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1.
Bioact Mater ; 19: 139-154, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35475028

RESUMO

Ligamentum flavum (LF) hypertrophy (LFH) has been recognised as one of the key contributors to lumbar spinal stenosis. Currently, no effective methods are available to ameliorate this hypertrophy. In this study, human umbilical cord mesenchymal stromal cell-derived extracellular vesicles (hUCMSC-EVs) were introduced for the first time as promising vehicles for drug delivery to treat LFH. The downregulation of miR-146a-5p and miR-221-3p expressions in human LF tissues negatively correlated with increased LF thickness. The hUCMSC-EVs enriched with these two miRNAs significantly suppressed LFH in vivo and notably ameliorated the progression of transforming growth factor ß1(TGF-ß1)-induced fibrosis in vitro after delivering these two miRNAs to mouse LF cells. The results further demonstrated that miR-146a-5p and miR-221-3p directly bonded to the 3'-UTR regions of SMAD4 mRNA, thereby inhibiting the TGF-ß/SMAD4 signalling pathway. Therefore, this translational study determined the effectiveness of a hUCMSC-EVs-based approach for the treatment of LFH and revealed the critical target of miR-146a-5p and miR-221-3p. Our findings provide new insights into promising therapeutics using a hUCMSC-EVs-based delivery system for patients with lumbar spinal stenosis.

2.
Front Genet ; 13: 854097, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35571014

RESUMO

Radiotherapy resistance is an important cause of treatment failure in esophageal squamous cell carcinoma (ESCC). Circular RNAs have attracted a lot of attention in cancer research, but their role in ESCC radiosensitivity has not been elucidated yet. Here, we aimed to evaluated the functional impacts of circ-0007022 on ESCC radiosensitivity. In this study, a stable radiotherapy-resistant cell line was established and verified by a series of functional experiments. Subsequently, high-throughput sequencing revealed that circ-0007022 was significantly overexpressed in the radiotherapy-resistant cell line and this conclusion was verified in ESCC patients' tumor tissues by real-time quantitative PCR. Moreover, loss-of-function and overexpression experiments in vitro and in vivo revealed that, after irradiation, the abilities of proliferation and migration in circ-0007022-overexpressing stable transgenic strain were significantly higher than that in circ-0007022-knockdown stable transgenic strain. Additionally, RNA Immunoprecipitation, RNA pull-down, luciferase reporter assays, and fluorescence in situ hybridization experiments demonstrated the mechanism of how circ-0007022 could sponge miR-338-3p and upregulate downstream target of miR-338-3p, neuropilin-1 (NRP1). Moreover, NRP1 led to poor prognosis for ESCC patients receiving radiotherapy, and NRP1 knock-down enhanced radiosensitivity of ESCC cells. Furthermore, circ-0007022 overexpression activated Epithelial-to-mesenchymal transition and PI3K/Akt pathway, and NRP1 knock-down could reversed this phenomenon. Finally, Akt Inhibitor reversed circ-0007022s role in radiotherapy in ESCC cells. Taken together, the circ-0007022/miR-338-3p/NRP1 axis enhances the radiation resistance of ESCC cells via regulating EMT and PI3K/Akt pathway. The new circRNA circ-0007022 is thus expected to be a therapeutic target for ESCC patients.

3.
Sci Rep ; 12(1): 7566, 2022 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-35534667

RESUMO

The COVID-19 pandemic makes protective visors important for protecting people in close contacts. However, the production of visors cannot be increased greatly in a short time, especially at the beginning of the pandemic. The 3D printing community contributed largely in fabricating the visor frames using the rapid and adaptive manufacturing ability. While there are many open source designs of face visors for affordable 3D printers, all these designs fabricate mono-sized frames without considering diverse users' dimensions. Here, a new method of visor post-processing technology enabled by closed loop controlled 4D printing is proposed. The new process can further deform the printed visor to any customized size for a more comfortable user experience. FEM analysis of the customized visor also shows consistent wearing experience in different circumstances compared with the old visor design. The fabrication precision and time cost of the method is studied experimentally. A case study regarding the reducing, reusing and recycling (3R) of customized visors in classrooms is proposed to enable the customized visors manufactured in a more sustainable way.


