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1.
Rapid Commun Mass Spectrom ; 38(20): e9898, 2024 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-39185580

RESUMEN

RATIONALE: Although Naomaitai capsule (NMC) is widely used in clinical practice and has a good curative effect for cerebral infarction, its material basis and mechanism of action remain unclear. METHODS: In this study, ultra-high-performance liquid chromatography (UHPLC) coupled with quadrupole Orbitrap MS technology was used to analyse the in vivo and in vitro components of NMC, and the Global Natural Products Social Molecular Networking website was used to further analyse the components of NMC. Next, systems biology approaches were employed to investigate the mechanism of action of NMC. Finally, molecular docking technology was used to verify the network pharmacological results. RESULTS: In total, 177 compounds were identified in vitro, including 65 terpenoids, 62 flavonoids, 25 organic acids and 11 quinones. 64 compounds were identified in the blood of mice, and the main active components included ginkgolide C, ginkgolide A, ligustilide, tanshinone IIB, olmelin, emodin and puerarin. The main targets in vivo included TP53, SRC, STAT3, PIK3CA and PIK3R1. CONCLUSIONS: In conclusion, this study has revealed that NMC acts on multiple targets in the body through various active components, exerting synergistic effects in the treatment of CI. Its mechanism of action may involve inhibiting neuronal apoptosis, oxidative stress and inflammatory responses as well as reducing cerebral vascular permeability and promoting cerebral vascular regeneration.


Asunto(s)
Medicamentos Herbarios Chinos , Simulación del Acoplamiento Molecular , Animales , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Ratones , Cromatografía Líquida de Alta Presión/métodos , Masculino , Espectrometría de Masas/métodos , Farmacología en Red , Cápsulas/química
3.
Biomed Chromatogr ; 38(9): e5948, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38981997

RESUMEN

Epimedium is a traditional Chinese medicine with a wide range of clinical applications; however, there have been numerous reports of adverse reactions in recent years. The most common side effect of Epimedium is liver injury. In this study, the liquid chromatography-mass spectrometry (LC-MS) method has been established to study the components of Epimedium and to identify the components absorbed into the blood of rats. Bioinformatics was used to screen out potential toxic components, and the integrating metabolomics method was used to explore the molecular mechanism of Epimedium-induced liver injury. The chemical constituents of Epimedium were identified by LC-MS, and 62 compounds were obtained, including 57 flavonoids, four organic acids and one alkaloid. The toxicity network of "Epimedium-component-target-liver injury" was constructed using bioinformatics research methods, and then the key hepatotoxic component icaritin was identified. Integrating metabolomics was used to investigate the changes in the metabolic profile of L-02 cells with different durations of icaritin administration compared with the control group, and 106 different metabolites were obtained. A total of 14 potential biomarkers significantly associated with cell survival were screened by Pearson correlation analysis combined with the L-02 cell survival rate. Our study preliminarily revealed the mechanism of hepatotoxicity induced by Epimedium.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas , Biología Computacional , Epimedium , Flavonoides , Metabolómica , Ratas Sprague-Dawley , Epimedium/química , Metabolómica/métodos , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Ratas , Flavonoides/química , Flavonoides/farmacología , Masculino , Humanos , Cromatografía Liquida/métodos , Línea Celular , Espectrometría de Masas/métodos , Medicamentos Herbarios Chinos/química , Metaboloma/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos
4.
Rapid Commun Mass Spectrom ; 38(14): e9766, 2024 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-38747108

RESUMEN

RATIONALE: Huahong tablet, a commonly used clinical Chinese patent medicine, shows good efficacy in treating pelvic inflammation and other gynaecological infectious diseases. However, the specific composition of Huahong tablets, which are complex herbal formulations, remains unclear. Therefore, this study aims to identify the active compounds and targets of Huahong tablets and investigate their mechanism of action in pelvic inflammatory diseases. METHODS: We utilised ultrahigh-performance liquid chromatography Q-Exactive-Orbitrap mass spectrometry and the relevant literature to identify the chemical components of Huahong tablets. The GNPS database was employed to further analyse and speculate on the components. Potential molecular targets of the active ingredients were predicted using the SwissTargetPrediction website. Protein-protein interaction analysis was conducted using the STRING database, with visualisation in Cytoscape 3.9.1. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the DAVID database. Additionally, a traditional Chinese medicine-ingredient-target-pathway network was constructed using Cytoscape 3.10.1. Molecular docking validation was carried out to investigate the interaction between core target and specific active ingredient. RESULTS: A total of 66 chemical components were identified, and 41 compounds were selected as potential active components based on the literature and the TCMSP database. Moreover, 38 core targets were identified as key targets in the treatment of pelvic inflammatory diseases with Huahong tablets. GO and KEGG enrichment analysis revealed 986 different biological functions and 167 signalling pathways. CONCLUSION: The active ingredients in Huahong tablets exert therapeutic effects on pelvic inflammatory diseases by acting on multiple targets and utilising different pathways. Molecular docking confirmed the high affinity between the specific active ingredients and disease targets.


