RESUMEN
Neuropathic pain is a chronic and severe syndrome for which effective therapy is insufficient and the release of ATP from microglia induced by sphingosine-1-phosphate (S1P) plays a vital role in neuropathic pain. Therefore, there is an urgent demand to develop highly sensitive and selective ATP biosensors for quantitative monitoring of low-concentration ATP in the complex nervous system, which helps in understanding the mechanism involved in neuropathic pain. Herein, we developed an electrochemical microsensor based on an entropy-driven bipedal DNA walker. First, the microsensor specifically recognized ATP via ATP aptamers, initiating the entropy-driven bipedal DNA walker. Subsequently, the bipedal DNA walker autonomously traversed the microelectrode interface, introducing methylene blue to the electrode surface and achieving cascade signal amplification. This microsensor showed excellent selectivity, stability, and a low limit of detection at 1.13 nM. The S1P-induced ATP release from BV2 cells was successfully monitored, and it was observed that dicumarol could inhibit this release, suggesting dicumarol as a potential treatment for neuropathic pain. The microsensor's small size exhibited significant potential for monitoring ATP level changes in neuropathic pain in vivo, which provides a new strategy for in situ and quantitative monitoring of nonelectroactive biomolecules associated with neurological diseases.
Asunto(s)
Técnicas Biosensibles , Lisofosfolípidos , Neuralgia , Esfingosina/análogos & derivados , Humanos , Entropía , Dicumarol , ADN/química , Microelectrodos , Adenosina Trifosfato , Técnicas Electroquímicas , Límite de DetecciónRESUMEN
Bioinformatics analysis of a whole genome sequence coupled with HPLC-DAD analysis revealed that Streptomyces sp. Hu103 has the capacity to produce skyllamycin analogues. A subsequent chemical investigation of this strain yielded four new cinnamoyl-containing cyclopeptides, anulamycins A-D (1-4), two new cinnamoyl-containing linear peptides, anulamycins E and F (5 and 6), and two known cyclopeptides, skyllamycins A (7) and B (8). Their structures including absolute configurations were elucidated by detailed analysis of NMR and HRESIMS/MS spectroscopic data and the advanced Marfey's method. Compounds 1-4 exhibited antibacterial activity comparable to those of skyllamycins A and B.
Asunto(s)
Streptomyces , Streptomyces/química , Lagos , Péptidos Cíclicos/química , Espectroscopía de Resonancia Magnética , Antibacterianos/química , Estructura MolecularRESUMEN
A chemical investigation of Streptomyces sp. Hu186 afforded two known quinone antibiotics, sarubicin A (1) and sarubicin B (2), together with three unusual variants, sarubicinols A-C (3-5), and two new 1,4-naphthoquinone metabolites, sarubicin B1 (6) and sarubicin B2 (7). Compounds 3-5 possess a rare 2-oxabicyclo [2.2.2] substructure and a benzoxazole ring system. Their structures were elucidated using 1D and 2D nuclear magnetic resonance and high-resolution electrospray ionization mass spectrometry data. The absolute configurations of the side-chain moieties in 4 and 5 were solved by electronic circular dichroism calculations. Compounds 1-7 showed moderate cytotoxic activity against four tumor cell lines.
Asunto(s)
Antineoplásicos , Streptomyces , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Benzoxazoles/farmacología , Línea Celular Tumoral , Estructura Molecular , Espectrometría de Masa por Ionización de Electrospray , Streptomyces/químicaRESUMEN
Tetrodecadazinone (1), a novel tetrodecamycin-pyridazinone hybrid possessing a new 1,2-dimethyl-1-(2-methylnonyl)decahydronaphthalene skeleton, and 4-hydroxydihydrotetrodecamycin (2) were separated from a culture of Streptomyces sp. HU051, together with a known compound, dihydrotetrodecamycin (3). Diverse spectroscopic approaches were applied to assign the structures of 1-3, and the structure of 1 was further confirmed by single crystal X-ray diffraction analysis. Compound 1 is the first example of a pyridazinone-containing natural product. Biosynthetically, 1 is proposed to be derived from a Michael addition reaction of a PKS-derived tetrodecamycin and a piperazic-acid-derived pyridazinone. Biological evaluation revealed 1 could reduce the expressions of extracellular matrix proteins (fibronectin and collagen I) and α-smooth muscle actin (α-SMA) in transforming growth factor-ß (TGF-ß1)-activated LX-2 cells. Preliminary mechanism study showed 1 exerted its anti-liver fibrosis effect by regulating TGF-ß1/Smad2/3 signaling pathway.
