , Espectrometria de Massas em Tandem
5.
Antimicrob Agents Chemother ; 66(5): e0222321, 2022 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-35491829

RESUMO

Doravirine (DOR), a non-nucleoside reverse transcriptase inhibitor (NNRTI), was approved for treatment of HIV-1 infection in 2018. In the pivotal phase 3 trials, DRIVE-FORWARD and DRIVE-AHEAD, 7 out of 747 (0.9%) treatment-naive participants treated with DOR plus two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) met protocol-defined virologic failure criteria and showed phenotypic resistance to DOR at week 48. The most common DOR resistance-associated mutation (RAM) detected in 5 of the 7 resistant isolates was F227C. Six isolates bearing NRTI RAMs (M184V and/or K65R) were resistant to lamivudine (3TC) and emtricitabine (FTC) but not to other approved NRTIs. All DOR-resistant isolates were susceptible or hypersusceptible (fold change of <0.25) to islatravir (ISL), a nucleoside reverse transcriptase translocation inhibitor (NRTTI). Isolate hypersusceptibility to ISL required F227C, in contrast to zidovudine, an NRTI, which required M184V. Based on the frequent emergence of F227C, we hypothesized that DOR and ISL would create a combination (DOR/ISL) with a high barrier to resistance. In de novo resistance selection studies in MT4-GFP cells (MT4 cells engineered to express green fluorescent protein), DOR/ISL synergistically prevented viral breakthrough at a threshold of 2× the half-maximal inhibitory concentration (IC50). DOR/ISL exhibited a higher barrier to resistance than DOR/3TC and dolutegravir (DTG)/3TC. Resistance analysis showed no emergence of substitutions at F227, an observation consistent with its ability to confer hypersusceptibility to ISL. Overall, the data demonstrate that DOR/ISL creates a 2-drug combination with a higher barrier to resistance, consistent with the reported clinical activity.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Desoxiadenosinas , Farmacorresistência Viral/genética , Emtricitabina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Transcriptase Reversa do HIV/genética , HIV-1/genética , Humanos , Lamivudina/farmacologia , Lamivudina/uso terapêutico , Mutação , Piridonas , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Triazóis
6.
Artigo em Inglês | MEDLINE | ID: mdl-35389298

RESUMO

An efficient synthetic method has been developed for the synthesis of 2'-deoxyguanosine from the more commercially available 2'-deoxyadenosine via late-stage C2 nitration in 48.7% total yield by a 5-step synthetic procedure. Crucially, 2'-deoxyadenosine was fully protected by bennzoyl groups and then nitrated at C2 by tetrabutylammonium nitrate/trifluoroacetic anhydride. The resulting 2-NO2 moiety was converted into 2-NH2 by Ni-catalyzed hydrogenolysis. Finally, 2'-deoxyguanosine was obtained from the diaminopurine intermediate by deaminase-catalyzed reaction. Furthermore, the 2-NO2 moiety also appeared to be a versatile handle to introduce a variety of functional groups, resulting in a divergent access to 2-substituted 2'-deoxyadenosine analogues.


Assuntos
Desoxiguanosina , Dióxido de Nitrogênio , Desoxiadenosinas
7.
Chembiochem ; 23(12): e202200222, 2022 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-35438834

RESUMO

Among various kinds of fluorine-substituted biomolecules, 2-fluoroadenine (2FA) and its derivatives have been actively investigated as therapeutic reagents, radio-sensitizers, and 19 F NMR probes. In spite of their excellent properties, DNA containing 2FA has not been studied well. For fundamental understanding and future applications to the development of functional nucleic acids, we characterized 2FA-containing oligonucleotides for canonical right-handed DNA duplex, G-quadruplex, and i-motif structures. Properties of 2FA were similar to native adenine due to the small size of the fluorine atom, but it showed unique features caused by high electronegativity. This work provides useful information for future application of 2FA-modified DNA.