Assuntos
COVID-19 , Pandemias , COVID-19/prevenção & controle , Humanos , Pandemias/prevenção & controle , Impressão Tridimensional
4.
Cancers (Basel) ; 14(9)2022 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-35565231

RESUMO

Breast cancer (BC) is a highly heterogeneous disease and presents a great threat to female health worldwide. Chemotherapy is one of the predominant strategies for the treatment of BC; however, multidrug resistance (MDR) has seriously affected or hindered the effect of chemotherapy. Recently, a growing number of studies have indicated that lncRNAs play vital and varied roles in BC chemoresistance, including apoptosis, autophagy, DNA repair, cell cycle, drug efflux, epithelial-mesenchymal transition (EMT), epigenetic modification and the tumor microenvironment (TME). Although thousands of lncRNAs have been implicated in the chemoresistance of BC, a systematic review of their regulatory mechanisms remains to be performed. In this review, we systematically summarized the mechanisms of MDR and the functions of lncRNAs mediated in the chemoresistance of BC from the latest literature. These findings significantly enhance the current understanding of lncRNAs and suggest that they may be promising prognostic biomarkers for BC patients receiving chemotherapy, as well as therapeutic targets to prevent or reverse chemoresistance.

5.
Soft Matter ; 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35506885

RESUMO

Three-dimensional (3D) self-assembled quantum dot (QD) aerogels have attracted attention due to the combined properties of both QDs and porous materials. However, the difficulty and complexity of structural composition control limit the practical application of 3D self-assembled QDs. Hence, convenient, available and multifunction QD aerogels need to be explored to promote broader practical applications. Herein, we propose a universal and facile self-assembly method of copper indium selenium (CISe) QD aerogels based on coordination interaction between Zn2+ and carboxyl. Both experiments and Monte Carlo simulations indicate that QDs are aggregated into oligomers by Zn2+, and then the oligomers are gradually interconnected to each other to form a 3D network as the concentration of Zn2+ increases. Moreover, Zn2+-induced 3D self-assembled aerogel could be depolymerized by EDTA reversibly. In combination with CISe QDs, Zn-CISe aerogel has been successfully applied in green pollution-free environment-friendly anti-counterfeiting and encryption systems.

6.
Trials ; 23(1): 367, 2022 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-35505437

RESUMO

BACKGROUND: Despite the recent findings presenting the benefits of measurement-based care (MBC) compared to treatment as usual (TAU), MBC is still not the standard of care used in clinical settings. The aim of the present study was to achieve the optimization of MBC (OMBC) for major depressive disorder (MDD) by establishing a comprehensive MBC framework based on all-round, continuous assessment for depression. METHODS: The target recruitment size is 900 patients, and the study is conducted at 8 centers in China. The patients are randomly assigned to the MBC and TAU groups at a 2:1 ratio. The subjects are scheduled to remain for 12 weeks in the acute phase and for 12 months in the maintenance phase. The primary outcomes are the complete remission rate and the proportion of patients with a 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR 16) total score ≤ 5 of the MBC and TAU groups at the acute phase, and the recurrence rate/time between the two groups is measured at the maintenance phase. Secondary outcomes included the changes in the parameters QIDS-SR 16, Patient Health Questionnaire-9 (PHQ-9), and 17-item Hamilton Rating Scale for Depression (HAMD-17) from baseline and the response rate between the two groups at the acute phase as well as the comparison of recurrence rate between the two groups at the end of the study. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-OOC-17012566 . The registration was performed retrospectively on 4 September 2017.