Asunto(s)
Antibacterianos/farmacología , Cirrosis Hepática/tratamiento farmacológico , Streptomyces/efectos de los fármacos , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Células Cultivadas , Relación Dosis-Respuesta a Droga , Humanos , Cirrosis Hepática/metabolismo , Cirrosis Hepática/microbiología , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Transducción de Señal/efectos de los fármacos , Proteína Smad2/antagonistas & inhibidores , Proteína Smad2/metabolismo , Proteína smad3/antagonistas & inhibidores , Proteína smad3/metabolismo , Relación Estructura-Actividad , Factor de Crecimiento Transformador beta1/antagonistas & inhibidores , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Two previously undescribed cyclopentenone metabolites, (S)-2-(3-acetylamino-2-methyl)propyl-3-butyl-2-cyclopenten-1-one (1) and (S)-2-(3-acetylamino-2-ethyl)propyl-3-butyl-2-cyclopenten-1-one (2), were isolated from the fermentation broth of the strain Streptomyces sp. HU119. The structures of 1 and 2 were determined by the comprehensive spectroscopic analysis, including 1 D, 2 D NMR, MS spectral analysis and the comparison with data from the literature. The absolute configurations were elucidated by experimental and calculated optical rotations (OR). Compounds 1 and 2 displayed weak cytotoxic activity.
Asunto(s)
Streptomyces , Streptomyces/química , Estructura Molecular , Ciclopentanos/farmacología , FermentaciónRESUMEN
Two new milbemycin metabolites, 13α-hydroxymilbemycin ß13 (1) and 26-methyl-13α-hydroxymilbemycin ß13 (2), were isolated from the fermentation broth of a genetically engineered strain Streptomyces avermitilis AVE-H39. Their structures were determined by the comprehensive spectroscopic data, including 1 D, 2 D NMR, MS spectral analysis and the comparison with data from the literature. Compounds 1 and 2 not only exhibited potent acaricidal activities against Tetranychus cinnabarinus, but also had nematocidal activity against Bursaphelenchus xylophilus.
Asunto(s)
Streptomyces , Macrólidos/farmacología , Estructura Molecular , Streptomyces/genéticaRESUMEN
Two new milbemycin derivatives, milbemycin M (1) and milbemycin N (2), were isolated from the culture of a genetically engineered strain Streptomyces bingchenggensis BCJ60. Their structures were elucidated through the interpretation of NMR and HR-ESI-MS spectroscopic data, as well as comparison with previous reports. The acaricidal and nematicidal activities of them against Tetranychus cinnabarinus and Bursaphelenchus xylophilus were tested. The results showed that compounds 1-2 possessed potent acaricidal and nematocidal activities.
Asunto(s)
Macrólidos , Streptomyces , Estructura Molecular , Streptomyces/genéticaRESUMEN
Two new derivatives of cytotoxic substance BE-52211, designed as BE-52211D (1) and BE-52211E (2), were isolated from the fermentation broth of the strain Streptomyces sp. HS-NF-813. Their structures were determined by 1D and 2D NMR techniques, ESI-MS and comparison with data from the literature. The absolute stereochemistry of 1 was elucidated by NMR data of the Mosher ester derivatives. Compounds 1 and 2 showed moderate cytotoxic activity against three human tumor cell lines.
Asunto(s)
Antineoplásicos , Streptomyces , Línea Celular Tumoral , Humanos , Espectroscopía de Resonancia Magnética , Estructura MolecularRESUMEN
The mangrove ecosystem is a rich resource for the discovery of actinomycetes with potential applications in pharmaceutical science. Besides the genus Streptomyces, Micromonospora is also a source of new bioactive agents. We screened Micromonospora from the rhizosphere soil of mangrove plants in Fujian province, China, and 51 strains were obtained. Among them, the extracts of 12 isolates inhibited the growth of human lung carcinoma A549 cells. Strain 110B exhibited better cytotoxic activity, and its bioactive constituents were investigated. Consequently, three new isoflavonoid glycosides, daidzein-4'-(2-deoxy-α-l-fucopyranoside) (1), daidzein-7-(2-deoxy-α-l-fucopyranoside) (2), and daidzein-4',7-di-(2-deoxy-α-l-fucopyranoside) (3) were isolated from the fermentation broth of strain 110B. The structures of the new compounds were determined by spectroscopic methods, including 1D and 2D nuclear magnetic resonance (NMR) and high-resolution electrospray ionization mass spectrometry (HR-ESIMS). The result of medium-changing experiments implicated that these new compounds were microbial biotransformation products of strain M. aurantiaca 110B. The three compounds displayed moderate cytotoxic activity to the human lung carcinoma cell line A549, hepatocellular liver carcinoma cell line HepG2, and the human colon tumor cell line HCT116, whereas none of them showed antifungal or antibacterial activities.