Asunto(s)
Medicamentos Herbarios Chinos , Farmacología en Red , Enfermedad Inflamatoria Pélvica , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Cromatografía Líquida de Alta Presión/métodos , Enfermedad Inflamatoria Pélvica/tratamiento farmacológico , Humanos , Espectrometría de Masas/métodos , Femenino , Mapas de Interacción de Proteínas/efectos de los fármacos , Comprimidos/química , Simulación del Acoplamiento Molecular
5.
Bioinform Adv ; 4(1): vbae063, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38736683

RESUMEN

Motivation: Ribonucleoside monophosphates (rNMPs) are the most abundant non-standard nucleotides embedded in genomic DNA. If the presence of rNMP in DNA cannot be controlled, it can lead to genome instability. The actual regulatory functions of rNMPs in DNA remain mainly unknown. Considering the association between rNMP embedment and various diseases and cancer, the phenomenon of rNMP embedment in DNA has become a prominent area of research in recent years. Results: We introduce the rNMPID database, which is the first database revealing rNMP-embedment characteristics, strand bias, and preferred incorporation patterns in the genomic DNA of samples from bacterial to human cells of different genetic backgrounds. The rNMPID database uses datasets generated by different rNMP-mapping techniques. It provides the researchers with a solid foundation to explore the features of rNMP embedded in the genomic DNA of multiple sources, and their association with cellular functions, and, in future, disease. It also significantly benefits researchers in the fields of genetics and genomics who aim to integrate their studies with the rNMP-embedment data. Availability and implementation: rNMPID is freely accessible on the web at https://www.rnmpid.org.

6.
Neurosurgery ; 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38690884

RESUMEN

BACKGROUND AND OBJECTIVES: The role of bypass surgery in intracranial atherosclerotic steno-occlusive diseases (ICADs) remains controversial. We aimed to analyze the surgical outcomes of bypass surgery in patients with the ICADs in a single tertiary institution. METHODS: Among 1018 cases of low-flow bypass surgery between 2003 and 2022, 215 patients with the ICAD refractory to medical treatment were finally enrolled in this study. Clinical and radiological outcomes were retrospectively evaluated, with survival analyses. RESULTS: All strokes, cerebral infarctions, and intracranial hemorrhages occurred in 12.1% (n = 26), 9.8% (n = 21), and 2.3% (n = 5), respectively, during the clinical follow-up of 54.6 ± 47.6 months (range, 0.6-237.8 months). Among all stroke events, 84.6% (n = 22) occurred within 30 postoperative days. The 2-year and 5-year cumulative risks of all strokes were 12.1% each. The mean modified Rankin Scale scores were 1.6 ± 1.1 (range, 0-5) preoperatively and 0.8 ± 1.2 (range, 0-6) at last (P < .01). The patency of direct bypass was 99.1% (n = 213) just before discharge and 96.3% (n = 184 of 191 patients with available tests) at the last angiographic follow-up of 27.0 ± 27.3 months (range, 2.3-97.3 months). All the patients with available data (n = 190) showed hemodynamic improvement on acetazolamide-challenged single-photon emission computed tomography with 99mTc-hexamethylpropyleneamine oxime during the follow-up of 38.6 ± 36.7 months (range, 2.3-158.6 months). CONCLUSION: Low-flow bypass surgery showed acceptable treatment outcomes in the prevention of recurrent stroke.

