RESUMO
Single-cell proteomics aims to characterize biological function and heterogeneity at the level of proteins in an unbiased manner. It is currently limited in proteomic depth, throughput, and robustness, which we address here by a streamlined multiplexed workflow using data-independent acquisition (mDIA). We demonstrate automated and complete dimethyl labeling of bulk or single-cell samples, without losing proteomic depth. Lys-N digestion enables five-plex quantification at MS1 and MS2 level. Because the multiplexed channels are quantitatively isolated from each other, mDIA accommodates a reference channel that does not interfere with the target channels. Our algorithm RefQuant takes advantage of this and confidently quantifies twice as many proteins per single cell compared to our previous work (Brunner et al, PMID 35226415), while our workflow currently allows routine analysis of 80 single cells per day. Finally, we combined mDIA with spatial proteomics to increase the throughput of Deep Visual Proteomics seven-fold for microdissection and four-fold for MS analysis. Applying this to primary cutaneous melanoma, we discovered proteomic signatures of cells within distinct tumor microenvironments, showcasing its potential for precision oncology.
Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Proteoma , Proteômica , Medicina de Precisão , Microambiente TumoralRESUMO
OBJECTIVE: To compare the clinical efficiency and safety of emergency extracorporeal shock wave lithotripsy (eESWL) and delayed extracorporeal shock wave lithotripsy (dESWL) in the treatment of ureteral stones. METHODS: Cochrane Library, PubMed, Google Scholar, and Web of Science were searched from January 1, 1992 to September 30, 2022, and all comparative studies involving eESWL and dESWL for ureteral calculi were included. Statistical analysis was performed using Review Manager 5.3 software. Funnel plot was used to evaluated publication bias. RESULTS: A total of 9 articles involving 976 patients diagnosed with ureteral stones were included. The results showed that the stone-free rate (SFR) after four weeks was significantly higher in the eESWL group than in the dESWL group [relative risk (RR) = 1.22, 95% confidence interval (CI): 1.13-1.32, P < 0.01]. In subgroup analysis of different stone locations, proximal ureteral calculi [RR = 1.25, 95% CI: 1.14-1.38, P < 0.01] and mid-to-distal ureteral calculi [RR = 1.18, 95% CI: 1.03-1.34, P < 0.05] all showed a higher SFR in the eESWL group. eESWL significantly shortened the stone-free time(SFT) [mean difference (MD) = -5.75, 95% CI: -9.33 to -2.17, P < 0.01]. In addition, eESWL significantly reduced auxiliary procedures [RR = 0.53, 95% CI: 0.40-0.70, P < 0.01]. No significant difference in complications was found between the two groups [RR = 0.90, 95% CI: 0.69-1.16, P > 0.05]. CONCLUSION: eESWL can significantly improve SFR, shorten SFT, and reduce auxiliary procedures.
Assuntos
Litotripsia , Cálculos Ureterais , Humanos , Cálculos Ureterais/terapia , Litotripsia/métodos , Resultado do TratamentoRESUMO
Inflammation is an important pathological feature of hyperuricemia, which in turn aggravates hyperuricemia. Astaxanthin is a carotenoid with strong antioxidant capacity and possesses many biological activities. This study was aimed to evaluate the effect of astaxanthin (ASX) on hyperuricemia and kidney inflammation in potassium oxonate (PO) and hypoxanthine (HX)-induced hyperuricemic mice. Male ICR mice were administered intragastrically with PO and HX (250 mg/kg, respectively) for 14 days. ASX was given by gavage one hour after PO and HX administration. ASX treatment significantly reversed PO and HX-induced hyperuricemia and kidney inflammation in mice as evidenced by decreased serum levels of uric acid (UA), creatinine (Cr), blood urea nitrogen (BUN), and inflammatory factors (IL-1ß, IL-6, and TNF-α) and increased activities of antioxidant enzymes (CAT, SOD and GSH-Px). Furthermore, ASX administration effectively inhibited the activities of key enzymes related to UA synthesis (xanthine oxidase (XOD) and adenosine deaminase (ADA)) and modulated the protein expressions of NF-κ B p65, p-NF-κ B p65, Iκ Bα, p-Iκ Bα, NLRP3, ASC, Caspase-1, and cleavedCaspase-1 involved in inflammation pathways. Our results suggested that ASX improved hyperuricemia and kidney inflammation induced by PO and HX, probably by reducing UA synthesis and suppressing the NF-κ B and NLRP3 pathways simultaneously.