Assuntos
Transtorno Depressivo Maior , Depressão/diagnóstico , Depressão/terapia , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/terapia , Humanos , Estudos Multicêntricos como Assunto , Escalas de Graduação Psiquiátrica , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Autorrelato
7.
Exp Neurol ; : 114103, 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35525307

RESUMO

Depression, a common and important cause of morbidity and mortality worldwide, is commonly treated with antidepressants, electric shock and psychotherapy. Recently, increasing evidence has shown that exercise can effectively alleviate depression. To determine the difference in efficacy between exercise and the classic antidepressant fluoxetine in treating depression, we established four groups: the Control, chronic unpredictable stress (CUS/STD), running (CUS/RUN) and fluoxetine (CUS/FLX) groups. The sucrose preference test (SPT), the forced swimming test (FST), the tail suspension test (TST), immunohistochemistry, immunofluorescence and stereological analyses were used to clarify the difference in therapeutic efficacy and mechanism between exercise and fluoxetine in the treatment of depression. In the seventh week, the sucrose preference of the CUS/RUN group was significantly higher than that of the CUS/STD group, while the sucrose preference of the CUS/FLX group did not differ from that of the CUS/STD group until the eighth week. Exercise reduced the immobility time in the FST and TST, while fluoxetine only reduced immobility time in the TST. Hippocampal structure analysis showed that the CUS/STD group exhibited an increase in immature neurons and a decrease in mature neurons. Exercise reduced the number of immature neurons and increased the number of mature neurons, but no increase in the number of mature neurons was observed after fluoxetine treatment. In addition, both running and fluoxetine reversed the decrease in the number of MAP2+ dendrites in depressed mice. Exercise increased the number of spinophilin-positive (Sp+) dendritic spines in the hippocampal CA1, CA3, and dentate gyrus (DG) regions, whereas fluoxetine only increased the number of SP+ spines in the DG. In summary, exercise promoted newborn neuron maturation in the DG and regulated neuronal plasticity in three hippocampal subregions, which might explain why running exerts earlier and more comprehensive antidepressant effects than fluoxetine.

8.
Artigo em Inglês | MEDLINE | ID: mdl-35525680

RESUMO

BACKGROUND AND AIMS: Till now, the prognostic value of lipoprotein(a) [Lp(a)] in patients with coronary artery disease (CAD) who underwent percutaneous coronary intervention (PCI) remains controversial. We therefore conducted this study to evaluate the effect of Lp(a) levels on clinical outcomes in this population. METHODS AND RESULTS: A total of 10,059 CAD patients who underwent PCI were prospectively enrolled in this cohort study, of which 6564 patients had Lp(a) ≤30 mg/dl and 3495 patients had Lp(a) > 30 mg/dl. The primary endpoint was major adverse cardiovascular and cerebrovascular event (MACCE), defined as a composite of all-cause death, myocardial infarction, stroke or unplanned revascularization. Multivariate Cox regression analysis and propensity-score matching analysis were performed. After propensity-score matching, 3449 pairs of patients were identified, and post-matching absolute standardized differences were <10% for all the covariates. At 2.4 years, the risk of MACCE was significantly higher in patients with elevated Lp(a) levels than those with normal Lp(a) levels in both overall population (13.0% vs. 11.4%; adjusted hazard ratio [HR] 1.142, 95% confidence interval [CI] 1.009-1.293; P = 0.040) and propensity-matched cohorts (13.0% vs. 11.2%; HR 1.167, 95%CI 1.019-1.337; P = 0.026). Of note, the predictive value of Lp(a) levels on MACCE tended to be more evident in individuals >65 years or those with left main and/or three-vessel disease. On the contrary, elevated Lp(a) levels had almost no effect on clinical outcomes in patients ≤65 years (P interaction = 0.021) as well as those who had one- or two-vessel coronary artery disease (P interaction = 0.086). CONCLUSION: In CAD patients who underwent PCI, elevated Lp(a) levels were positively related to higher risk of MACCE at 2.4-year follow-up, especially in patients >65 years and those with left main and/or three-vessel disease. REGISTRATION NUMBER: not applicable.