7.
Cell Death Dis ; 15(4): 267, 2024 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-38622131

RESUMEN

Isochlorate dehydrogenase 1 (IDH1) is an important metabolic enzyme for the production of α-ketoglutarate (α-KG), which has antitumor effects and is considered to have potential antitumor effects. The activation of IDH1 as a pathway for the development of anticancer drugs has not been attempted. We demonstrated that IDH1 can limit glycolysis in hepatocellular carcinoma (HCC) cells to activate the tumor immune microenvironment. In addition, through proteomic microarray analysis, we identified a natural small molecule, scutellarin (Scu), which activates IDH1 and inhibits the growth of HCC cells. By selectively modifying Cys297, Scu promotes IDH1 active dimer formation and increases α-KG production, leading to ubiquitination and degradation of HIF1a. The loss of HIF1a further leads to the inhibition of glycolysis in HCC cells. The activation of IDH1 by Scu can significantly increase the level of α-KG in tumor tissue, downregulate the HIF1a signaling pathway, and activate the tumor immune microenvironment in vivo. This study demonstrated the inhibitory effect of IDH1-α-KG-HIF1a on the growth of HCC cells and evaluated the inhibitory effect of Scu, the first IDH1 small molecule agonist, which provides a reference for cancer immunotherapy involving activated IDH1.


Asunto(s)
Carcinoma Hepatocelular , Glucuronatos , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Proteómica , Apigenina/farmacología , Apigenina/uso terapéutico , Ácidos Cetoglutáricos/metabolismo , Microambiente Tumoral , Isocitrato Deshidrogenasa
8.
J Ovarian Res ; 17(1): 88, 2024 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-38664732

RESUMEN

OBJECTIVES: Ovarian cancer (OC) can occur at different ages and is affected by a variety of factors. In order to evaluate the risk of cardiovascular mortality in patients with ovarian cancer, we included influencing factors including age, histological type, surgical method, chemotherapy, whether distant metastasis, race and developed a nomogram to evaluate the ability to predict occurrence. At present, we have not found any correlation studies on cardiovascular death events in patients with ovarian cancer. This study was designed to provide targeted measures for effective prevention of cardiovascular death in patients with ovarian cancer. METHODS: Kaplan-Meier analysis and multivariable Cox proportional model were performed to evaluate the effectiveness of cardiovascular diseases on overall survival (OS) and ovarian cancer-specific survival (OCSS). We compared multiple groups including clinical, demographic, therapeutic characteristics and histological types. Cox risk regression analysis, Kaplan-Meier survival curves, and propensity score matching were employed for analyzing the data. RESULTS: A total of 88,653 ovarian cancer patients were collected, of which 2,282 (2.57%) patients died due to cardiovascular-related diseases. Age, chemotherapy and whether satisfactory cytoreduction surgery is still the most important factors affecting the prognosis of ovarian cancer patients, while different histological types, diagnosis time, and race also have a certain impact on the prognosis. The newly developed nomogram model showed excellent predictive performance, with a C-index of 0.759 (95%CI: 0.757-0.761) for the group. Elderly patients with ovarian cancer are still a high-risk group for cardiovascular death [HR: 21.07 (95%CI: 5.21-85.30), p < 0.001]. The calibration curve showed good agreement from predicted survival probabilities to actual observations. CONCLUSION: This study found that age, histology, surgery, race, chemotherapy, and tumor metastasis are independent prognostic factors for cardiovascular death in patients with ovarian cancer. The nomogram-based model can accurately predict the OS of ovarian cancer patients. It is expected to inform clinical decision-making and help develop targeted treatment strategies for this population.


Asunto(s)
Enfermedades Cardiovasculares , Neoplasias Ováricas , Humanos , Femenino , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/complicaciones , Neoplasias Ováricas/patología , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/complicaciones , Persona de Mediana Edad , Anciano , Nomogramas , Adulto , Pronóstico , Factores de Riesgo , Estimación de Kaplan-Meier , Modelos de Riesgos Proporcionales , Anciano de 80 o más Años
9.
Food Funct ; 15(10): 5414-5428, 2024 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-38639438