Assuntos
Hiperuricemia , Animais , Antioxidantes/farmacologia , Hiperuricemia/induzido quimicamente , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Hipoxantina/efeitos adversos , Inflamação/tratamento farmacológico , Inflamação/patologia , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ácido Oxônico , Transdução de Sinais , Fator de Transcrição RelA/metabolismo , Ácido Úrico/metabolismo , Ácido Úrico/farmacologia , Xantina Oxidase/efeitos adversos , Xantina Oxidase/metabolismo , XantofilasRESUMO
BACKGROUND: To compare the postoperative continence and clinical outcomes of Retzius-sparing robot-assisted laparoscopic radical prostatectomy (RS-RALP) with non-RS RALP for patients with prostate cancer. METHODS: We searched PUBMED, EMBASE and the Cochrane Central Register from 1999 to 2019 for studies comparing RS-RALP to non-RS RALP for the treatment of prostate cancer. We used RevMan 5.2 to pool the data. RESULTS: A total of seven studies involving 1620 patients were included in our meta-analysis. No significant difference was found in positive surgical margins (PSM), bilateral nerve-sparing, postoperative hernia, complications, blood loss, or operative time. Postoperative continence was better with RS-RALP compared with non-RS RALP (OR = 1.02, OR: 2.86, 95% CI 1.94-4.20, p < 0.05). CONCLUSIONS: RS-RALP had a better recovery of postoperative continence than non-RS RALP. The perioperative outcomes were comparable for the two methods.
Assuntos
Laparoscopia , Prostatectomia/métodos , Procedimentos Cirúrgicos Robóticos/métodos , Humanos , Masculino , Tratamentos com Preservação do ÓrgãoRESUMO
This study was designed to investigate the effects and underlying mechanisms of Astaxanthin (AST) on high-fructose-induced hyperuricemia (HUA) from the perspectives of the uric acid (UA) synthesis and excretion in rat models. Following six weeks of a 10% fructose diet, the level of serum UA effectively decreased in the AST groups as compared to the model group. The enzymatic activities of xanthine oxidase (XOD) and adenosine deaminase (ADA) were significantly inhibited, and the mRNA expression levels of XOD and ADA significantly decreased after the AST administration. These results suggested that the AST reduced UA synthesis by inhibiting the mRNA expressions and enzyme activities of XOD and ADA, thereby contributing to HUA improvement. On the hand, the relative expressions of the mRNA and protein of kidney reabsorption transport proteins (GLUT9 and URAT1) were significantly down-regulated by AST, while that of the kidney secretion proteins (OAT1, OAT3 and ABCG2) were significantly up-regulated by AST. These results indicated that the AST promoted UA excretion by regulating the urate transport proteins, and thus alleviated HUA. This study suggested that the AST could serve as an effective alternative to traditional medicinal drugs for the prevention of fructose-induced HUA.
Assuntos
Inibidores de Adenosina Desaminase/farmacologia , Adenosina Desaminase/metabolismo , Hiperuricemia/prevenção & controle , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Ácido Úrico/sangue , Xantina Oxidase/antagonistas & inibidores , Adenosina Desaminase/genética , Animais , Biomarcadores/sangue , Biomarcadores/urina , Modelos Animais de Doenças , Frutose , Hiperuricemia/induzido quimicamente , Hiperuricemia/enzimologia , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Ratos Sprague-Dawley , Reabsorção Renal/efeitos dos fármacos , Ácido Úrico/urina , Xantina Oxidase/genética , Xantina Oxidase/metabolismo , Xantofilas/farmacologiaRESUMO
BACKGROUND: To compare the perioperative outcomes and safety of transperitoneal laparoscopic adrenalectomy with those of retroperitoneal laparoscopic adrenalectomy for patients with pheochromocytoma. METHODS: We searched PubMed, EMBASE and the Cochrane Central Register for studies from 1999 to 2019 to assess the perioperative outcomes and safety of transperitoneal laparoscopic adrenalectomy and the retroperitoneal approach for laparoscopic adrenalectomy in patients with pheochromocytoma. After data extraction and quality assessments, we used RevMan 5.2 to pool the data. RESULTS: Four retrospective studies were obtained in our meta-analysis. Patients who underwent retroperitoneal laparoscopic adrenalectomy were associated with shorter operative time (WMD: 34.91, 95% CI: 27.02 to 42.80, I2 = 15%; p < 0.01), less intraoperative blood loss (WMD: 139.32, 95% CI: 125.38 to 153.26, I2 = 0, p < 0.01), and a shorter hospital stay (WMD: 2, 95% CI: 1.18 to 2.82, I2 = 82%, p < 0.01) than patients who underwent transperitoneal laparoscopic adrenalectomy. No significant differences were found in the complication rate (OR: 1.58, 95% CI: 0.58 to 4.33, I2 = 0; p = 0.38) or in the incidence of hemodynamic crisis (OR: 0.74, 95% CI: 0.19 to 2.94, p = 0.67) between the two groups. CONCLUSION: Retroperitoneal laparoscopic adrenalectomy could achieve better perioperative outcomes than the transperitoneal approach for patients with pheochromocytoma.
