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1.
Int J Pharm ; 655: 124072, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38561133

RESUMO

We explored the potential of overcoming the dense interstitial barrier in pancreatic cancer treatment by enhancing the uptake of hydrophilic chemotherapeutic drugs. In this study, we synthesized the squalenoyl-chidamide prodrug (SQ-CHI), linking lipophilic squalene (SQ) with the hydrophilic antitumor drug chidamide (CHI) through a trypsin-responsive bond. Self-assembled nanoparticles with sigma receptor-bound aminoethyl anisamide (AEAA) modification, forming AEAA-PEG-SQ-CHI NPs (A-C NPs, size 116.6 ± 0.4 nm), and reference nanoparticles without AEAA modification, forming mPEG-SQ-CHI NPs (M-C NPs, size 88.3 ± 0.3 nm), were prepared. A-C NPs exhibited significantly higher in vitro CHI release (74.7 %) in 0.5 % trypsin medium compared to release (20.2 %) in medium without trypsin. In vitro cell uptake assays revealed 3.6 and 2.3times higher permeation of A-C NPs into tumorspheres of PSN-1/HPSC or CFPAC-1/HPSC, respectively, compared to M-C NPs. Following intraperitoneal administration to subcutaneous tumor-bearing nude mice, the A-C NPs group demonstrated significant anti-pancreatic cancer efficacy, inducing cancer cell apoptosis and inhibiting proliferation in vivo. Mechanistic studies revealed that AEAA surface modification on nanoparticles promoted intracellular uptake through caveolin-mediated endocytosis. This nanoparticle system presents a novel therapeutic approach for pancreatic cancer treatment, offering a delivery strategy to enhance efficacy through improved tumor permeation, trypsin-responsive drug release, and specific cell surface receptor-mediated intracellular uptake.


Assuntos
Aminopiridinas , Benzamidas , Nanopartículas , Neoplasias Pancreáticas , Pró-Fármacos , Animais , Camundongos , Caveolinas/uso terapêutico , Camundongos Nus , Tripsina , Nanopartículas/química , Pró-Fármacos/química , Neoplasias Pancreáticas/tratamento farmacológico , Linhagem Celular Tumoral
2.
Front Plant Sci ; 15: 1364826, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38504893

RESUMO

Marginal lands, such as those with saline soils, have potential as alternative resources for cultivating dedicated biomass crops used in the production of renewable energy and chemicals. Optimum utilization of marginal lands can not only alleviate the competition for arable land use with primary food crops, but also contribute to bioenergy products and soil improvement. Miscanthus sacchariflorus and M. lutarioriparius are prominent perennial plants suitable for sustainable bioenergy production in saline soils. However, their responses to salt stress remain largely unexplored. In this study, we utilized 318 genotypes of M. sacchariflorus and M. lutarioriparius to assess their salt tolerance levels under 150 mM NaCl using 14 traits, and subsequently established a mini-core elite collection for salt tolerance. Our results revealed substantial variation in salt tolerance among the evaluated genotypes. Salt-tolerant genotypes exhibited significantly lower Na+ content, and K+ content was positively correlated with Na+ content. Interestingly, a few genotypes with higher Na+ levels in shoots showed improved shoot growth characteristics. This observation suggests that M. sacchariflorus and M. lutarioriparius adapt to salt stress by regulating ion homeostasis, primarily through enhanced K+ uptake, shoot Na+ exclusion, and Na+ sequestration in shoot vacuoles. To evaluate salt tolerance comprehensively, we developed an assessment value (D value) based on the membership function values of the 14 traits. We identified three highly salt-tolerant, 50 salt-tolerant, 127 moderately salt-tolerant, 117 salt-sensitive, and 21 highly salt-sensitive genotypes at the seedling stage by employing the D value. A mathematical evaluation model for salt tolerance was established for M. sacchariflorus and M. lutarioriparius at the seedling stage. Notably, the mini-core collection containing 64 genotypes developed using the Core Hunter algorithm effectively represented the overall variability of the entire collection. This mini-core collection serves as a valuable gene pool for future in-depth investigations of salt tolerance mechanisms in Miscanthus.

