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Applying the emerging molecular networking strategy, an uncommon cembranoid orthoester, sarcotortin A (1), featuring a 3/14/8/5-fused scaffold, an unusual eunicellane-type diterpenoid, sarcotorolide A (2), and two new biscembranoids, ximaolides M and N (7 and 8), along with nine known terpenoids 3-6 and 9-13 were isolated from the Hainan soft coral Sarcophyton tortuosum. The structure and absolute configuration of all new compounds were established by a combination of spectroscopic data, X-ray diffraction analysis, and/or quantum chemical computational approaches. The plausible biogenetic relationship among these skeletally different terpenoids was proposed and discussed. In in vitro bioassay, new compound 7 exhibited a remarkable inhibitory activity against protein tyrosine phosphatases 1B (PTP1B) with the IC50 value of 8.06â µM. In addition, compounds 4 and 10 displayed significant inhibitory effects on lipopolysaccharide (LPS)-induced inflammatory responses in RAW264.7 macrophages cells with the IC50 values of 19.13 and 16.45â µM, respectively. Compound 9 showed interesting cytotoxicity against H1975, MDA-MB231, A549, and H1299 cancer cell lines with IC50 values of 31.59, 34.96, 43.87, and 27.93â µM, respectively.
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Antozoos , Diterpenos , Animales , Terpenos/química , Estructura Molecular , Antozoos/química , Diterpenos/química , Cristalografía por Rayos XRESUMEN
Dehydroepiandrosterone (DHEA) is an FDA-approved food supplement used as an assisted reproductive sex hormone. The bioavailability is severely limited by its poor solubility (23 µg/mL). Herein, we aimed to modulate its solubility through cocrystallization. Eight cocrystals of DHEA with pyrocatechol (CAT), hydroquinone (HQ), resorcinol (RES), phloroglucinol (PG), 1,5-dihydroxy naphthalene (DHN), p-hydroxybenzoic acid (PHBA), gallic acid (GA), and 5-hydroxyisophthalic acid (5HIPA) were designed and synthesized. Some basic characterization tools, including powder X-ray diffraction, thermogravimetric analysis, differential scanning calorimetry, and Fourier transform infrared spectroscopy, were also applied in our work for basic analyses of cocrystals. It is indicated that DHEA-GA exhibits its superiority in dissolution and pharmacokinetic behaviors. While the area under the curve values of DHEA-GA is improved at the ratio of 2.2, the corresponding bioavailability of DHEA is expected to be accordingly increased.
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Bexarotene (BEX) was approved by the FDA in 1999 for the treatment of cutaneous T-cell lymphoma (CTCL). The poor aqueous solubility causes the low bioavailability of the drug and thereby limits the clinical application. In this study, we developed a GCN-based deep learning model (CocrystalGCN) for in-silico screening of the cocrystals of BEX. The results show that our model obtained high performance relative to baseline models. The top 30 of 109 coformer candidates were scored by CocrystalGCN and then validated experimentally. Finally, cocrystals of BEX-pyrazine, BEX-2,5-dimethylpyrazine, BEX-methyl isonicotinate, and BEX-ethyl isonicotinate were successfully obtained. The crystal structures were determined by single-crystal X-ray diffraction. Powder X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis were utilized to characterize these multi-component forms. All cocrystals present superior solubility and dissolution over the parent drug. The pharmacokinetic studies show that the plasma exposures (AUC0-8h) of BEX-pyrazine and BEX-2,5-dimethylpyrazine are 1.7 and 1.8 times that of the commercially available BEX powder, respectively. This work sets a good example for integrating virtual prediction and experimental screening to discover the new cocrystals of water-insoluble drugs.