Assuntos
Neoplasias das Glândulas Suprarrenais/cirurgia , Adrenalectomia/métodos , Laparoscopia/métodos , Feocromocitoma/cirurgia , Perda Sanguínea Cirúrgica , Humanos , Tempo de Internação , Duração da Cirurgia , Espaço Retroperitoneal/cirurgiaRESUMO
10-Hydroxycamptothecin (HCPT) is a DNA inhibitor of topoisomerase I and exerts antitumor activities against various types of cancer. However, reversible conversion from a pharmacologically active lactone form to an inactive carboxylate form of HCPT and poor water solubility hamper its clinical applications. To overcome these shortcomings, we designed a fine self-microemulsifying drug delivery system (SMEDDS) for HCPT to effectively protect HCPT in its active lactone form as well as improving dissolution rates. A formulation of HCPT-SMEDDS that contained ethyl oleate, D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), and polyethylene glycol 400 (PEG400) was optimized by using the central composite design and response surface methodology. Following 1:100 aqueous dilution of the optimized HCPT-SMEDDS, the droplet size of resulting microemulsions was 25.6 ± 0.7 nm, and the zeta potential was - 15.2 ± 0.4 mV. The optimized HCPT-SMEDDS appeared to stabilize the lactone moiety of HCPT with 73.6% being present in the pharmacologically active lactone forms in simulated intestinal fluid, but only 45.7% for free HCPT. Furthermore, the physically stable formulation showed the active lactone form predominated in HCPT-SMEDDS (> 95%) for 6 months under the accelerated storage condition. Meanwhile, the optimized SMEDDS formulation also significantly improved dissolution rates and membrane permeability of the lactone form of HCPT. Therefore, HCPT-SMEDDS involved designing for the ease of manufacture, and provided a potent oral dosage form for preserving its active lactone form as well as enhancing the dissolution rate.
Assuntos
Camptotecina/análogos & derivados , Sistemas de Liberação de Medicamentos/métodos , Estabilidade de Medicamentos , Emulsões/administração & dosagem , Administração Oral , Animais , Disponibilidade Biológica , Camptotecina/administração & dosagem , Camptotecina/química , Masculino , Tamanho da Partícula , SolubilidadeRESUMO
In the past decade, tandem mass spectrometry (MS/MS)-based bottom-up proteomics has become the method of choice for analyzing post-translational modifications (PTMs) in complex mixtures. The key to the identification of the PTM-containing peptides and localization of the PTM-modified residues is to measure the similarities between the theoretical spectra and the experimental ones. An accurate prediction of the theoretical MS/MS spectra of the modified peptides will improve the similarity measurement. Here, we proposed the deep-learning-based pDeep2 model for PTMs. We used the transfer learning technique to train pDeep2, facilitating the training with a limited scale of benchmark PTM data. Using the public synthetic PTM data sets, including the synthetic phosphopeptides and 21 synthetic PTMs from ProteomeTools, we showed that the model trained by transfer learning was accurate (>80% Pearson correlation coefficients were higher than 0.9), and was significantly better than the models trained without transfer learning. We also showed that accurate prediction of the fragment ion intensities of the PTM neutral loss, for example, the phosphoric acid loss (-98 Da) of the phosphopeptide, will improve the discriminating power to distinguish the true phosphorylated residue from its adjacent candidate sites. pDeep2 is available at https://github.com/pFindStudio/pDeep/tree/master/pDeep2 .