3.
Adv Sci (Weinh) ; : e2306333, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38526196

RESUMO

Synthetic biology aims to engineer transgene switches for precise therapeutic protein control in cell-based gene therapies. However, off-the-shelf trigger-inducible gene circuits are usually switched on by single or structurally similar molecules. This study presents a mammalian gene-switch platform that controls therapeutic gene expression by a wide range of molecules generating low, non-toxic levels of reactive oxygen species (ROS). In this system, KEAP1 (Kelch-like ECH-associated protein 1) serves as ROS sensor, regulating the translocation of NRF2 (nuclear factor erythroid 2-related factor 2) to the nucleus, where NRF2 binds to  antioxidant response elements (ARE) to activate the expression of a gene of interest. It is found that a promoter containing eight-tandem ARE repeats is highly sensitive to the low ROS levels generated by the soluble and volatile molecules, which include food preservatives, food additives, pharmaceuticals, and signal transduction inducers. In a proof-of-concept study, it is shown that many of these compounds can independently trigger microencapsulated engineered cells to produce sufficient insulin to restore normoglycemia in experimental type-1 diabetic mice. It is believed that this system greatly extends the variety of small-molecule inducers available to drive therapeutic gene switches.

4.
Cell Discov ; 10(1): 9, 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38263404

RESUMO

Viral proteases and clinically safe inhibitors were employed to build integrated compact regulators of protein activity (iCROP) for post-translational regulation of functional proteins by tunable proteolytic activity. In the absence of inhibitor, the co-localized/fused protease cleaves a target peptide sequence introduced in an exposed loop of the protein of interest, irreversibly fragmenting the protein structure and destroying its functionality. We selected three proteases and demonstrated the versatility of the iCROP framework by validating it to regulate the functional activity of ten different proteins. iCROP switches can be delivered either as mRNA or DNA, and provide rapid actuation kinetics with large induction ratios, while remaining strongly suppressed in the off state without inhibitor. iCROPs for effectors of the NF-κB and NFAT signaling pathways were assembled and confirmed to enable precise activation/inhibition of downstream events in response to protease inhibitors. In lipopolysaccharide-treated mice, iCROP-sr-IκBα suppressed cytokine release ("cytokine storm") by rescuing the activity of IκBα, which suppresses NF-κB signaling. We also constructed compact inducible CRISPR-(d)Cas9 variants and showed that iCROP-Cas9-mediated knockout of the PCSK9 gene in the liver lowered blood LDL-cholesterol levels in mice. iCROP-based protein switches will facilitate protein-level regulation in basic research and translational applications.

5.
Int J Biol Macromol ; 260(Pt 1): 129364, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38219927

RESUMO

Radium-223 dichloride is the first approved alpha particle-emitting radiopharmaceutical for patients with castration-resistant prostate cancer with symptomatic bone metastases and no known visceral metastases. A large percentage of intestinal enrichment and a slow clearance rate were the main causes of gastrointestinal adverse events after 223RaCl2 administration. The molecular weight of sodium alginate in aqueous solution was determined to be 656 kDa. Sodium alginate exhibits a higher affinity for adsorbing Ra2+ compared to other metal ions belonging to the second main group. Sodium alginate as low as 0.5 g/rat reduced intestinal damage by remodeling 223RaCl2 distribution without affecting bone resorption. Intestinal villi were preserved and enterocyte activity was maintained after sodium alginate intervention. Sodium alginate reduced DNA oxidative damage and lipid peroxidation and maintained endogenous antioxidant status by increasing superoxide dismutase levels and total antioxidant capacity. Furthermore, sodium alginate treatment mitigated DNA damage and apoptosis. The administration of sodium alginate effectively maintained the integrity of the intestinal microbiota, which had undergone perturbations due to radiation exposure. This study demonstrated that sodium alginate could be applied to reduce the adverse effects caused by radiation exposure to the intestine during 223RaCl2-treated and reduced intestinal damage resulted from 223RaCl2 accumulation without affecting bone uptake.