Asunto(s)
Supervivencia Celular/efectos de los fármacos , Micromonospora/química , Células A549 , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Glicósidos/química , Glicósidos/aislamiento & purificación , Glicósidos/farmacología , Células HCT116 , Células Hep G2 , Humanos , Isoflavonas/química , Microbiología del SueloRESUMEN
Two new naphthalenone derivatives, 5-hydroxy-4-oxo-2-(2-oxopropyl)-1,2,3,4-tetrahydronaphthalen-1-yl acetate (1) and 5-hydroxy-2-(2-hydroxypropyl)naphthalene-1,4-dione (2), together with two new anthrone derivatives, (S)-2,5-dihydroxy-2-methyl-1,2,3,4-tetrahydroanthracene-9,10-dione (3) and 4,5-dihydroxy-2-methyl-9H-xanthen-9-one (4), were isolated from the fermentation broth of endophytic Micromonospora sp. NEAU-gq13. Their structures were determined by 1D-NMR, 2D-NMR, and HR-ESI-MS analysis. Compounds 2 and 3 exhibited strong cytotoxic activity against human central nervous system cancer (SF-268) with the IC50 values of 3.04 and 5.66 µg/ml, respectively. Moreover, compound 2 also displayed potent activity against human liver cancer (HepG2) with an IC50 value of 1.01 µg/ml.
Asunto(s)
Antineoplásicos , Micromonospora , Naftoquinonas , Antracenos , Humanos , Estructura MolecularRESUMEN
Histone deacetylases (HDACs), especially HDAC1, 2, 3 and 4, are abundantly expressed and over-activated in prostate cancer that is correlated with the poor prognosis. Thus, inhibition of HDAC activity has emerged as a potential alternative option for prostate cancer therapy. Chromopeptide A is a depsipeptide isolated from the marine sediment-derived bacterium Chromobacterium sp. HS-13-94; it has a chemical structure highly similar to FK228, a class I HDAC inhibitor that is approved by FDA for treating T-cell lymphoma. In this study, we determined whether chromopeptide A, like FK228, acted as a class I HDAC inhibitor, and whether chromopeptide A could inhibit the growth and migration of human prostate cancer in vitro and in vivo. HDAC enzyme selectivity and kinetic analysis revealed that chromopeptide A selectively inhibited the enzymatic activities of HDAC1, 2, 3 and 8 in a substrate non-competitive manner with comparable IC50 values for each HDAC member as FK228 in vitro. Importantly, chromopeptide A dose-dependently suppressed the proliferation of human prostate cancer cell lines PC3, DU145 and LNCaP with IC50 values of 2.43±0.02, 2.08±0.16, and 1.75±0.06 nmol/L, respectively, accompanied by dose-dependent inhibition of HDAC enzymatic activity in PC3 and DU145 cells. Chromopeptide A (0.2-50 nmol/L) caused G2/M phase arrest and induced apoptosis in the prostate cancer cell lines. Moreover, chromopeptide A dose-dependently inhibited the migration of PC3 cells. In mice bearing PC3 prostate cancer xenografts, intravenous injection of chromopeptide A (1.6, 3.2 mg/kg, once a week for 18 d) significantly suppressed the tumor growth, which was associated with increased expression levels of Ac-H3 and p21 in tumor tissues. Our results identify chromopeptide A as a novel class I HDAC inhibitor and provide therapeutic strategies that may be implemented in prostate cancer.
Asunto(s)
Antineoplásicos/uso terapéutico , Inhibidores de Histona Desacetilasas/uso terapéutico , Péptidos Cíclicos/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Xenoinjertos , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Trasplante de Neoplasias , Neoplasias de la Próstata/patologíaRESUMEN
Three new sesquiterpenoids, salplebeones A - C (1 - 3), were isolated from the ethanol-soluble extract of the aerial part of Salvia plebeia R. Br. Their structures were established by detailed analysis of NMR and MS spectra. Salplebeone A was an eudesmane lactone, while salplebeones B and C were rare eudesmane sesquiterpenoids, containing 12,8-lactam groups. Antiproliferative activities of salplebeones A - C to myeloid leukemia cell lines were evaluated.