RESUMEN

Pitaya is a well-known fruit widely cultivated in tropical and subtropical tropical regions, and is characterized by its flesh colour into red, white, and yellow pitaya. Red pitaya has dark red flesh and is the preferred choice among consumers due to its superior taste compared to other varieties. Red pitaya has been known to cause diarrhoea, and studies have reported that pitaya does this by drawing moisture into the intestines, resulting in defecation. However, the exact mechanism of action is still unclear. In this study, mass spectrometry was employed to identify small molecular compounds in red pitaya powder, and a loperamide hydrochloride-induced early constipation mouse model was used to assess the efficacy of red pitaya. 16S rDNA and non-targeted metabolomics techniques were used to systematically reveal the regulatory characteristics of the intestinal flora and to identify the intestinal metabolites associated with constipation. The results showed that 44 novel small molecular compounds were identified from red pitaya powder, including a variety of phenolic acids and flavonoids. Pathological results showed that administration of red pitaya powder at a high dose (1000 mg kg-1) significantly ameliorated the abnormal expansion of intestinal goblet cells observed in the early stages of constipation. In addition, early constipation increased metabolites such as serotonin and 5-hydroxytryptophol, which were normalized following the ingestion of red pitaya powder. Furthermore, Erysipelatoclostridium, Parasutterella, and other abnormal gut microbiota associated with early constipation returned to healthy levels after the ingestion of red pitaya powder. Finally, significant correlations were observed between the expression of 33 different serum metabolites and the abundance of eight kinds of intestinal flora. Consequently, red pitaya holds potential as a safe food supplement for the prevention or amelioration of early-stage constipation.


Asunto(s)
Estreñimiento , Microbioma Gastrointestinal , Estreñimiento/tratamiento farmacológico , Estreñimiento/metabolismo , Animales , Ratones , Microbioma Gastrointestinal/efectos de los fármacos , Masculino , Cactaceae/química , Frutas/química , Metaboloma , Modelos Animales de Enfermedad , Metabolómica , Humanos
10.
Sci Rep ; 14(1): 8358, 2024 04 10.
Artículo en Inglés | MEDLINE | ID: mdl-38600292

RESUMEN

The necessity of bilateral bypass in adult moyamoya disease (MMD) remains unclear despite its recommendation for pediatric and hemorrhagic cases. We aimed to investigate the natural course of hemodynamically stable unoperated hemispheres after bypass surgery for symptomatic and hemodynamically unstable hemispheres in adult patients with ischemic MMD. Among 288 patients, the mean age at the first operation of the unstable hemispheres was 40.8 ± 12.2 years. The mean follow-up period was 62.9 ± 46.5 months. 45 patients (15.6%) experienced stroke events in the unoperated hemisphere, consisting of hemorrhagic stroke in 8 (2.8%) and ischemic stroke in 37 (12.8%), including progressive transient ischemic attack in 25 (8.7%) and infarction in 12 (4.2%). Among them, 39 patients (13.5%) underwent bypass surgery. The annual risk of total stroke is 3.0%/patient-year, with 2.5% for ischemic stroke and 0.5% for hemorrhagic stroke. The 5- and 10-year cumulative risks of ischemic stroke were 13.4% and 18.3%, respectively, and those of hemorrhagic stroke were each 3.2%. The natural course of hemodynamically stable hemispheres contralateral to the operated ones appeared fairly good. Additional bypass surgery on the unoperated hemispheres should be considered for symptomatic and hemodynamically unstable hemispheres in adult patients with ischemic MMD during the follow-up.


Asunto(s)
Revascularización Cerebral , Accidente Cerebrovascular Hemorrágico , Accidente Cerebrovascular Isquémico , Enfermedad de Moyamoya , Accidente Cerebrovascular , Adulto , Humanos , Niño , Persona de Mediana Edad , Enfermedad de Moyamoya/cirugía , Resultado del Tratamiento , Estudios Retrospectivos
11.
J Asian Nat Prod Res ; 26(2): 177-188, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38166573

RESUMEN

Two pairs of new dihydrophenanthro[b]furan enantiomers blephebibnols G-H (1-2), one new dihydrophenanthro[b]furan derivative blephebibnol I (3), along with four known analogues (4-7), were isolated from the tubers of Bletilla striata. Their structures including the absolute configurations were determined by the combination of spectroscopic data analysis, ECD and NMR calculations. Compounds 1a, 1b, and 2b showed inhibition of NO production in LPS-stimulated BV-2 cells, with IC50 values ranging from 4.11 to 14.65 µM. Further mechanistic study revealed that 1a suppressed the phosphorylation of p65 subunit to regulate the NF-κB signaling pathway. In addition, some compounds displayed selective cytotoxic activities against HCT-116, HepG2, A549, or HGC27 cancer cell lines with IC50 values ranging from 0.1 to 8.23 µM.