Assuntos
Neoplasias Ósseas , Neoplasias da Próstata , Masculino , Humanos , Ratos , Animais , Neoplasias Ósseas/tratamento farmacológico , Compostos Radiofarmacêuticos , Neoplasias da Próstata/patologia , Intestinos/patologia , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico
6.
Int J Biol Macromol ; 257(Pt 2): 128756, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38092098

RESUMO

Pancreatic cancer (PC) has a poor prognosis due to chemotherapy resistance and unfavorable drug transportation. Albumin conjugates are commonly used as drug carriers to overcome these obstacles. However, membrane-bound glycoprotein mucin 4 (MUC4) has emerged as a promising biomarker among the genetic mutations affecting albumin conjugates therapeutic window. Human serum albumin-conjugated arsenic trioxide (HSA-ATO) has shown potential in treating solid tumors but is limited in PC therapy due to unclear targets and mechanisms. This study investigated the transport mechanisms and therapeutic efficacy of HSA-ATO in PC cells with different MUC4 mutation statuses. Results revealed improved penetration of ATO into PC tumors through conjugated with HSA. However, MUC4 mutation significantly affected treatment sensitivity and HSA-ATO uptake both in vitro and in vivo. Mutant MUC4 cells exhibited over ten times higher IC50 for HSA-ATO and approximately half the uptake compared to wildtype cells. Further research demonstrated that ALPL activation by HSA-ATO enhanced transcytosis in wildtype MUC4 PC cells but not in mutant MUC4 cells, leading to impaired uptake and weaker antitumor effects. Reprogramming the transport process holds potential for enhancing albumin conjugate efficacy in PC patients with different MUC4 mutation statuses, paving the way for stratified treatment using these delivery vehicles.


Assuntos
Fosfatase Alcalina , Neoplasias Pancreáticas , Humanos , Trióxido de Arsênio/farmacologia , Trióxido de Arsênio/uso terapêutico , Mucina-4/genética , Mucina-4/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Albumina Sérica Humana/uso terapêutico , Transcitose , Linhagem Celular Tumoral
7.
Front Endocrinol (Lausanne) ; 14: 1209978, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38075078

RESUMO

Purpose: The purpose of this study was to develop and validate a nomogram for estimating the risk of distant metastases (DM) in the early postoperative phase of medullary thyroid cancer (MTC). Patients and methods: We retrospectively reviewed cases of patients diagnosed with MTC from the Surveillance, Epidemiology, and End Results (SEER) database from 2007 to 2017. In addition, we gathered data on patients who diagnosed as MTC at Department of Thyroid Surgery in the First Hospital of Jilin University between 2009 and 2021. Four machine learning algorithms were used for modeling, including random forest classifier (RFC), gradient boosting decision tree (GBDT), logistic regression (LR), and support vector machine (SVM). The optimal model was selected based on accuracy, recall, specificity, receiver operating characteristic curve (ROC), and area under curve (AUC). After that, the Hosmer-Lemeshow goodness-of-fit test, the brier score (BS) and calibration curve were used for validation of the best model, which allowed us to measure the discrepancy between the projected value and the actual value. Results: Through feature selection, we finally clarified that the following four features are associated with distant metastases of MTC, which are age, surgery, primary tumor (T) and nodes (N). The AUC values of the four models in the internal test set were as follows: random forest: 0.8786 (95% CI, 0.8070-0.9503), GBDT: 0.8402 (95% CI, 0.7606-0.9199), logistic regression: 0.8670(95%CI,0.7927-0.9413), and SVM: 0.8673 (95% CI, 0.7931-0.9415). As can be shown, there was no statistically significant difference in their AUC values. The highest AUC value of the four models were chosen as the best model since. The model was evaluated on the internal test set, and the accuracy was 0.84, recall was 0.76, and specificity was 0.87. The ROC curve was drawn, and the AUC was 0.8786 (95% CI, 0.8070-0.9503), which was higher than the other three models. The model was visualized using the nomogram and its net benefit was shown in both the Decision Curve Analysis (DCA) and Clinical Impact Curve (CIC). Conclusion: Proposed model had good discrimination ability and could preliminarily screen high-risk patients for DM in the early postoperative period.