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Isotretinoin is the first-line drug for treatment of severe acne. Only one polymorph was reported even though it has been launched for nearly 40 years, and its clinic application was however limited by its stability and solubility challenges. In our study, two new polymorphs of isotretinoin were discovered and fully characterized. The transformation relationships between these solid forms were fully discussed, and a visible color change during single-crystal-to-single-crystal phase transition with the conformational change was investigated. Form II is determined to be thermodynamic stable form at room temperature, but metastable form at body temperature. The results show that form II is an ideal solid state possessing both superior thermal stability (60â, open air) and higher absorption once delivered into body. The thermal stability can be associated with the crystal structure such as torsion angle. The relative bioavailability of form II is higher than form I as expected, and the bioavailability of form II formulation is about 2 times as that of the marketed form I capsule. Therefore, form II formulation could provide an alternative for better performing isotretinoin.
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Isotretinoína , Cristalización , Conformación Molecular , Transición de Fase , SolubilidadRESUMEN
A novel norditerpenoid, sinusiaetone A (1), featuring an uncommon bicyclo[11.3.0]hexadecane carbon skeleton, and four polyoxygenated cembranoids (2-5) were isolated from the Hainan soft coral Sinularia siaesensis. Their structures were established by spectroscopic analysis, X-ray diffraction, quantum chemical computational approaches, and/or a modified Mosher's method. A plausible biosynthetic pathway of 1 and its biogenetic relationship with 2-5 were proposed. New compounds 1-3 displayed an interesting inhibitory activity against lipopolysaccharide-induced inflammation in BV-2 microglial cells.
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Antozoos/química , Antiinflamatorios/farmacología , Compuestos Bicíclicos con Puentes/farmacología , Diterpenos/química , Lipopolisacáridos/farmacología , Alcanos , Animales , Antiinflamatorios/química , Compuestos Bicíclicos con Puentes/química , Lipopolisacáridos/química , Estructura MolecularRESUMEN
A novel diterpenoid, sinueretone A (1), featuring an unprecedented tricyclo[12.1.0.05,9]pentadecane carbon framework, along with two new (2 and 3) and one known (4) casbane diterpenoids were isolated from the South China Sea soft coral Sinularia erecta. The structures of the new compounds, especially their absolute stereochemistry, were established by extensive spectroscopic analysis, various quantum chemical calculations, and/or X-ray diffraction analyses. A plausible biogenetic relationship of 1-4 was proposed, which gave an insight for future biomimetic synthesis of the novel compounds. In a bioassay, compounds 1 and 2 displayed interesting anti-inflammatory activity by the inhibition of lipopolysaccharide-induced tumor necrosis factor-α protein release.
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Antozoos , Diterpenos , Alcanos , Animales , Carbono , Estructura MolecularRESUMEN
d-α-tocopherol (d-αToc), the most biologically active form of natural Vitamin E, is oily in appearance and unstable to oxygen. Esterification and encapsulation are generally needed to stabilize and solidify d-αToc for the purpose of its expanding applications. In this study, we propose a more effective way to stabilize and solidify d-αToc oil in one step. By cocrystallization, the melting point of d-αToc is significantly increased, such that the oily d-αToc is successfully transformed into solid form at room temperature. The single crystal structure of d-αToc was firstly uncovered and the molecular interaction in cocrystals was revealed. Crystalline Vitamin E shows high stability to light and temperature. Its spherical crystallization affords good powder flowability, which is extremely important as food or feed additives. Moreover, cocrystal Vitamin E remains the original form of tocopherol without esterification and thus has a great advantage on higher bioavailability. Cocrystallization of oily d-αToc spares the use of acetic ester and a mass of excipients, which is of great environmental importance and greatly reduces the production cost.
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Vitamina E , alfa-Tocoferol , Disponibilidad Biológica , Cristalización , Excipientes , SolubilidadRESUMEN
Awareness of prevention is enhanced to reduce the rate of infection by media coverage, which plays an important role in preventing and controlling infectious diseases. Based on epidemic situation of the Corona Virus Disease 2019 (COVID-19) in Hubei, an SIHRS epidemic model with media coverage was proposed. Firstly, by the basic reproduction number R0, the globally asymptotically stable of the disease-free equilibrium and the endemic equilibrium were proved. Then, based on the reported epidemic data of Hubei Province from January 26 to February 13, numerical simulations are used to verify the analysis results, and the impact of peak time and the scale of disease transmission were mainly considered with different information implementation rate and the contact rate. It was shown that with the decrease of information implementation rate, the peak of confirmed cases would be delayed to reach, and would increase significantly. Therefore, in order to do a better prevention measures after resumption of work, it is very necessary to maintain the amount of information and implementation rate of media coverage.