RESUMO
Icaritin, a prenylflavonoid derivative from Epimedium Genus, has been reported to exhibit tumor inhibitory effects on many types of tumor cells. Numerous studies have demonstrated that microRNAs (miRs) involve in the biological process of carcinogenesis by controlling expression of their target mRNAs to facilitate tumor growth, invasion, angiogenesis, and immune evasion. miR-124 was reported to involve in the icaritin-induced mitochondrial apoptosis in human carcinoma cells. However, the roles of other miRs in the anti-tumor effects of icaritin and its underlying mechanisms still need to be elucidated. In the present study, realtime-PCR results showed that miR-10a was significantly down-regulated after icaritin treatment in human non-small cell lung cancer cells (A549). Over-expression of miR-10a in A549 cells dramatically abrogated the anti-tumor effects of icaritin on cell proliferation, apoptosis, migration, while suppression of miR-10a partially reproduced the anti-tumor effects of icaritin. Furthermore, we found that the regulation of miR-10a in the anti-tumor effects of icaritin was mediated via the PTEN/AKT/ERK pathway by directly targeting to PTEN. Taken together, miR-10a targets PTEN to mediate the anti-tumor effect of icaritin in A549 cells, which provides a novel insight into the anti-tumor mechanism of icaritin and may provide a new strategy for lung cancer therapy.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Glicoproteínas de Membrana/genética , MicroRNAs , Receptores Imunológicos/genética , Células A549 , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação para Baixo , Flavonoides , Humanos , PTEN Fosfo-Hidrolase , Proteínas Proto-Oncogênicas c-akt , Transdução de SinaisRESUMO
BACKGROUND The aim of this study was to investigate the expression of long non-coding RNAs (lncRNA) cancer susceptibility candidate 2a (CASC2a) in patients with urothelial carcinoma of the bladder (UCB) and its predictive value in the recurrence of UCB after radical cystectomy (RC). MATERIAL AND METHODS Tumor and paired adjacent normal tissues were obtained from 112 patients with UCB who underwent RC in our hospital from March 2010 to March 2012. The expression of CASC2a was evaluated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and fluorescence in situ hybridization (FISH). RESULTS CASC2a was down-regulated in UCB tissues, and was highly negatively correlated with the pT, pN, tumor size, and lymphovascular invasion (LVI). The sensitivities of CASC2a for diagnosing UCB and its recurrence after RC were 89.30% and 81.55%, respectively, and the specificities were 71.43% and 58.21%, respectively. Patients with a high expression of CASC2a had a higher 5-year recurrence-free survival rate than those with low expression of CASC2a. Kaplan-Meier survival analysis demonstrated that the pT, pN, tumor grade, tumor size, concomitant carcinoma in situ (CIS), LVI, soft tissue surgical margin (STSM), and CASC2a expression were related to the recurrence in patients undergoing RC for UCB. Cox proportional hazard model analysis showed that CASC2 expression, pT4, lymph node metastasis, and CIS were independent risk factors. CONCLUSIONS CASC2a was down-regulated in patients with UCB, and was associated with the risk of recurrence among patients undergoing RC, indicating that lncRNAs could act as predictive biomarkers and potential therapeutic targets in bladder cancer, including CASC2a.
Assuntos
Biomarcadores Tumorais/metabolismo , Cistectomia , Predisposição Genética para Doença , Recidiva Local de Neoplasia/genética , RNA Longo não Codificante/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/cirurgia , Urotélio/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Recidiva Local de Neoplasia/patologia , Modelos de Riscos Proporcionais , RNA Longo não Codificante/metabolismo , Curva ROC , Neoplasias da Bexiga Urinária/patologiaRESUMO
In tandem mass spectrometry (MS/MS)-based proteomics, search engines rely on comparison between an experimental MS/MS spectrum and the theoretical spectra of the candidate peptides. Hence, accurate prediction of the theoretical spectra of peptides appears to be particularly important. Here, we present pDeep, a deep neural network-based model for the spectrum prediction of peptides. Using the bidirectional long short-term memory (BiLSTM), pDeep can predict higher-energy collisional dissociation, electron-transfer dissociation, and electron-transfer and higher-energy collision dissociation MS/MS spectra of peptides with >0.9 median Pearson correlation coefficients. Further, we showed that intermediate layer of the neural network could reveal physicochemical properties of amino acids, for example the similarities of fragmentation behaviors between amino acids. We also showed the potential of pDeep to distinguish extremely similar peptides (peptides that contain isobaric amino acids, for example, GG = N, AG = Q, or even I = L), which were very difficult to distinguish using traditional search engines.