Assuntos
Flúor , Quadruplex G , DNA/química , Desoxiadenosinas , Flúor/química , Conformação de Ácido Nucleico , Oligonucleotídeos/química
8.
Int J Med Mushrooms ; 24(3): 65-75, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35467807

RESUMO

Type 2 diabetes mellitus (T2DM) is a major risk factor for cardiovascular diseases. The reduction of mitochondrial protein sirtuin protein 3 (SIRT3) has been reported to contribute to the development of T2DM by impacting mitochondrial respiration. Cordycepin is an adenosine derivative and is isolated from the culture filtrate of Cordyceps militaris. This study explored the protective effect of cordycepin on vascular impairment induced by T2DM and its properties and protective mechanism. In this study, a T2DM rat model was established. The endothelium-dependent relaxation of the thoracic aorta ring decreased in T2DM rats could be reversed by cordycepin. Next, mitochondrial impairment in human umbilical vein endothelial cells was detected by JC-1 staining. In vitro studies revealed that cordycepin plays a beneficial role in advanced glycation end product-induced endothelial mitochondrial impairment. Moreover, according to the cordycepin molecular docking analysis, cordycepin can bind to SIRT3. Cordycepin increased the expression and activation of SIRT3 in a dose-dependent manner. SIRT3 interruption blocked the protective effect of cordycepin on mitochondria in human umbilical vein endothelial cells. Cordycepin can conclusively protect vascular function impaired by T2DM, and the mechanism may potentially be involved in SIRT3 signaling pathways.


Assuntos
Cordyceps , Diabetes Mellitus Tipo 2 , Sirtuína 3 , Animais , Cordyceps/metabolismo , Desoxiadenosinas , Diabetes Mellitus Tipo 2/tratamento farmacológico , Células Endoteliais , Endotélio/metabolismo , Simulação de Acoplamento Molecular , Ratos , Sirtuína 3/genética , Sirtuína 3/metabolismo
9.
Eur J Pharmacol ; 924: 174952, 2022 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-35427564

RESUMO

BACKGROUND: Hypobaric hypoxia exposure leads to brain edema, followed by neuropsychological disorders. However, the related mechanism and effective treatments are still unclear. The study aimed to discuss the neuroprotective effects of Cordycepin on hypobaric hypoxia-induced cognitive impairment. METHODS: The study contained two parts. In the first part, rats underwent hypobaric hypoxia (HH) exposure for 7 days, with or without Cordycepin (10 mg/kg) or lipopolysaccharide (LPS,10 mg/kg) treatment once a day. In the second part, rats underwent HH exposure for 7 days, with or without TAK242 (3 mg/kg) and Cordycepin (10 mg/kg) once a day. Open field and Morris water maze test were performed one day after the 7days treatment. The BBB permeability was detected by the uptake of NaF. Western bloting was used to detect the levels of TLR4/MyD88/NF-κB pathway related proteins in the hippocampus. The hippocampal and serous levels of cytokines were detected by ELISA. The structure of tight junctions in the hippocampus was observed under the transmission electron microscopy. RESULTS: Both acute HH and LPS exposure could activate the TLR4 pathway and neuroinflammation, further induced BBB disruption and cognitive injury. Cordycepin could inhibit the activation of theTLR-4/NF-κB/MMP-9 pathway, which further attenuated cognitive dysfunction, and disruption of the blood-brain barrier (BBB) in HH and LPS exposed rats. Furthermore, TAK242, a TLR4 antagonist, also inhibited the activation of theTLR-4/NF-κB/MMP-9 pathway and BBB disruption, as well as attenuated HH induced cognitive impairment. CONCLUSIONS: Cordycepin could ameliorate HH-induced neuroinflammation, BBB disruption, and cognitive damage partly by inhibiting the TLR-4/NF-κB/MMP-9 pathway.