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Betacoronavirus , Medios de Comunicación , Infecciones por Coronavirus/epidemiología , Pandemias , Neumonía Viral/epidemiología , Número Básico de Reproducción/estadística & datos numéricos , COVID-19 , China/epidemiología , Simulación por Computador , Infecciones por Coronavirus/prevención & control , Infecciones por Coronavirus/transmisión , Epidemias/prevención & control , Epidemias/estadística & datos numéricos , Humanos , Conceptos Matemáticos , Modelos Biológicos , Pandemias/prevención & control , Pandemias/estadística & datos numéricos , Neumonía Viral/prevención & control , Neumonía Viral/transmisión , Cuarentena/estadística & datos numéricos , SARS-CoV-2 , Medios de Comunicación SocialesRESUMEN
OBJECTIVE: We aimed to evaluate the incidence, risk factors, and prognosis of bloodstream infections (BSIs) during extracorporeal membrane oxygenation (ECMO) treatment in a Chinese population. METHODS: Patients receiving ECMO treatment from January 2013 to August 2019 were retrospectively studied. The incidence of BSIs was calculated. The clinical characteristics between patients with a BSI (BSI group) and without a BSI (non-BSI group). RESULTS: Among 69 included patients, 19 (27.5%) developed at least one BSI. Gram-negative bacteria (73.7%) were mainly responsible for the BSIs, with Klebsiella pneumoniae (6/19, 31.5%) ranking as the top related pathogen. The BSI group had a greater proportion of methicillin-resistant Staphylococcus aureus (MRSA) prophylactic regimens (52.6% vs. 26.0%, P = 0.036), a higher pre-ECMO Sequential Organ Failure Assessment (SOFA) score (11 vs. 8, P = 0.008), more applications of continuous renal replacement therapy (CRRT) during ECMO (63.1% vs. 36.1%, P = 0.042). Longer ECMO support duration, period of ventilator use before ECMO weaning and hospital stay were observed in the BSI group. The SOFA score (OR: 1.174; 95% CI: 1.039-1.326; P = 0.010) was an independent risk factor for BSIs. CONCLUSION: BSIs during ECMO therapy frequently involve Gram-negative bacteria. Stringent care and monitoring should be provided for patients with high SOFA scores.
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OBJECTIVE: To compare the effect of electroacupuncture (EA) of acupoint group for "reinforcing the kidney and regulating Governor Vessel" and acopoint group for "reinforcing the kidney and lung and regulating Governor Vessel" on lear-ning-memory ability and expression of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) proteins in the hippocampus and prefrontal cortex (PFC) in Alzheimer's disease ï¼ADï¼ rats, so as to explore the efficacy of the two acupoint groups and mechanisms underlying improvement of AD. METHODS: Forty male SD rats were randomly divided into control, sham operation, model, "Baihui" + "Shenshu" (GV20+BL23, for "reinforcing the kidney and regulating Governor Vessel") EA and GV20+BL23+ "Feishu" (BL13, GV20+BL23+BL13, for "reinforcing the kidney and lung and regulating Governor Vessel") EA groups (n=8 rats in each group). The AD model was established by bilateral injection of amyloid ß peptide ï¼Aß25-35ï¼10 µL) into bilateral hippocampus, and rats of the sham operation group received injection of normal saline. After successful establishment of the modelï¼EA (2 Hz, 2 mA) was applied to these acupoints for 15 min, once daily for 10 days. Then, the learning-memory ability was assessed by using Morris water maze tests, and the expression levels of TNF-α and IL-1ß proteins in the PFC and hippocampus tissues were detected by using Western blot. RESULTS: Following modeling, the average escape latency of place navigation test were significantly increased (P<0.05) and the platform crossing times of spatial probe test was significantly decreased in the model group than in the control and sham operation groups (P<0.05). The expression levels of IL-1ß and TNF-α proteins in the PFC and hippocampus were apparently up-regulated in the model group than in the control and the sham operation groups (P<0.000 1, P<0.001, P<0.01). After the intervention, the increase of the average escape latency and expression of IL-1ß and TNF-α in the PFC and hippocampus, and the decrease of space exploration test were revised in both GV20+BL23 EA and GV20+BL23+BL13 EA groups (P<0.05,P<0.01). No significant differences were found between the GV20+BL23 and GV20+BL23+BL13 EA groups in the above mentioned indexes (P>0.05). CONCLUSION: EA of both GV20+BL23 and GV20+BL23+BL13 acupoint can improve learning-memory ability of AD rats, which is associated with their effects in down-regulating the expression of IL-1ß and TNF-α in the PFC and hippocampus to reduce inflammatory reaction. There were no significant differences between the two acupoint groups in the therapeutic effects.