Asunto(s)
Orchidaceae , Transducción de Señal , Estructura Molecular , Espectroscopía de Resonancia Magnética , FN-kappa B , Orchidaceae/química
12.
Nucleic Acids Res ; 52(3): 1207-1225, 2024 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-38117983

RESUMEN

Abundant ribonucleoside-triphosphate (rNTP) incorporation into DNA by DNA polymerases in the form of ribonucleoside monophosphates (rNMPs) is a widespread phenomenon in nature, resulting in DNA-structural change and genome instability. The rNMP distribution, characteristics, hotspots and association with DNA metabolic processes in human mitochondrial DNA (hmtDNA) remain mostly unknown. Here, we utilize the ribose-seq technique to capture embedded rNMPs in hmtDNA of six different cell types. In most cell types, the rNMPs are preferentially embedded on the light strand of hmtDNA with a strong bias towards rCMPs; while in the liver-tissue cells, the rNMPs are predominately found on the heavy strand. We uncover common rNMP hotspots and conserved rNMP-enriched zones across the entire hmtDNA, including in the control region, which links the rNMP presence to the frequent hmtDNA replication-failure events. We show a strong correlation between coding-sequence size and rNMP-embedment frequency per nucleotide on the non-template, light strand in all cell types, supporting the presence of transient RNA-DNA hybrids preceding light-strand replication. Moreover, we detect rNMP-embedment patterns that are only partly conserved across the different cell types and are distinct from those found in yeast mtDNA. The study opens new research directions to understand the biology of hmtDNA and genomic rNMPs.


Asunto(s)
Replicación del ADN , Genoma Mitocondrial , Ribonucleósidos , Humanos , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Ribonucleósidos/metabolismo , Ribonucleótidos/genética , Ribonucleótidos/metabolismo
13.
Cureus ; 15(12): e50351, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38089953

RESUMEN

Background and objectives Cyclophosphamide (CP) is widely used as a chemotherapy drug for the treatment of malignant tumors and autoimmune diseases, but it has strong toxic and side effects and can cause permanent damage to the ovaries, which affects women's quality of life. This study aimed to investigate the anti-premature ovarian failure protective effect of allantoin isolated from Dioscorea opposita Thunb. Methods Firstly, 75 mg/kg CP was injected into rats to establish an in vivo model of premature ovarian failure (POF). The POF rats were divided into the normal control group (NC), premature ovarian failure group (POF), and POF group treated with allantoin (ALL I 140 mg/kg and ALL II 70 mg/kg, daily 21 days). It investigated the estrous cycles, hormone levels, apoptosis rate, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), mitophagy, and protein marker (Bax, Bcl2, LC3B, L-1ß, caspase-1 and NLRP3). Results The results indicated that allantoin alleviated cyclophosphamide-induced premature ovarian failure in female rats, decreased the anoestrum, increased the level of estradiol (E2), and decreased the levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), decreased apoptosis rate, MMP, mitophagy and ROS in ovarian granulosa cells of POF rats, down-regulated L-1ß, caspase-1, LC3B-II/LC3B-I in ovarian tissue, and up-regulated the Bcl2 and NLRP3. Conclusions Our study revealed the ovarian-protective effect of allantoin in CP-induced premature ovarian failure for the first time, the effect was achieved through attenuation of the apoptosis, autophagy, and pyroptosis. The study underlines the potential clinical application of allantoin as a protectant agent for premature ovarian failure.

14.
Int J Mol Sci ; 24(8)2023 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-37108572

RESUMEN

DJ-1 (also known as PARK7) is a multifunctional enzyme in human beings that is highly conserved and that has also been discovered in diverse species (ranging from prokaryotes to eukaryotes). Its complex enzymatic and non-enzymatic activities (such as anti-oxidation, anti-glycation, and protein quality control), as well as its role as a transcriptional coactivator, enable DJ-1 to serve as an essential regulator in multiple cellular processes (e.g., epigenetic regulations) and make it a promising therapeutic target for diverse diseases (especially cancer and Parkinson's disease). Due to its nature as a Swiss army knife enzyme with various functions, DJ-1 has attracted a large amount of research interest, from different perspectives. In this review, we give a brief summary of the recent advances with respect to DJ-1 research in biomedicine and psychology, as well as the progress made in attempts to develop DJ-1 into a druggable target for therapy.