Assuntos
Disfunção Cognitiva , NF-kappa B , Animais , Barreira Hematoencefálica/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Desoxiadenosinas , Hipóxia/metabolismo , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , Metaloproteinase 9 da Matriz/metabolismo , NF-kappa B/metabolismo , Ratos , Receptor 4 Toll-Like/metabolismo
10.
J Biol Chem ; 298(5): 101876, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35358513

RESUMO

Deoxyguanosine kinase (dGK) is reported responsible for the phosphorylation of deoxyadenosine (dA) and deoxyguanosine (dG) in the mitochondrial purine salvage pathway. Antiviral nucleoside analogs known as nucleoside reverse transcriptase inhibitors (NRTIs) must be phosphorylated by host enzymes for the analog to become active. We address the possibility that NRTI purine analogs may be competitive inhibitors of dGK. From a group of such analogs, we demonstrate that entecavir (ETV) competitively inhibited the phosphorylation of dG and dA in rat mitochondria. Mitochondria from the brain, heart, kidney, and liver showed a marked preference for phosphorylation of dG over dA (10-30-fold) and ETV over dA (2.5-4-fold). We found that ETV inhibited the phosphorylation of dG with an IC50 of 15.3 ± 2.2 µM and that ETV and dG were both potent inhibitors of dA phosphorylation with IC50s of 0.034 ± 0.007 and 0.028 ± 0.006 µM, respectively. In addition, the phosphorylation of dG and ETV followed Michaelis-Menten kinetics and each competitively inhibited the phosphorylation of the other. We observed that the kinetics of dA phosphorylation were strikingly different from those of dG phosphorylation, with an exponentially lower affinity for dGK and no effect of dA on dG or ETV phosphorylation. Finally, in an isolated heart perfusion model, we demonstrated that dG, dA, and ETV were phosphorylated and dG phosphorylation was inhibited by ETV. Taken together, these data demonstrate that dGK is inhibited by ETV and that the primary role of dGK is in the phosphorylation of dG rather than dA.


Assuntos
Guanina , Fosfotransferases (Aceptor do Grupo Álcool) , Animais , Desoxiadenosinas/metabolismo , Desoxiadenosinas/farmacologia , Desoxiguanosina , Guanina/análogos & derivados , Mitocôndrias/metabolismo , Fosforilação , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Ratos
11.
Geriatr Gerontol Int ; 22(5): 433-440, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35352454

RESUMO

AIMS: Aging is a critical contributing factor for cardiovascular diseases. The d-galactose-induced accelerated aging model is comparable to physiological aging from the cellular to the physiological level. The d-galactose treatment induces mitochondrial dysfunction, increased reactive oxygen species (ROS) production, and upregulation of senescence-related genes. Cordycepin, a functional element in Chinese traditional medicine, has multiple beneficial effects as an antioxidant and ROS scavenger, and has been reported to be effective in a number of ischemia models. This paper aims to investigate the cardioprotective effects of cordycepin in the d-galactose accelerated aging model. METHODS: In the current study, we employed the d-galactose accelerated aging model to study the cardioprotective effect of cordycepin. Eight-week-old Sprague-Dawley rats, randomly divided into five groups, were given vehicle, d-galactose (150 mg/kg/day), and cordycepin at 5, 10, and 20 mg/kg per day. At the end of the 8-week treatment, rat cardiac structure and function were assessed with echocardiographic imaging and hemodynamic parameter analysis. RESULTS: Cordycepin upregulated the expression of Klotho in serum and heart tissues. The expressions of senescence markers ß-galactosidase, p21, and oxidative stress marker malondialdehyde (MDA) were downregulated by cordycepin treatment. Reduction of levels and activity of the antioxidant factors superoxide dismutase (SOD) and catalase (CAT) induced by by d-galactose treatment was ameliorated by cordycepin. Furthermore, cordycepin activated AMPK signaling in d-galactose-treated rats. After 8 weeks of treatment, we found that cordycepin improved myocardia contractility and hypertension caused by d-galactose treatment. Mechanistically, reduced expression of the Klotho protein SOD1 caused by d-galactose was recovered in rats co-treated with cordycepin. CONCLUSION: Cordycepin could protect against cardiac dysfunction in a d-galactose-induced aging rat model, suggesting the therapeutic cardioprotective potential of cordycepin in aging. Geriatr Gerontol Int 2022; 22: 433-440.