9.
Clin Transl Oncol ; 2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-35364771

RESUMO

PURPOSE: Esophageal squamous cell carcinoma is associated with high morbidity and mortality rate for which radiotherapy is the main treatment modality. Niraparib, a Poly (ADP-ribose) polymerase 1 inhibitors (PARPi) was previously reported to confer radiosensitivity in different malignancies including non-small cell lung cancer. In this study, we assessed the in vivo ability of niraparib in conferring radiosensitivity to esophageal squamous cell carcinoma cells. MATERIALS AND METHODS: In this study, KYSE-30 and KYSE-150 cell lines were selected as in vivo esophageal squamous cell carcinoma models. The experimental groups were: niraparib tosylate alone, radiotherapy alone, control (no intervention), and combination therapy (radiotherapy + niraparib tosylate). Cell cytotoxicity assay, colony formation assay, flow cytometry, immunofluorescence, Western blotting, immunohistochemistry, lentivirus transfection analysis, and xenograft models were used for confirming radiosensitizing ability of niraparib and to investigate the possible cellular mechanism involved in radiosensitization. RESULTS: The colony formation efficiency of the combination group was significantly much lower than that of the single radiation group (P < 0.01). Cell cytotoxicity assay demonstrated a significant reduction in proliferation of irradiated cells after treatment with niraparib tosylate compared to niraparib tosylate alone (P < 0.01). Cell apoptosis significantly increased in the combination group compared to either niraparib tosylate or radiotherapy alone (P < 0.01). Rate of tumor suppression rate was significantly high in the combined treatment group (P < 0.01) but, significantly decreased in nude mice. Western blot and lentivirus infection model suggested overexpression of FANCG genes to confer radiosensitivity. CONCLUSION: These results suggest that the synergistic effect of niraparib tosylate and radiation may be related to the down-regulation of FANCG.

10.
RSC Adv ; 12(10): 5919-5927, 2022 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-35424560

RESUMO

I2/TBHP-promoted, one-pot, multi pathway synthesis of imidazopyridines and thiazoles has been achieved through readily available ethylarenes, ethylenearenes and ethynearenes. I2/TBHP as an initiator and oxidant is used to realize the C-H functionalization of this domino reaction. Simple and available starting materials, wide range of functional group tolerance, high potential for drug activity of the products and application in production are the advantageous features of this method.

11.
Adv Mater ; : e2201422, 2022 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-35429018

RESUMO

Cancers heavily threaten human life, therefore, the high-accuracy diagnosis is vital to protect human beings from the suffer of cancers. While the biopsy and imaging methods have been widely used as current technologies for cancer diagnosis, new detection platform by metabolic analysis is expecting due to the significant advantages of fast, simple, and cost-effective with low body-intolerance. However, the signal of molecule biomarkers is too weak to acquire high-accuracy diagnosis. Herein, we developed precisely engineered metal-organic frameworks (MOFs) for laser desorption/ionization mass spectrometry (LDI MS), allowing favourable charge transfer within molecule-substrate interface and mitigated thermal dissipation by adjusting the phonon scattering with metal nodes. Consequently, we achieved a surprising signal enhancement of ∼10,000-fold, resulting in diagnosis of three major cancers (liver/lung/kidney cancer) with area-under-the-curve (AUC) of 0.908-0.964 and accuracy of 83.2%-90.6%, which promises a universal detection tool for large-scale clinical diagnosis of human cancers. This article is protected by copyright. All rights reserved.