Asunto(s)
Enfermedad de Parkinson , Humanos , Proteína Desglicasa DJ-1/metabolismo , Estrés Oxidativo
15.
Angew Chem Int Ed Engl ; 62(18): e202300658, 2023 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-36883199

RESUMEN

Although two-dimensional (2D) chiral sheet structures are attractive because of their unique chemical and physical properties, single layer 2D chiral network structures with switchable pore interior remain elusive. Here we report spontaneous chirality induction in a single layer 2D network structure formed from the self-assembly of tetrapod azobenzene molecules. The chirality induction arises from multiple sublayers slipped in a preferred direction in which the sublayer consists of unidentical molecular arrangements in the in-plane a and b directions, breaking both the plane of symmetry and inversion symmetry. The protruded azobenzene units in the pore interior can be selectively isomerized upon UV irradiation, resulting in a reversible deformation of the chiral pores while maintaining the 2D frameworks. The chiral network can thus selectively entrap one enantiomer from a racemic solution with near perfect enantioselectivity, and then release it upon UV irradiation.

16.
Angew Chem Int Ed Engl ; 62(2): e202214499, 2023 01 09.
Artículo en Inglés | MEDLINE | ID: mdl-36354214

RESUMEN

Nature connects multiple fuel-driven chemical/enzymatic reaction networks (CRNs/ERNs) via cross-regulation to hierarchically control biofunctions for a tailored adaption in complex sensory landscapes. Herein, we introduce a facile example of communication and cross-regulation among two fuel-driven DNA-based ERNs regulated by a concatenated RNA transcription regulator. ERN1 ("sender") is designed for the fuel-driven promoter formation for T7 RNA polymerase, which activates RNA transcription. The produced RNA can deactivate or activate DNA in ERN2 ("receiver") by toehold-mediated strand displacement, leading to a communication between two ERNs. The RNA from ERN1 can repress or promote the fuel-driven state of ERN2; ERN2 in turn feedbacks to regulate the lifetime of ERN1. Furthermore, the incorporation of RNase H allows for RNA degradation and enables the autonomous recovery of ERN2. We believe that concatenation of multiple CRNs/ERNs provides a basis for the design of more elaborate autonomous regulatory mechanisms in systems chemistry and synthetic biology.


Asunto(s)
ADN , ARN , ADN/metabolismo , Regiones Promotoras Genéticas
17.
BMC Cancer ; 22(1): 1221, 2022 Nov 28.
Artículo en Inglés | MEDLINE | ID: mdl-36437460

RESUMEN

PURPOSE: Molecular subgrouping of medulloblastoma has become important due to its impact on risk group stratification. Immunohistochemistry (IHC) has been widely used but it has innate limitations. The NanoString assay has been proposed as an alternative method. This study aims to present the characteristics of medulloblastoma subgrouped by the NanoString assay and to compare the subgrouping results with the IHC method. METHODS: Pediatric patients with histological diagnosis of medulloblastoma who underwent surgery from 2007 to 2021 were included. Clinical characteristics, pathological findings were reviewed. Molecular subgrouping was performed by IHC and by NanoString nCounter Elements TagSets assay. Test for concordance between two methods was made. RESULTS: Among a total of 101 patients analyzed, subgrouping using the NanoString assay resulted in 14 (13.8%) WNT, 20 (19.8%) SHH, 18 (17.8%) Group 3, and 39 (38.6%) Group 4 subgroup cases. Survival analysis revealed the following from best to worse prognosis: WNT, Group 4, SHH, and Group 3. In SHH subgroup the large cell/anaplastic histology was present in 30% of cases. Seventy-one cases were analyzed for concordance between NanoString and IHC. Cohen's kappa value indicated moderate agreement but identification of Groups 3 and 4 with IHC using NPR3 and KCNA1 markers exhibited poor results. CONCLUSIONS: The NanoString assay of Korean medulloblastoma patients revealed a more aggressive clinical course in the SHH subgroup which may be explained by a higher proportion of large cell/anaplastic histology being present in this subgroup. IHC did not distinguish Group 3 or 4 accurately. The NanoString assay may represent a good alternative method for practical use in the clinical field.