Assuntos
Aprendizado Profundo , Peptídeos/química , Espectrometria de Massas em Tandem , Bases de Dados de Proteínas/estatística & dados numéricos , Proteoma/química , Proteômica/métodos , Proteômica/estatística & dados numéricos , Espectrometria de Massas em Tandem/estatística & dados numéricosRESUMO
Cytoplasmic male sterile (CMS) rice has been widely used for hybrid rice seed production in China. However, CMS rice suffers from undesirable flowering habits including scattered floret opening time (FOT), which causes different FOTs among parental rice plants and greatly reduces hybrid rice seed production. Little is known about the mechanism of scattered FOT in CMS rice. Our results demonstrate that scattered FOT in CMS rice Zhenshan 97A (ZS97A) resulted from the lack of a driving force to open florets, which was directly caused by retarded lodicule expansion. Our results indicate that retarded lodicule expansion in ZS97A was caused by reduced water accumulation due to retarded accumulation of osmotic regulation substances (ORSs). Further, the retardation in accumulation of ORSs and water were caused by jasmonic acid (JA) deficiency, resulting from down-regulation of OsAOC expression. Applying JA restored scattered FOT in ZS97A by promoting ORS and water accumulation, and inducing the expansion of the lodicules. Taken together, JA deficiency inhibited lodicule expansion by retarding the accumulation of ORSs and water, leading to scattered FOT in CMS rice ZS97A.
Assuntos
Ciclopentanos/metabolismo , Flores/fisiologia , Oryza/metabolismo , Oxilipinas/metabolismo , Quimera , Ciclopentanos/farmacologia , Flores/genética , Regulação da Expressão Gênica de Plantas , Oryza/efeitos dos fármacos , Oryza/fisiologia , Oxilipinas/farmacologia , Infertilidade das Plantas , Água/metabolismoRESUMO
PURPOSE: To introduce grafting fixed with the periosteum (dumpling technique) as an alternative surgical technique for augmented corticotomy-assisted orthodontics in the lower anterior region and evaluate the preliminary outcomes. MATERIALS AND METHODS: Eleven patients (9 women, 2 men; mean age, 21.4 yr) with a thin alveolus or alveolar defect in the lower anterior region by clinical and radiographic examination underwent an augmented corticotomy using the new dumpling technique. Cone-beam computerized tomography was used to evaluate morphologic changes of the lower anterior ridge before treatment (T0) and 1 week (T1) and 6 months (T2) after the bone-augmentation procedure. Repeated-measures analysis of variance with Bonferroni multiple-comparison test was used to compare variables at each time point. RESULTS: No severe postsurgical complications occurred in any patient. The mean alveolar bone thickness of the labial plate increased from T0 to T1 (P < .001) and decreased from T1 to T2 (P < .001). However, compared with T0, there was still a significant increase in horizontal bone thickness at T2 (P < .05). The vertical alveolar bone level increased from T0 to T1 (P < .001) and was maintained from T1 to T2 (P > .05). No significant differences were found in root length of the lower anterior teeth at these 3 time points (P > .05). CONCLUSIONS: In this preliminary study, the dumpling technique for augmented corticotomy-assisted surgical orthodontics showed alveolar bone augmentation by increasing the vertical alveolar height and the horizontal bone thickness in the labial aspect of the anterior mandibular area. However, long-term follow-up is necessary.
Assuntos
Aumento do Rebordo Alveolar/métodos , Transplante Ósseo/métodos , Mandíbula/cirurgia , Ortodontia Corretiva/métodos , Osteotomia/métodos , Periósteo/cirurgia , Processo Alveolar/diagnóstico por imagem , Autoenxertos/transplante , Substitutos Ósseos/uso terapêutico , Colágeno , Tomografia Computadorizada de Feixe Cônico/métodos , Feminino , Seguimentos , Humanos , Masculino , Mandíbula/diagnóstico por imagem , Membranas Artificiais , Minerais/uso terapêutico , Piezocirurgia/métodos , Técnicas de Sutura , Raiz Dentária/diagnóstico por imagem , Resultado do Tratamento , Adulto JovemRESUMO
Mechanofluorochromic materials, which are dependent on changes in physical molecular packing modes, have attracted considerable interest over the past ten years. In this review, recent progress in the area of pure organic mechanofluorochromism is summarized, and majority of the reported organic mechanofluorochromic systems are discussed, along with their derived structure-property relationships. The existence of a structural relationship between aggregation-induced emission compounds and mechanofluorochromism is recognized based on our recent results, which considered aggregation-induced emission compounds as a well of mechanofluorochromic materials. The established structure-property relationship will guide researchers in identifying and synthesizing more mechanofluorochromic materials.