12.
Food Funct ; 13(9): 5189-5201, 2022 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-35438091

RESUMO

Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease and threatens human health worldwide. As shown in our previous study, co-supplementation with phytosterol ester (PSE) (3.3 g day-1) and n-3 polyunsaturated fatty acids (PUFAs) (450 mg eicosapentaenoic acid (EPA) + 1500 mg docosahexaenoic acid (DHA) per day) was more effective at ameliorating hepatic steatosis than treatment with PSE or n-3 PUFAs alone. In the present study, we further investigated the changes in the serum metabolic profiles of subjects with NAFLD in response to n-3 PUFAs and PSE. Thirty-one differentially altered serum metabolites were annotated using the nontargeted ultra-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UPLC-Q-TOF-MSE) analysis technique. Multivariable statistical and clustering analyses showed that co-supplementation of n-3 PUFAs and PSE was more effective at improving metabolic disorders in patients with NAFLD than treatment with n-3 PUFAs or PSE alone. The regulated metabolic pathways included metabolism of retinol, linoleic acid, arachidonic acid, glycerophospholipid, sphingolipid, and steroid hormone biosynthesis. Overall, the co-supplementation of n-3 PUFAs and PSE significantly increased the serum levels of PUFA-containing phosphatidylcholine (PC), lysophosphatidylcholine (LysoPC), perillyl alcohol and retinyl ester in patients with NAFLD after 12 weeks of intervention, and the levels of PC (14:0/20:5, 15:0/20:5), LysoPC (20:5, 22:6) and retinyl ester correlated negatively with the degree of hepatic steatosis. The regulatory effect of co-supplementation of n-3 PUFAs and PSE on metabolomic profiles may explain their potential role in alleviating hepatic steatosis in patients with NAFLD.


Assuntos
Ácidos Graxos Ômega-3 , Hepatopatia Gordurosa não Alcoólica , Fitosteróis , Ácidos Docosa-Hexaenoicos , Ácido Eicosapentaenoico , Humanos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ésteres de Retinil
13.
Biosens Bioelectron ; 210: 114254, 2022 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-35462295

RESUMO

On-site screening of diabetes and precise diagnosis of diabetic complications may provide a conduit for early intervention and disease burden reduction. However, stratified metabolic analysis needs designed materials for colorimetric detection of targeted biomarkers and direct metabolic fingerprinting of the native blood. Here, an advanced dual-modal nanoplatform is constructed based on PdPtAu alloys, which serve both as the nanoenzymes in colorimetric sensing for targeted metabolite quantitation and as matrix in laser desorption/ionization mass spectrometry for untargeted metabolic fingerprinting. The platform achieved rapid glucose quantitation toward point-of-care testing of 27 participants and identified diabetic retinopathy from diabetic population with a sensitivity and specificity of 84.6%. We further assessed the generalizability of the nanoplatform for real-case applications, through the captured digital images and computing resources equipped in smartphones. The results advance the design of material-based platforms for stratified metabolic analysis and display promise to fit in the current hierarchical medical system in practice.

15.
Small Methods ; 6(5): e2200264, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35388987

RESUMO

Glaucoma is a common optic neuropathy disease affecting over 76 million people. Both timely diagnosis and progression monitoring are critical but challenging. Conventional characterization of glaucoma needs a combination of methods, calling for tedious procedures and experienced doctors. Herein, a platform through machine learning of tear metabolic fingerprinting (TMF) using nanoparticle enhanced laser desorption-ionization mass spectrometry is built. Direct TMF is obtained noninvasively, with fast speed and high reproducibility, using trace tear samples (down to 10 nL). Consequently, glaucoma patients are screened against healthy controls with the area under the curve (AUC) of 0.866, through machine learning of TMF. Further, primary open-angle glaucoma (POAG) is differentiated from primary angle-closure glaucoma (PACG) and an early-stage POAG is identified. Finally, a biomarker panel of six metabolites for glaucoma characterization (including screening, subtyping, and early diagnosis) with AUC of 0.827-0.891 is constructed, showing related metabolic pathways. The work will provide insights into eye diseases not limited to glaucoma.