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Puntos de Acupuntura , Enfermedad de Alzheimer , Electroacupuntura , Péptidos beta-Amiloides , Animales , Hipocampo , Interleucina-1beta , Masculino , Corteza Prefrontal , Ratas , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfaRESUMEN
An unprecedented organocatalytic enantioselective [4 + 2] cycloaddition reaction of vinyl quinolines with dienals is achieved with the synergistic activation of CH3SO3H and a chiral aminocatalyst. The power of the process is demonstrated by its high efficiency of the production of new synthetically and biologically valued chiral quinoline architectures in high yields and with excellent enantioselectivities.
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OBJECTIVE: To investigate the effect of electroacupuncture on the P35/P25-cyclin-dependent kinase 5 (CDK5)-Tau pathway in rats with Alzheimer's disease (AD), as well as the mechanism of electroacupuncture in the prevention and treatment of AD. METHODS: Sprague-Dawley rats were randomly divided into control group, sham-operation group, model group, and electroacupuncture treatment group, with 12 rats in each group. A rat model of AD was established by injection of Aß25-35 into the bilateral hippocampus. The rats in the electroacupuncture treatment group were given electroacupuncture at "Baihui" (GV20) and "Shenshu" (BL23) once a day, 15 min each time, for 10 days. Morris water maze was used to evaluate learning and memory abilities, immunohistochemistry was used to measure the distribution and expression of P35/P25, CDK5, and Tau5 in the hippocampus, and Western blot was used to measure the expression of the above mentioned proteins, phosphory-lated Tau(Ser199, Ser202). RESULTS: In the visual platform test, there were no significant differences in escape latency and search path between groups (P>0.05). In the hidden platform test, there were no significant differences in escape latency and search path between the control group and the sham-operation group (P>0.05); the model group had significantly longer escape latency and search path than the control group and the sham-operation group (P<0.05). Compared with the model group, the electroacupuncture treatment group had significantly shorter escape latency and search path (P<0.05). In the spatial exploration test, there was no significant difference in the number of platform crossings between the control group and the sham-operation group (P<0.05). The model group had a significantly lower number of platform crossings than the control group and the sham-operation group (P<0.01, P<0.05). The electroacupuncture treatment group had a significantly higher number of platform crossings than the model group (P<0.05). Compared with the control group and the sham-operation group, the model group had significant increases in the protein expression of P35/P25 and CDK5 (P<0.001), and the electroacupuncture treatment group had significant reductions compared with the model group (P<0.001). There was no significant difference in the protein expression of Tau5 between groups (P>0.05). The model group had significantly higher protein expression of phosphorylated Tau(Ser199, Ser202) in the hippocampus than the control group and the sham-operation group (P<0.01, P<0.05). The electroacupuncture treatment group had significantly lower protein expression of phosphorylated Tau(Ser199ï¼Ser202) than the model group (P<0.05, P<0.01). CONCLUSION: Electroacupuncture may delay the progression of AD by affecting the expression of proteins involved in the P35/P25-CDK5-Tau pathway in the hippocampus of rats.