Assuntos
Carcinoma Neuroendócrino , Neoplasias da Glândula Tireoide , Humanos , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/cirurgia , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/cirurgia , Período Pós-Operatório
8.
Front Endocrinol (Lausanne) ; 14: 1235354, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38027093

RESUMO

Background: Because the diameter of the suspicious lymph nodes is less than 1 cm and adjacent to important structures in the neck, the diagnosis of small LLNM is important but difficult without the help of fine needle aspiration (FNA). There are no relevant reports of risk factors that predict the risk of suspicious <1 cm LLNM. Methods: A total of 159 PTMC patients with suspicious <1 cm LLNM were included in the study. Multivariate logistic regression analysis was used to identify ultrasound independent predictors of LLNM. A predictive model was developed according to multivariate logistic regression and evaluated by Hosmer-Lemeshow fit test. Results: Age ≤ 38 years old, the largest PTMC was located in the upper part, and the presence of liquefaction or microcalcification in suspicious lymph nodes were independent risk factors for LLNM (univariate analysis P = 0.00, 0.00, 0.00; multivariate analysis P = 0.00, 0.02, 0.00. OR = 4.66 [CI: 1.78-12.21], 3.04 [CI: 1.24-7.46], 6.39 [CI: 1.85-22.00]). The predictive model for the diagnosis of suspicious <1 cm lymph nodes was established as: P = ex/(1 + ex). X = -1.29 + (1.11 × whether the largest tumor is located in the upper part) + (1.54 × whether the age is ≤ 38 years) + (1.85 × whether the suspicious lymph nodes have liquefaction/microcalcification). The Hosmer-Lemeshow fit test was used to test the predicted ability, and it found that the predictive model had a good fit and prediction accuracy (X2 = 6.214, P = 0.623 > 0.05). Chi squared trend analysis showed that the increase in the number of risk factors gradually increased the malignancy possibility of suspicious <1 cm lymph nodes (chi squared trend test, P = 0.00). Conclusions: Age ≤ 38 years old, the largest PTMC located in the upper part, and the presence of liquefaction or microcalcification in suspicious lymph nodes were independent risk factors for suspicious <1 cm LLNM in PTMC patients. Our result show that it is feasible to evaluate the malignant possibility of these lymph nodes using the number of risk factors.


Assuntos
Calcinose , Neoplasias da Glândula Tireoide , Humanos , Adulto , Metástase Linfática/patologia , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/patologia , Linfonodos/patologia , Calcinose/patologia
9.
Front Cell Dev Biol ; 11: 1257173, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38020914