Assuntos
Envelhecimento , Antioxidantes , Desoxiadenosinas , Envelhecimento/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Desoxiadenosinas/farmacologia , Galactose/toxicidade , Humanos , Malondialdeído , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio
12.
Pharmacol Res ; 178: 106191, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35346845

RESUMO

Metabolic inflammation is a crucial factor in the pathogenesis of obesity and promotes related complications. Accumulating evidence has indicated that regulating intestinal integrity and the gut microbiota may be new treatment strategies for metabolic inflammation and obesity. Cordycepin has been reported to improve obesity, but the mechanism is not yet clear. Here, we showed that cordycepin considerably alleviated systemic inflammation while reducing body weight gain and metabolic disorders in Western diet (WD)-fed mice. Further investigations showed that cordycepin significantly ameliorated WD-induced damage to the intestinal barrier and decreased the leakage of lipopolysaccharide (LPS) into the blood in mice by suppressing intestinal inflammation, oxidative stress damage, and decreasing intestinal epithelial cell apoptosis and pyroptosis. In addition, by using metagenomic sequencing, we found that cordycepin could also regulate the homeostasis of intestinal flora, including selectively increasing the abundance of Akkermansia muciniphila and reducing the production of fecal LPS. Besides, we demonstrated that the intestinal flora partially mediated the beneficial effects of cordycepin on improving intestinal barrier function, and obesity-related symptoms in WD-fed mice by a fecal microbiota transplantation experiment. Hence, our findings provided new insights into the role of cordycepin in improving metabolic inflammation and obesity from the perspective of regulating the intestinal barrier function and intestinal flora, and further provided data support for the utility of cordycepin in the treatment of obesity and its complications.


Assuntos
Microbioma Gastrointestinal , Animais , Desoxiadenosinas , Dieta Hiperlipídica/efeitos adversos , Dieta Ocidental/efeitos adversos , Inflamação/complicações , Inflamação/tratamento farmacológico , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo
13.
Biotechnol Lett ; 44(4): 581-593, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35262812

RESUMO

Cordycepin (3'-deoxyadenosine) is a nucleoside analogue and biosynthesised by Cordyceps militaris, an entomopathogenic fungus. In this study, an epigenetic modifier was applied to static liquid cultures to enhance cordycepin production. C. militaris was cultured in a static liquid culture, and valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, was supplemented in order to modifying the epigenetic status. Gene regulatory network was explored to understand the molecular mechanisms underlying cordycepin production. 50 micromolar of VPA enhanced cordycepin production by 41.187% via the upregulation of 5'-nucleotidase, adenylate kinase, phosphorybosyltransferase, Cns1, Cns2, Cnsa3, and Cns4 of C. militaris for at least 2 days after VPA treatment. The maximum production of cordycepin was 2,835.32 ± 34.35 mg/L in 400 mL-working volume. A scaled-up culture was established with a working volume of 10 L, which led to the slight decrease of cordycepin production. This might due to multifactorial effects, for instance limited aeration and an uneven dispersion of nutrients in the culture system. This scaled-up culture was still needed further optimization. The modification of epigenetic status by VPA significantly enhanced cordycepin production by altering key gene regulatory network of C. militaris. The strategy established in this study might be applicable to other microorganism culture in order to improving the production of bioactive compounds. This work aimed to enhance the production of cordycepin by modifying the epigenetic status of C. militaris, in which subsequently altered gene regulatory network of cordycepin biosynthesis pathway. The weekly supplementation of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, significantly improve cordycepin production over 40%, compared to the untreated control, and the gene regulatory network of C. militaris was also adapted.