Asunto(s)
Neoplasias Cerebelosas , Meduloblastoma , Humanos , Niño , Meduloblastoma/diagnóstico , Meduloblastoma/genética , Neoplasias Cerebelosas/diagnóstico , Neoplasias Cerebelosas/genética , Inmunohistoquímica , Pronóstico , Análisis de Supervivencia
18.
Angew Chem Int Ed Engl ; 61(10): e202113477, 2022 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-35026052

RESUMEN

The development of synthetic non-equilibrium systems opens doors for man-made life-like materials. Yet, creating distinct transient functions from artificial fuel-driven structures remains a challenge. Building on our ATP-driven dynamic covalent DNA assembly in an enzymatic reaction network of concurrent ATP-powered ligation and restriction, we introduce ATP-fueled transient organization of functional subunits for various functions. The programmability of the ligation/restriction site allows to precisely organize multiple sticky-end-encoded oligo segments into double-stranded (ds) DNA complexes. We demonstrate principles of ATP-driven organization into sequence-defined oligomers by sensing barcode-embedded targets with different defects. Furthermore, ATP-fueled DNAzymes for substrate cleavage are achieved by transiently ligating two DNAzyme subunits into a dsDNA complex, rendering ATP-fueled transient catalytic function.

19.
Acc Chem Res ; 54(14): 2959-2968, 2021 07 20.
Artículo en Inglés | MEDLINE | ID: mdl-34213905

RESUMEN

Nanopore structures in nature play a crucial role in performing many sophisticated functions such as signal transduction, mass transport, ion channel, and enzyme reaction. Inspired by pore-forming proteins, considerable effort has been made to design self-assembling molecules that are able to form nanostructures with internal pores in aqueous media. These nanostructures offer ample opportunity for applications because their internal pores are able to perform a number of unique functions required for a confined nanospace. However, unlike nanopore assembly in nature, the synthetic nanopore structures are mostly based on a fixed pore that impedes performing adaptable regulation of properties to environmental change. This limitation can be overcome by integration of hydrophilic oligo(ethylene oxide) dendrons into aromatic building blocks for nanopore self-assembly, because the dendritic chains undergo large conformational changes triggered by environmental change. The transition of the oligoether chains triggers the aromatic nanopore assembly to undergo reversible pore deformation through closing, squeezing, and shape change without structural collapse. These switching properties allow the aromatic nanopore structures to perform adaptable, complex functions which are difficult to achieve using a fixed pore assembly.In this Account, we summarize our recent progress in the development of switchable nanopore structures by self-assembly of rigid aromatic amphiphiles grafted by hydrophilic oligo(ethylene oxide) dendrons in aqueous media. We show that combining oligoether chains into aromatic segments generates switchable aromatic nanopore structures in aqueous media such as hollow tubules, toroidal structures, and 2D porous sheets depending on the shape of the aromatic building block. Next, we discuss the chemical principle behind the switching motion of the aromatic nanopore structures triggered by external stimuli. We show that the internal pores of the aromatic nanostructures are able to undergo reversible switching between open-closed or expanded-contracted states triggered by external stimuli such as temperature, pH, and salts. In the case of toroidal structures, closed ring-like aromatic frameworks can be spirally open triggered by heat treatment, which spontaneously initiate helical polymerization. Additionally, we discuss switchable functions carried out by the aromatic nanopores such as driving helicity inversion of DNA, consecutive enzymatic action, reversible actuation of lipid vesicles, and pumping of captured guests out of internal pores. By understanding the underlying chemical principle required for dynamic mechanical motion, aromatic assembly can be exploited more broadly to create emergent nanopore structures with functions as complex as those of biological systems.

20.
Mini Rev Med Chem ; 21(2): 150-170, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-32727325

RESUMEN

In recent decades, much attention has been given to cyclopropyl scaffolds, which commonly exist in natural products and synthetic organic molecules. Clinical drug molecules with cyclopropyl rings are an area of focus in therapeutic research due to their interesting chemical properties and unique pharmacology activity. These molecular drugs against different targets are applicable in some therapeutic treatment fields including cancer, infection, respiratory disorder, cardiovascular and cerebrovascular diseases, dysphrenia, nervous system disorders, endocrine and metabolic disorders, skin disease, digestive disorders, urogenital diseases, otolaryngological and dental diseases, and eye diseases. This review is a guide for pharmacologists who are in search of valid preclinical/clinical drug compounds where the progress, from 1961 to the present day, of approved marketed drugs containing cyclopropyl scaffold is examined.


Asunto(s)
Ciclopropanos/química , Antibacterianos/química , Antibacterianos/farmacología , Ciprofloxacina/química , Ciprofloxacina/farmacología , Ciclopropanos/metabolismo , Evaluación Preclínica de Medicamentos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Hepacivirus/efectos de los fármacos , Humanos , Oligopéptidos/química , Oligopéptidos/metabolismo , Oligopéptidos/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/metabolismo
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