Assuntos
Corantes Fluorescentes/química , Polímeros/química , Cristalização , Luz , Luminescência , Fenômenos Mecânicos , Modelos MolecularesRESUMO
Organic type-I photosensitizers (PSs) which produce aggressive reactive oxygen species (ROS) with less oxygen-dependent exhibit attractive curative effect for photodynamic therapy (PDT), as they adapt better to hypoxia microenvironment in tumors. However, the reported type-I PSs are limited and its exacted mechanism of oxygen dependence is still unclear. Herein, new selenium-containing type-I PSs of Se6 and Se5 with benzoselenadiazole acceptor has been designed and possessed aggregation-induced emission characteristic. Benefited from double heavy-atom-effect of selenium and bromine, Se6 shows a smaller energy gap (ΔEST ) of 0.03 eV and improves ROS efficiency. Interestingly, type-I radicals of both long-lived superoxide anion (O2 â¢â¾ ) and short-lived hydroxyl (⢠OH) are generated from them upon irradiation. This may provide a switch-hitter of dual-radical with complementary lifetimes for PDT. More importantly, simultaneous processes to produce ⢠OH are revealed, including disproportionation of O2 â¢â¾ and reaction between excited PS and water. Actually, Se6 displays superior in-vitro PDT performance to commercial chlorin e6 (Ce6), under normoxia or hypoxia. After intravenous injection, a significantly in-vivo PDT performance is demonstrated on Se6, where tumor growth inhibition rates of 99% is higher than Ce6. These findings offer new insights about both molecular design and mechanism study of type-I PSs.
Assuntos
Neoplasias , Fotoquimioterapia , Selênio , Humanos , Fármacos Fotossensibilizantes/uso terapêutico , Espécies Reativas de Oxigênio , Superóxidos , Radical Hidroxila , Neoplasias/tratamento farmacológico , Oxigênio , Hipóxia , Microambiente TumoralRESUMO
A novel series of tacrine-caffeic acid hybrids (5a-f) were designed and synthesized by combining caffeic acid (CA) with tacrine. The antioxidant study revealed that all the hybrids have much more antioxidant capacities compared to CA. Among these compounds, 5e showed the highest selectivity in inhibiting acetylcholinesterase (AChE) over butyrylcholinesterase (BuChE). Enzyme kinetic study had suggested that 5e binds to both catalytic (CAS) and peripheral anionic sites (PAS) of AChE. Moreover, compound 5e also inhibited self- or AChE-induced ß-amyloid(1-40) aggregation, as well as had potent neuroprotective effects against H(2)O(2)- and glutamate- induced cell death with low toxicity in HT22 cells.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Ácidos Cafeicos/química , Ácidos Cafeicos/farmacologia , Tacrina/química , Tacrina/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Antioxidantes/síntese química , Antioxidantes/química , Antioxidantes/farmacologia , Butirilcolinesterase/metabolismo , Ácidos Cafeicos/síntese química , Morte Celular/efeitos dos fármacos , Linhagem Celular , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Peróxido de Hidrogênio/metabolismo , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Tacrina/síntese químicaRESUMO
A novel piezochromic fluorescent (PCF) compound with aggregation-induced emission (AIE) effect and morphology-alterable emission property was developed. The amorphous and crystalline aggregates were obtained, and their spectroscopic properties and morphological structures were reversibly and repeatedly exhibited upon pressing (fuming) or annealing. The piezochromic fluorescent nature was generated through crystalline-amorphous phase transformation. It was proposed that AIE compounds existing a twisted propeller-shaped conformation will exhibit PCF activity. The common relationship betweeen AIE and PCF established will guide researchers in identifying and synthesizing more piezochromic fluorescent materials.