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Enfermedad de Alzheimer , Electroacupuntura , Animales , Quinasa 5 Dependiente de la Ciclina , Hipocampo , Ratas , Ratas Sprague-DawleyRESUMEN
Spiroalanfurantones A-D (1-4), four eudesmanolide-furan sesquiterpene adducts with an unprecedented pentacyclic 6/6/5/5/5 skeleton, were isolated from the roots of Inula helenium. Their structures were elucidated by spectroscopic data analysis and single-crystal X-ray diffraction analysis. The plausible biosynthetic pathway for 1-4 is presented. Bioassay showed that compounds 1 and 2 significantly inhibited nitric oxide production in lipopolysaccharide-induced RAW264.7 macrophages with IC50 values of 17.3 and 9.5 µM, respectively.
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In this study, a monoglucosyl rebaudioside A product was isolated from the mixture of glucosylated rebaudioside A obtained from the most reported and industrial used cyclodextrin glycosyl transferase, Toruzyme 3.0 L (CGTase, Toruzyme 3.0 L). The molecular structure of the monoglucosyl rebaudioside A was characterized using LC-MS/MS and methylation analysis combined with 1D and 2D NMR, indicating that it is 13-[(2-O-(3-α-O-D-glucopyranosyl)-ß-D-glucopyranosyl-3-O-ß-D-glucopyranosyl-ß-D-glucopyranosyl)oxy] ent-kaur-16-en-19-oic acid ß-D-glucopyranosyl ester (also known as RQ3, which naturally exists in Stevia extract as an isomer of rebaudioside D). This study may help to further understand the reaction mechanism of glucosylation of steviol glycoside assisted by Toruzyme 3.0 L in the aspect of molecule linkage pattern, and also benefit the application of the glucosylated rebaudiosides.
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Diterpenos de Tipo Kaurano/química , Glucosiltransferasas/química , Glicósidos/química , Biocatálisis , Glicosilación , Isomerismo , Estructura Molecular , Espectrometría de Masas en TándemRESUMEN
Organic crystals are generally considered to be brittle, inelastic materials, which pose challenges for application in flexible devices. Inspired by α helical proteins for their key structural role in flexible hair, here, we describe the construction of a spring-like hydrogen bonded network through the self-assembly of a-OH/e-OH cyclohexanol derivatives.
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Research on new supramolecular synthons facilitates the progress of materials design. Herein, the ability of sp2 carbonyl oxygen atoms to act as halogen-bond acceptors was established through cocrystallization. Four sets of carbonyl compounds, including aldehydes, ketones, esters, and amides, were selected as halogen-bond acceptors. In the absence of strong hydrogen bonds, 14 out of 16 combinations of halogen-bond donors and acceptors could form cocrystals, whereby the supramolecular synthon C=Oâ â â X acts as the main interaction. Further, the geometric parameters of the C=Oâ â â X interaction were statistically revealed on the basis of the crystallographic database. The bifurcated interaction mode that has been observed in other halogen-bond synthons rarely occurs in the case of C=Oâ â â X. The robustness of C=Oâ â â X makes its application in crystal engineering possible and opens up new opportunities in designing multicomponent fluorescent materials, as indicated by multicolor emission of cocrystals D through C=Oâ â â X interactions.
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A novel diterpenoid, sarcomililate A (1), possessing a previously undescribed tricyclo[11.3.0.02,16]hexadecane scaffold, along with two new cembranoids, sarcomililatols A and B (2 and 3), and two known related diterpenoids (4 and 5), was isolated from the Hainan soft coral Sarcophyton mililatensis. The complete chemical structure including absolute configuration (AC) of 1 was unambiguously determined by a combination of residual dipolar coupling (RDC)-based NMR analysis, TDDFT-ECD (ECD = electronic circular dichroism) calculation, and Snatzke's method. The AC of 1 was further confirmed by a comparison with 2, whose AC was determined by anomalous X-ray diffraction. A plausible biogenetic relationship of 1-3 was further proposed. All the reported compounds exhibited interesting inhibitory effects on the ConA-induced T lymphocytes and/or lipopolysaccharide (LPS)-induced B lymphocytes proliferation.