Assuntos
Cordyceps , Cordyceps/genética , Cordyceps/metabolismo , Desoxiadenosinas , Epigênese Genética , Histona Desacetilases/metabolismo , Ácido Valproico/metabolismo , Ácido Valproico/farmacologia
14.
Int Immunopharmacol ; 107: 108695, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35305385

RESUMO

Cordycepin, also known as 3'-deoxyadenosine, is an extract from Cordyceps militaris, which has been reported as an anti-inflammation and anti-tumor substance without toxicity. However, the pharmacological mechanism of Cordycepin on tumor immunity under its anti-tumor effect has not yet been elucidated. Herein, we investigated Cordycepin's anti-tumor effect on colon cancer both in vitro and in vivo. Our results show that Cordycepin can inhibit growth, migration, and promoted apoptosis of CT26 cells in a dose-dependent manner. Cordycepin suppressed the growth of colon cancer in mouse subcutaneous tumor model by modulating tumor immune microenvironment where CD4+ T, CD8+ T, M1 type macrophages, NK cells were up-regulated. Further investigations revealed that Cordycepin inhibited phagocytosis immune checkpoint CD47 protein expression by reducing BNIP3 expression. In addition, Cordycepin also inhibited the expression of TSP1 in tumor cells and Jurkat cells, which may reduce the binding of TSP1 to CD47, thereby reducing T cell apoptosis and allowing more T cells to infiltrate into tumors. And in vitro co-culture experiments proved that Cordycepin could enhance the phagocytosis of CT26 cells by macrophages. These results explained the underlying mechanism of the anti-tumor immunity of Cordycepin. In conclusion, our results identify a novel mechanism by which Cordycepin inhibits phagocytosis immune checkpoint CD47 in tumor cells to promote tumor cells phagocytosis of macrophages. Cordycepin may be able to serve as a more effective immunotherapeutic drug against colon cancer.


Assuntos
Antígeno CD47 , Neoplasias do Colo , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Desoxiadenosinas/farmacologia , Desoxiadenosinas/uso terapêutico , Camundongos , Fagocitose , Microambiente Tumoral
15.
J Physiol Biochem ; 78(2): 401-413, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35230668

RESUMO

To estimate the cardioprotective mechanism of cordycepin on myocardial ischemia/reperfusion (I/R) injury. The left anterior descending artery of mice was ligated transiently to establish the myocardial I/R model. TTC/Evans Blue staining and TUNEL assay were performed to quantify the infarct size and apoptosis index. The cardiac function was evaluated by echocardiography. Neonatal rat ventricular cardiomyocytes (NRVCs) underwent hypoxia and reoxygenation (H/R). MTS and LDH were detected to measured cell viability and necrosis respectively. The results suggested that cordycepin could markedly decrease apoptosis, reduce infarct size, and improve cardiac function in mice subjected to I/R injury, alongside with enhanced autophagy. In NRVCs, cordycepin treatment obviously reduced ROS production. In addition, cordycepin partly promoted autophagy in the context of H/R injury by regulating AMPK/mTOR pathway. Our data demonstrated that cordycepin exerts cardio-protective effect and promotes cardiac functional recovery following myocardial I/R by enhancing autophagy via AMPK-mTOR signaling pathway.


Assuntos
Desoxiadenosinas , Traumatismo por Reperfusão Miocárdica , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Apoptose , Autofagia , Células Cultivadas , Desoxiadenosinas/farmacologia , Infarto/metabolismo , Camundongos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/metabolismo , Ratos , Serina-Treonina Quinases TOR/metabolismo
16.
Front Immunol ; 13: 847171, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35355997

RESUMO

Adenosine synthase A (AdsA) is a key virulence factor of Staphylococcus aureus, a dangerous microbe that causes fatal diseases in humans. Together with staphylococcal nuclease, AdsA generates deoxyadenosine (dAdo) from neutrophil extracellular DNA traps thereby igniting caspase-3-dependent cell death in host immune cells that aim at penetrating infectious foci. Powered by a multi-technological approach, we here illustrate that the enzymatic activity of AdsA in abscess-mimicking microenvironments is not restricted to the biogenesis of dAdo but rather comprises excessive biosynthesis of deoxyguanosine (dGuo), a cytotoxic deoxyribonucleoside generated by S. aureus to eradicate macrophages of human and animal origin. Based on a genome-wide CRISPR-Cas9 knock-out screen, we further demonstrate that dGuo-induced cytotoxicity in phagocytes involves targeting of the mammalian purine salvage pathway-apoptosis axis, a signaling cascade that is concomitantly stimulated by staphylococcal dAdo. Strikingly, synchronous targeting of this route by AdsA-derived dGuo and dAdo boosts macrophage cell death, indicating that S. aureus multiplexes death-effector deoxyribonucleosides to maximize intra-host survival. Overall, these data provide unique insights into the cunning lifestyle of a deadly pathogen and may help to design therapeutic intervention strategies to combat multidrug-resistant staphylococci.