16.
J Am Heart Assoc ; 11(9): e023578, 2022 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-35475627

RESUMO

Background Lp(a) (lipoprotein[a]) plays an important role in predicting cardiovascular events in patients with coronary artery disease through its proatherogenic and prothrombotic effects. We hypothesized that prolonged dual antiplatelet therapy (DAPT) might be beneficial for patients undergoing percutaneous coronary intervention who had elevated Lp(a) levels. This study aimed to evaluate the effect of Lp(a) on the efficacy and safety of prolonged DAPT versus shortened DAPT in stable patients with coronary artery disease who were treated with a drug-eluting stent. Methods and Results We selected 3201 stable patients with CAD from the prospective Fuwai Percutaneous Coronary Intervention Registry, of which 2124 patients had Lp(a) ≤30 mg/dL, and 1077 patients had Lp(a) >30 mg/dL. Patients were divided into 4 groups according to Lp(a) levels and the duration of DAPT therapy (≤1 year versus >1 year). The primary end point was major adverse cardiovascular and cerebrovascular event, defined as a composite of all-cause death, myocardial infarction, or stroke. The median follow-up time was 2.5 years. Among patients with elevated Lp(a) levels, DAPT >1 year presented lower risk of major adverse cardiovascular and cerebrovascular event and definite/probable stent thrombosis compared with DAPT ≤1 year. In contrast, in patients with normal Lp(a) levels, the risks of major adverse cardiovascular and cerebrovascular event and definite/probable stent thrombosis were not significantly different between the DAPT >1 year and DAPT ≤1 year groups. Prolonged DAPT had 2.4-times higher risk of clinically relevant bleeding than shortened DAPT in patients with normal Lp(a) levels, although without statistical difference. Conclusions In stable patients with coronary artery disease, who underwent percutaneous coronary intervention with a drug-eluting stent, prolonged DAPT was associated with reduced risk of cardiovascular events among those with elevated Lp(a) levels, whereas it did not show statistically significant evidence of benefit for reducing ischemic events and tended to increase clinically relevant bleeding among those with normal Lp(a) levels.


Assuntos
Doença da Artéria Coronariana , Stents Farmacológicos , Intervenção Coronária Percutânea , Doença da Artéria Coronariana/terapia , Quimioterapia Combinada , Humanos , Lipoproteína(a) , Intervenção Coronária Percutânea/efeitos adversos , Inibidores da Agregação Plaquetária/efeitos adversos , Estudos Prospectivos , Resultado do Tratamento
17.
Int J Artif Organs ; 45(5): 523-532, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35416082

RESUMO

BACKGROUND: Acute liver failure (ALF), which can potentially be treated with an artificial liver, is a fatal condition. The purpose of this study was to evaluate the safety and effectiveness of a novel hybrid bioartificial liver system (NHBLS) using simulated liver failure serum in vitro. METHODS: The bioreactor in experimental group was cultivated with primary porcine hepatocytes, whereas in control group was not. Next, the simulated liver failure serum was treated using the NHBLS for 10 h. Changes in albumin (ALB), total bilirubin (TBIL), ammonia (Amm), total bile acid (TBA), creatinine (Cr), and blood urea nitrogen (BUN) were measured before treatment (0 h) and every 2 h during treatment. In addition, changes in NHBLS pressures, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lidocaine metabolism were also recorded. RESULTS: The NHBLS worked steadily without unexpected occurrences during the treatment. Blood culture showed no bacterial growth after 7 days, and the endotoxin level was less than 0.5 EU. The TBIL, TBA, Cr, and BUN levels in both groups were markedly lower than those at 0 h (p < 0.05). The Amm level in experimental group was significantly lower than that in control group (p < 0.05). NHBLS pressures were also stable, and the hepatocytes in the bioreactor functioned well. CONCLUSIONS: The preparation method for the simulated liver failure serum was optimized successfully, and the safety and effectiveness of the NHBLS in vitro were verified. Furthermore, the NHBLS significantly reduced the levels of Amm which can lead to hepatic encephalopathy.


Assuntos
Falência Hepática Aguda , Fígado Artificial , Alanina Transaminase/metabolismo , Animais , Bilirrubina , Hepatócitos/metabolismo , Fígado/metabolismo , Falência Hepática Aguda/terapia , Suínos
18.
Front Plant Sci ; 13: 852377, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35401630