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Alcanos/química , Antozoos/química , Diterpenos/química , Hidrocarburos Cíclicos/química , Animales , Cristalografía por Rayos X , Modelos Moleculares , Conformación Molecular , Resonancia Magnética Nuclear BiomolecularRESUMEN
Mitochondrial dysfunction is an early feature of Alzheimer's disease (AD). Accumulated damaged mitochondria, which are associated with impaired mitophagy, contribute to neurodegeneration in AD. We show levels of Disrupted-in-schizophrenia-1 (DISC1), which is genetically associated with psychiatric disorders and AD, decrease in the brains of AD patients and transgenic model mice and in Aß-treated cultured cells. Disrupted-in-schizophrenia-1 contains a canonical LC3-interacting region (LIR) motif (210 FSFI213 ), through which DISC1 directly binds to LC3-I/II. Overexpression of DISC1 enhances mitophagy through its binding to LC3, whereas knocking-down of DISC1 blocks Aß-induced mitophagy. We further observe overexpression of DISC1, but not its mutant (muFSFI) which abolishes the interaction of DISC1 with LC3, rescues Aß-induced mitochondrial dysfunction, loss of spines, suppressed long-term potentiation (LTP). Overexpression of DISC1 via adeno-associated virus (serotype 8, AAV8) in the hippocampus of 8-month-old APP/PS1 transgenic mice for 4 months rescues cognitive deficits, synaptic loss, and Aß plaque accumulation, in a way dependent on the interaction of DISC1 with LC3. These results indicate that DISC1 is a novel mitophagy receptor, which protects synaptic plasticity from Aß accumulation-induced toxicity through promoting mitophagy.
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Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Mitofagia , Proteínas del Tejido Nervioso/metabolismo , Plasticidad Neuronal , Enfermedad de Alzheimer/complicaciones , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Autofagosomas/efectos de los fármacos , Autofagosomas/metabolismo , Autofagosomas/ultraestructura , Encéfalo/metabolismo , Encéfalo/patología , Carbonil Cianuro m-Clorofenil Hidrazona/farmacología , Trastornos del Conocimiento/complicaciones , Trastornos del Conocimiento/fisiopatología , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Células HeLa , Humanos , Masculino , Ratones Transgénicos , Proteínas Asociadas a Microtúbulos/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/ultraestructura , Mitofagia/efectos de los fármacos , Modelos Biológicos , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Plasticidad Neuronal/efectos de los fármacos , Unión Proteica/efectos de los fármacosRESUMEN
Discrimination of active pharmaceutical ingredients (APIs) existing as neutral molecules or salts is essential and complicated. However, the discrimination of pharmaceutical salts by confocal Raman micro-spectroscopy remains relatively poorly understood. In this paper, four new salts of triamterene (Tri) cocrystallized with nicotinic acid (NA), benzoic acid (BA), p-toluenesulfonic acid (TA), or isonicotinic acid (INA) were prepared and characterized comprehensively by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), polarized light microscopy (PLM), and dynamic vapor sorption (DVS). Ionized pteridine is identified by marker peaks in the confocal Raman micro-spectra that are characteristic of C[double bond, length as m-dash]N. The single crystal structures of Tri-NA·H2O and Tri-TA further demonstrate that a proton transfers from the carboxylic group of NA or TA to the pyrimidine N1 atom of Tri and their salts formation take place. The intrinsic dissolution rate (IDR) and apparent equilibrium solubility of these four salts are improved compared to the pure Tri component, especially for Tri-BA. This study provides a valuable insight into pharmaceutical salt discrimination by vibrational spectroscopy and presents that the combination of Tri with an acid can be a possible and promising alternative formulation of Tri.