Asunto(s)
Salvia/química , Sesquiterpenos de Eudesmano/química , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/aislamiento & purificación , Medicamentos Herbarios Chinos/farmacología , Humanos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Conformación Molecular , Salvia/metabolismo , Sesquiterpenos de Eudesmano/aislamiento & purificación , Sesquiterpenos de Eudesmano/farmacologíaRESUMEN
Two new tenvermectins, tenvermectins C (1) and D (2), were isolated from Streptomyces avermitilis MHJ1011. Their structures were determined by extensive spectroscopic analysis and by comparison with a related known compound, tenvermectin A. Compounds 1 and 2 exhibited potent nematocidal and acaricidal activities against Bursaphelenchus xylophilus and Tetranychus cinnabarinus.
Asunto(s)
Acaricidas/química , Acaricidas/aislamiento & purificación , Antinematodos/aislamiento & purificación , Macrólidos/aislamiento & purificación , Streptomyces/química , Acaricidas/farmacología , Animales , Antinematodos/química , Antinematodos/farmacología , Ingeniería Genética , Macrólidos/química , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Streptomyces/genética , Tetranychidae/efectos de los fármacosRESUMEN
A new naphthalenepropanoic acid analog (1) was isolated from the broth of the actinomycetes Micromonospora sp. HS-HM-036. The structure of compound 1 was determined based on MS and extensive NMR analysis. A preliminary investigation of the biological activity of compound 1 was also described.
Asunto(s)
Antibacterianos/aislamiento & purificación , Micromonospora/química , Naftalenos/aislamiento & purificación , Antibacterianos/química , Bacillus subtilis/efectos de los fármacos , Biología Marina , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Naftalenos/química , Naftalenos/farmacología , Resonancia Magnética Nuclear Biomolecular , Pseudomonas aeruginosa/efectos de los fármacosRESUMEN
A new spectinabilin derivative (1) was isolated from the fermentation broth of the ant-derived Streptomyces sp. 1H-GS5, and the structure was elucidated by extensive spectroscopic analysis. Compound 1 showed cytotoxicity against human tumor cell lines A549, HCT-116, and HepG2 with IC50 values of 9.7, 12.8, and 9.1 µg/ml, respectively, which was relative higher than that of spectinabilin.
Asunto(s)
Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Hormigas/microbiología , Pironas/aislamiento & purificación , Pironas/farmacología , Streptomyces/química , Animales , Antineoplásicos/química , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Células Hep G2 , Humanos , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Fragmentos de Péptidos/química , Pironas/química , Sustancia P/análogos & derivados , Sustancia P/químicaRESUMEN
Two new macrocyclic lactones, 4,25-diethyl-4,25-demethyl-milbemycin ß3 (1) and 27-formaldehyde-milbemycin ß14 (2), were isolated from a genetically engineered strain Streptomyces bingchenggensis BCJ60. Their structures were determined on the basis of spectroscopic analysis, including 1D and 2D NMR techniques as well as ESI-MS and comparison with data from the literature. The acaricidal and nematocidal capacities of compounds 1 and 2 were evaluated against Tetranychus cinnabarinus and Bursaphelenchus xylophilus, respectively. The results showed that the two new macrocyclic lactones 1 and 2 possessed potent acaricidal and nematocidal activities.
Asunto(s)
Acaricidas/aislamiento & purificación , Acaricidas/farmacología , Antinematodos/aislamiento & purificación , Antinematodos/farmacología , Ingeniería Genética , Lactonas/aislamiento & purificación , Lactonas/farmacología , Macrólidos/aislamiento & purificación , Macrólidos/farmacología , Streptomyces/química , Streptomyces/genética , Acaricidas/química , Animales , Antinematodos/química , Lactonas/química , Macrólidos/química , Estructura Molecular , TetranychidaeRESUMEN
To systematically evaluate the safety of Kudiezi injection. Databases such as Cochrane library, Medline, EMbase, Web of Science, Clinical Trials, CBM, CNKI, VIP, Wanfang and Chinese Clinical Trial Register were searched to collect the literature on all the study types of Kudiezi injection. Two researchers screened literature, assessed quality and extracted data according to inclusion and exclusion criteria. All studies were assessed by using internationally recognized methodological quality assessment tools or reporting quality evaluation criteria; Meta-analysis of adverse drug reaction/adverse events (ADR/AE) of Kudiezi injection was performed by using Stata 12.0 software. There were 411 clinical studies included, out of which 315 studies were analyzed finally. 18 072 patients in total used kudiezi injection, and there were 330 cases with ADRs and 13 cases with AEs. The most common ADR related system was the central and peripheral nervous system, with a weighted incidence of 2.9% [95%CI(0.022, 0.036)]. From the current evidence, the overall safety of Kudiezi injection was acceptable. Although data could be collected from all kinds of published reports, there are lack of mechanism experiments or observational studies with large samples of Kudiezi injection. Therefore, it is necessary to carry out further research on the safety of Kudiezi injection. Meanwhile, off label use of Kudiezi injection is common, so it is urgent for relevant governmental departments to formulate drug use specifications and provide better guidance for clinical drug use.
Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Medicamentos Herbarios Chinos/efectos adversos , Humanos , Incidencia , InyeccionesRESUMEN
UNLABELLED: Spinosad, a highly effective insecticide, has an excellent environmental and mammalian toxicological profile. Global market demand for spinosad is huge and growing. However, after much effort, there has been almost no improvement in the spinosad yield from the original producer, Saccharopolyspora spinosa Here, we report the heterologous expression of spinosad using Saccharopolyspora erythraea as a host. The native erythromycin polyketide synthase (PKS) genes in S. erythraea were replaced by the assembled spinosad gene cluster through iterative recombination. The production of spinosad could be detected in the recombinant strains containing the whole biosynthesis gene cluster. Both metabolic engineering and UV mutagenesis were applied to further improve the yield of spinosad. The final strain, AT-ES04PS-3007, which could produce spinosad with a titer of 830 mg/liter, has significant potential in industrial applications. IMPORTANCE: This work provides an innovative and promising way to improve the industrial production of spinosad. At the same time, it also describes a successful method of heterologous expression for target metabolites of interest by replacing large gene clusters.
Asunto(s)
Insecticidas/metabolismo , Macrólidos/metabolismo , Saccharopolyspora/metabolismo , Clonación Molecular , Combinación de Medicamentos , Expresión Génica , Ingeniería Metabólica , Redes y Vías Metabólicas/genética , Familia de MultigenesRESUMEN
Three new 16-membered macrolide compounds, 13α-O-α-l-oleandrosyl milbemycin ß3 (1), 13α-O-α-l-oleandrosyl-25-ethyl milbemycin ß3 (2), 13α-O-α-l-oleandrosyl-25-isopropyl milbemycin ß3 (3), were isolated from the genetically engineered strains Streptomyces avermitilis MHJ1011. Their structures were determined on the basis of spectroscopic analysis, including 1D and 2D NMR techniques as well as ESI-MS and comparison with data from the literature. Both compounds 1-3 displayed impressive acaricidal activity against larval mites with the IC50 values of 0.0327, 0.0276 and 0.0235mg/L, respectively, which are higher than those of 13α-hydroxy milbemycin ß3 and 13α-hydroxy-25-ethyl milbemycin ß3.
Asunto(s)
Ingeniería Genética , Macrólidos/farmacología , Ácaros/efectos de los fármacos , Streptomyces/química , Animales , Relación Dosis-Respuesta a Droga , Macrólidos/química , Macrólidos/aislamiento & purificación , Conformación Molecular , Relación Estructura-ActividadRESUMEN
Chronic renal failure(CRF) is one of the common diseases. Shenshuaining capsule (SSN) can be used to treat patients with CRF, and many randomized control trials(RCTs) have been conducted to investigate its efficacy. The current review aims to systematically evaluate the efficacy and safety of SSN as an adjuvant treatment for patients with CRF. Eleven English and Chinese electronic databases (up to October 2015), were searched to identify RCTs on SSN for CRF. Two reviewers independently extracted the data and assessed the quality of included studies by using Cochrane Handbook 5.1.Meta-analysis was carried out by using Revman 5.3 software. If the Meta-analysis was not suitable for some outcomes, only descriptive analysis would be conducted.429 related articles were identified and finally a total of 25 RCTs (1 937 patients including 1 059 patients of treatment group and 878 patients of control group) were included. The SSN treatment group was more effective than the control group in terms of clinical efficiency, blood urea nitrogen(BUN), serum creatinine(Scr) and creatinine clearance(Ccr). However, the efficacy of SSN on increasing hemoglobin (Hb) could not be determined. No serious adverse drug events or reactions were reported. SSN capsules have certain efficacy and safety in the adjuvant treatment for chronic renal failure. However, due to the generally low methodological quality of the included studies, this review can not provide high-quality evidence to prove the clinical efficacy of this drug. More well-designed and large-scale multi-center randomized controlled trials should be conducted in the future for verification.