RESUMO

Gynostemma longipes contains an abundance of dammarane-type ginsenosides and gypenosides that exhibit extensive pharmacological activities. Increasing attention has been paid to the elucidation of cytochrome P450 monooxygenases (CYPs) and UDP-dependent glycosyltransferases (UGTs) that participate downstream of ginsenoside biosynthesis in the Panax genus. However, information on oxidosqualene cyclases (OSCs), the upstream genes responsible for the biosynthesis of different skeletons of ginsenoside and gypenosides, is rarely reported. Here, an integrative study of the metabolome and the transcriptome in the leaf, stolon, and rattan was conducted and the function of GlOSC1 was demonstrated. In total, 46 triterpenes were detected and found to be highly abundant in the stolon, whereas gene expression analysis indicated that the upstream OSC genes responsible for saponin skeleton biosynthesis were highly expressed in the leaf. These findings indicated that the saponin skeletons were mainly biosynthesized in the leaf by OSCs, and subsequently transferred to the stolon via CYPs and UGTs biosynthesis to form various ginsenoside and gypenosides. Additionally, a new dammarane-II synthase (DDS), GlOSC1, was identified by bioinformatics analysis, yeast expression assay, and enzyme assays. The results of the liquid chromatography-mass spectrometry (LC-MS) analysis proved that GlOSC1 could catalyze 2,3-oxidosqualene to form dammarenediol-II via cyclization. This work uncovered the biosynthetic mechanism of dammarenediol-II, an important starting substrate for ginsenoside and gypenosides biosynthesis, and may achieve the increased yield of valuable ginsenosides and gypenosides produced under excess substrate in a yeast cell factory through synthetic biology strategy.

19.
Clin Cancer Res ; 2022 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-35443062

RESUMO

PURPOSE: Neoadjuvant chemotherapy prior to definitive surgery has been utilized widely for locally advanced oral squamous cell carcinoma (OSCC). We evaluated neoadjuvant erlotinib with platinum-docetaxel vs. placebo with platinum-docetaxel in stage III-IVB OSCC patients. EXPERIMENTAL DESIGN: Patients with newly diagnosed stage III, IVA, IVB (AJCC 7th) OSCC amenable to surgical resection were included. Patients were randomized to receive up to 3 cycles of chemotherapy with concurrent erlotinib or placebo, followed by surgery. The primary endpoint was major pathologic response (MPR) rate, secondary endpoints included safety, overall (OS) and progression-free survival (PFS). RESULTS: Fifty-two patients received at least one cycle of treatment and 47 were evaluable with surgical resection. MPR rate was not different between erlotinib (30%, 7/23) and placebo arms (41.7%, 10/24) (p=0.55). At median follow up of 26.5 months, there was no difference on OS or PFS between groups. Patients who received erlotinib with chemotherapy and achieved MPR (n=7) had no recurrence. The treatment-related adverse event rates were not different between the two groups (96% vs. 96%). However, rash, mostly low grade, was more common in the erlotinib arm (79% vs. 50%). Transcriptomic analysis in the pre-treatment samples indicated that genes in protein glycosylation and Wnt signaling pathways were associated with benefit in those treated with erlotinib plus chemotherapy. CONCLUSIONS: The addition of erlotinib to platinum-taxane chemotherapy was well-tolerated but did not induce higher rates of MPR or PFS or OS survival benefit. Patients who received chemotherapy with erlotinib and achieved major pathological responses had excellent clinical outcome.

20.
J Phys Chem Lett ; 13(15): 3462-3469, 2022 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-35413203

RESUMO

In recent years, the development and application of integrated probes for theranostics have attracted more and more attention. However, few biological probes can meet the needs of in vivo and in vitro long-term near-infrared imaging and photodynamic therapy, especially with a certain subcellular organelle targeting ability. Here, 2-chlorophenothiazine as a pharmacophore is linked to the mitochondrial targeting group pyridine cation through an alkyl chain, which is further linked to triphenylamine-based aggregation-induced emission groups to obtain two aggregation-induced emission luminogens (AIEgens). Only the presence or absence of thiophene causes two AIEgens to exhibit different structure-oriented characteristics. Although they are different with respec to mitochondrial targeting, cellular imaging, and cytotoxicity, they all have excellent in vivo and in vitro long-term near-infrared imaging and photodynamic therapy capabilities.


Assuntos
Fotoquimioterapia , Corantes Fluorescentes , Mitocôndrias , Imagem Óptica , Fotoquimioterapia/métodos , Tiofenos
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