Assuntos
Infecções Estafilocócicas , Staphylococcus aureus , Animais , Desoxiadenosinas/farmacologia , Mamíferos/metabolismo , Neutrófilos , Staphylococcus/metabolismo
17.
J Antimicrob Chemother ; 77(4): 1000-1004, 2022 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-35134162

RESUMO

BACKGROUND: Islatravir (4'-ethynyl-2-fluoro-2'-deoxyadenosine; EFdA) is a first-in-class nucleoside reverse transcriptase translocation inhibitor (NRTTI) being investigated for HIV treatment and prevention. EFdA is intracellularly phosphorylated to EFdA-triphosphate (EFdA-tp), a competitive substrate of deoxyadenosine-triphosphate (dATP). Thus, translating safety and efficacy findings from preclinical studies relies on the assumption that EFdA's intracellular pharmacology can be extrapolated across species. OBJECTIVES: We investigated how EFdA is phosphorylated across animal species commonly used for preclinical models in drug development to identify those that most closely matched humans. METHODS: PBMCs were isolated from whole blood of six species (human, rhesus macaque non-human primate (rmNHP), rat, minipig, dog, and rabbit) using Ficoll separation and counted on a haemocytometer by Trypan blue staining. One million live cells were cultured in media supplemented with 10 U/mL human IL-2, 10% FBS and 1% antibiotics and treated with 0, 17, 170, and 1700 nM EFdA (n = 3 replicates per concentration). After 24 h, representative cell counts were derived from untreated control wells (as above), cells were washed in PBS, and lysed with 70:30 methanol:water. EFdA-tp and dATP concentrations were quantified by HPLC-MS/MS and normalized to the representative live cell counts for each species. RESULTS: When compared to human values, EFdA-tp concentrations for each EFdA treatment concentration were lower in all species (rmNHP 1.5-2.1-fold, rat 4.5-15-fold, minipig 37-71-fold, dog and rabbit >100-fold). Additionally, rmNHP and dog PBMCs exhibited significantly higher (7-10-fold; P < 0.001) dATP when compared with human PBMCs. CONCLUSIONS: Given intracellular pharmacology differences, these preclinical models may be a conservative estimate of EFdA's intracellular pharmacokinetics and efficacy in humans.


Assuntos
Desoxiadenosinas , Modelos Biológicos , Inibidores da Transcriptase Reversa , Animais , Fármacos Anti-HIV/farmacologia , Desoxiadenosinas/farmacologia , Cães , Infecções por HIV/tratamento farmacológico , Macaca mulatta , Coelhos , Ratos , Projetos de Pesquisa , Inibidores da Transcriptase Reversa/farmacologia , Especificidade da Espécie , Suínos , Porco Miniatura , Espectrometria de Massas em Tandem
18.
Science ; 375(6580): 515-522, 2022 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-35113693

RESUMO

The discovery of N6-methyldeoxyadenine (6mA) across eukaryotes led to a search for additional epigenetic mechanisms. However, some studies have highlighted confounding factors that challenge the prevalence of 6mA in eukaryotes. We developed a metagenomic method to quantitatively deconvolve 6mA events from a genomic DNA sample into species of interest, genomic regions, and sources of contamination. Applying this method, we observed high-resolution 6mA deposition in two protozoa. We found that commensal or soil bacteria explained the vast majority of 6mA in insect and plant samples. We found no evidence of high abundance of 6mA in Drosophila, Arabidopsis, or humans. Plasmids used for genetic manipulation, even those from Dam methyltransferase mutant Escherichia coli, could carry abundant 6mA, confounding the evaluation of candidate 6mA methyltransferases and demethylases. On the basis of this work, we advocate for a reassessment of 6mA in eukaryotes.