Assuntos
Compostos de Anilina/química , Etilenos/química , Fluorescência , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Modelos Moleculares , Estrutura MolecularRESUMO
Machine learning and in particular deep learning (DL) are increasingly important in mass spectrometry (MS)-based proteomics. Recent DL models can predict the retention time, ion mobility and fragment intensities of a peptide just from the amino acid sequence with good accuracy. However, DL is a very rapidly developing field with new neural network architectures frequently appearing, which are challenging to incorporate for proteomics researchers. Here we introduce AlphaPeptDeep, a modular Python framework built on the PyTorch DL library that learns and predicts the properties of peptides ( https://github.com/MannLabs/alphapeptdeep ). It features a model shop that enables non-specialists to create models in just a few lines of code. AlphaPeptDeep represents post-translational modifications in a generic manner, even if only the chemical composition is known. Extensive use of transfer learning obviates the need for large data sets to refine models for particular experimental conditions. The AlphaPeptDeep models for predicting retention time, collisional cross sections and fragment intensities are at least on par with existing tools. Additional sequence-based properties can also be predicted by AlphaPeptDeep, as demonstrated with a HLA peptide prediction model to improve HLA peptide identification for data-independent acquisition ( https://github.com/MannLabs/PeptDeep-HLA ).
Assuntos
Aprendizado Profundo , Proteômica , Proteômica/métodos , Peptídeos/química , Sequência de Aminoácidos , Redes Neurais de ComputaçãoRESUMO
We aimed to investigate the effects of infection on serum concentrations of different antipsychotics in inpatients with respiratory tract infections treated with psychiatric drugs, including risperidone, clozapine, quetiapine, and aripiprazole. All patients underwent therapeutic drug monitoring (TDM) and routine blood tests during infection and noninfection periods. The Wilcoxon signed-rank test was used to analyze intra-individual differences in dose-corrected serum concentrations (C/D) levels in infection and noninfection periods. To study the effects of infection intensity on drug concentrations, white blood cells (WBCs) parameters and C/D levels were analyzed by Spearman's correlation analysis using all samples. The median C/D levels of risperidone (risperidone + 9-OH, n = 36) and clozapine (n = 42) were significantly higher (P < 0.001), whereas the median C/D levels of quetiapine (n = 21) and aripiprazole (n = 13) were slightly significantly higher (P < 0.01) in infection than in noninfection period. A significant positive association between C/D levels and WBC parameters was observed for risperidone, clozapine, and quetiapine. These results indicated reduced clearance of all drugs evaluated, especially clozapine and risperidone, due to infection. Therefore, during infection in patients receiving risperidone, clozapine, quetiapine, or aripiprazole, TDM should be performed to minimize the possible adverse effects associated with elevated drug concentrations.
Assuntos
Antipsicóticos , Infecções Respiratórias , Antipsicóticos/sangue , Antipsicóticos/uso terapêutico , Aripiprazol/sangue , Aripiprazol/uso terapêutico , Clozapina/sangue , Clozapina/uso terapêutico , Humanos , Fumarato de Quetiapina/sangue , Fumarato de Quetiapina/uso terapêutico , Infecções Respiratórias/sangue , Infecções Respiratórias/tratamento farmacológico , Risperidona/sangue , Risperidona/uso terapêuticoRESUMO
We develop a simple hydrothermal method to prepare a novel nitrogen-doped carbon dots (N-CDs) originated from green carbon source Liu-bao tea and ethylene diamine. The N-CDs emits strong and stable blue fluorescence (Em = 440 nm) under the excitation wavelength of 350 nm with a quantum yield of 35%. And it is used as an excellent fluorescent output for the sensitive and visual dual-mode determination of isoniazid. The fluorescence of N-CDs is "turned off" first by manganese dioxide (MnO2) nanosheets due to inner filter effect, MnO2 nanosheets can also oxidize TMB (3,3',5,5'- tetramethylbenzidine) to blue oxTMB. Isoniazid, however, can reduce MnO2 nanosheets to Mn2+, turning on the fluorescence again. The color of the solution fades from blue to colorless because less TMB can be oxidized. Under the optimal conditions, the dual-mode method has a satisfying linear relationship ranging from 2.0 to 120.0 µM with a limit of detection of 0.7 µM (S/N = 3). And it has been applied successfully to colorimetric and fluorescent determination of isoniazid in tablets and clinical plasma samples, with recoveries ranging from 94.0% to 102.4%. The properties of N-CDs and MnO2 nanosheets were thoroughly characterized using TEM, FT-IR, XPS, AFM and fluorescence spectrophotometer, the quenching mechanism was also discussed.