Assuntos
Metilação de DNA , DNA/química , Desoxiadenosinas/análise , Eucariotos/genética , Animais , Arabidopsis/genética , Neoplasias Encefálicas/genética , Chlamydomonas reinhardtii/genética , DNA/genética , DNA Bacteriano/química , DNA Bacteriano/genética , DNA Fúngico/química , DNA Fúngico/genética , DNA de Protozoário/química , DNA de Protozoário/genética , Drosophila melanogaster/genética , Drosophila melanogaster/microbiologia , Epigênese Genética , Escherichia coli/genética , Eucariotos/metabolismo , Glioblastoma/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucócitos Mononucleares/química , Metagenômica , Plasmídeos , Análise de Sequência de DNA , Tetrahymena thermophila/genética
19.
Pathog Dis ; 80(1)2022 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-35191475

RESUMO

Helicobacter pylori is one of the dominant members of gastric microbiota associated with gastritis. Chronic H. pylori colonization may yield detrimental consequences, including mucosal layer atrophy, gastritis, and gastric cancer. The traditional antibiotic treatment might result in antibiotic resistance. To overcome this obstacle, this study aims to investigate the potential antibacterial and anti-inflammatory effects of cordycepin on mice infected with H. pylori. A mouse model of H. pylori infection was established. The expression levels of target genes were evaluated by qRT-PCR, western blotting, or ELISA. The infiltrated Th17 cell population was determined by flow cytometry analysis. Our results demonstrated that the administration of cordycepin exhibited up to 3-fold antibacterial effect against H. pyloriin vivo. Cordycepin treatment resulted in around 50% inflammatory cytokine production (e.g. IL-6 and IL-1ß) and about 60% immune cell infiltration (e.g. Th17 cells) when compared to vehicle control group. Thus, we confirmed that cordycepin conferred antibacterial and anti-inflammatory effects on H. pylori-infected mice. Cordycepin may serve as a potential candidate for developing a therapeutic regimen for H. pylori-induced gastritis.


Assuntos
Gastrite , Helicobacter pylori , Animais , Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Desoxiadenosinas , Gastrite/tratamento farmacológico , Camundongos
20.
BMC Pharmacol Toxicol ; 23(1): 12, 2022 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-35120580

RESUMO

BACKGROUND: Cordycepin is a purine nucleoside anti-metabolite and anti-biotic isolated from the fungus Cordyceps militaris, which has potential anti-neoplastic activities. This study aimed to investigate the effect of cordycepin in inhibiting colon cancer development. METHODS: The proliferation of cordycepin-treated HCT116 and Caco-2 colon cancer cell lines was assessed with 3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and the viability was measured with colony formation assay. At the same time, cordycepin responsive gene and microRNAs (miRNAs, miRs) were screened by qRT-PCR. MYC over-expressing HCT116 and Caco-2 cell lines were constructed, which were further transfected with miR-26a. Inhibitory effect of cordycepin on cell proliferation was evaluated with cell viability assay, cell number count, and colony formation assay. The relative expression of MYC and miR-26a was detected by qRT-PCR and Western blot. RESULTS: Cordycepin inhibited colon cancer cell proliferation by down-regulating MYC mRNA/protein expression and up-regulating miR-26a in both HCT116 and Caco-2 cells. MYC over-expression could suppress the expression of miR-26a, which could be restored by cordycepin treatment. Additional miR-26a transfection in MYC over-expressing cells could reverse MYC over-expression-promoted proliferation, which could be further potentiated by cordycepin treatment. CONCLUSION: Cordycepin is able to suppress colon cancer cell proliferation, likely mediated by the MYC/miR-26a pathway, supporting its potential for the treatment of colon cancer.


Assuntos
Neoplasias do Colo , MicroRNAs , Células CACO-2 , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Desoxiadenosinas , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...