RESUMO

Tumor radioresistance remains a key clinical challenge. The Hedgehog (HH) signaling pathway and glioma-associated oncogene (GLI) are aberrantly activated in several cancers and are thought to contribute to cancer radioresistance by influencing DNA repair, reactive oxygen species production, apoptosis, autophagy, cancer stem cells, the cell cycle, and the tumor microenvironment. GLI is reported to activate the main DNA repair pathways, to interact with cell cycle regulators like Cyclin D and Cyclin E, to inhibit apoptosis via the activation of B-cell lymphoma-2, Forkhead Box M1, and the MYC proto-oncogene, to upregulate cell stemness related genes (Nanog, POU class 5 homeobox 1, SRY-box transcription factor 2, and the BMI1 proto-oncogene), and to promote cancer stem cell transformation. The inactivation of Patched, the receptor of HH, prevents caspase-mediated apoptosis. This causes some cancer cells to survive while others become cancer stem cells, resulting in cancer recurrence. Combination treatment using HH inhibitors (including GLI inhibitors) and conventional therapies may enhance treatment efficacy. However, the clinical use of HH signaling inhibitors is associated with toxic side effects and drug resistance. Nevertheless, selective HH agonists, which may relieve the adverse effects of inhibitors, have been developed in mouse models. Combination therapy with other pathway inhibitors or immunotherapy may effectively overcome resistance to HH inhibitors. A comprehensive cancer radiotherapy with HH or GLI inhibitor is more likely to enhance cancer treatment efficacy while further studies are still needed to overcome its adverse effects and drug resistance.

10.
Front Endocrinol (Lausanne) ; 14: 1185327, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37780614

RESUMO

Objective: Active surveillance (AS) has been recommended as the first-line treatment strategy for low-risk (LR) papillary thyroid microcarcinoma (PTMC) according to the guidelines. However, preoperative imaging and fine-needle aspiration could not rule out a small group of patients with aggressive PTMC with large-volume lymph node micro-metastasis, extrathryoidal invasion to surrounding soft tissue, or high-grade malignancy from the AS candidates. Methods: Among 2,809 PTMC patients, 2,473 patients were enrolled in this study according to the inclusion criteria. Backward stepwise multivariate logistic regression analysis was used to filter clinical characteristics and ultrasound features to identify independent predictors of high-risk (HR) patients. A nomogram was developed and validated according to selected risk factors for the identification of an HR subgroup among "LR" PTMC patients before operation. Results: For identifying independent risk factors, multivariable logistic regression analysis was performed using the backward stepwise method and revealed that male sex [3.91 (2.58-5.92)], older age [0.94 (0.92-0.96)], largest tumor diameter [26.7 (10.57-69.22)], bilaterality [1.44 (1.01-2.3)], and multifocality [1.14 (1.01-2.26)] were independent predictors of the HR group. Based on these independent risk factors, a nomogram model was developed for predicting the probability of HR. The C index was 0.806 (95% CI, 0.765-0.847), which indicated satisfactory accuracy of the nomogram in predicting the probability of HR. Conclusion: Taken together, we developed and validated a nomogram model to predict HR of PTMC, which could be useful for patient counseling and facilitating treatment-related decision-making.


Assuntos
Carcinoma Papilar , Neoplasias da Glândula Tireoide , Humanos , Masculino , Nomogramas , Conduta Expectante , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/patologia , Carcinoma Papilar/diagnóstico , Carcinoma Papilar/cirurgia , Carcinoma Papilar/patologia , Metástase Linfática
11.
J Med Biochem ; 42(3): 505-512, 2023 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-37790213

RESUMO

Background: This study was aimed to evaluate the efficacy of pramipexole combined with ganglioside for PD treatment and pramipexole monotherapy, so as to provide reference for clinical practice. Methods: 61 PD patients selected from June 2019 to December 2020 at our hospital were divided into two groups. The control group (n=31) was given dopasizide oral treatment, and the treatment group (n=30) was given ganglioside combined with pramipexole. The clinical efficacy, adverse reactions, motor function scores, UPDRS scores, PDQ-39 scale scores, TNF-a levels, and related serum factor levels were measured in this study.

12.
FASEB J ; 37(10): e23188, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37732586

RESUMO

Diabetic nephropathy (DN) is an important complication of diabetes and the leading cause of end-stage renal disease globally. Renal tubular damage occurs to varying degrees in the early stages of DN prior to glomerular damage. Renalase (RNLS) is an amine oxidase, which is produced and secreted by the renal tubular epithelial cells. RNLS is reportedly closely related to renal tubular injury in acute and chronic kidney diseases. Herein, we aimed to evaluate the changes in tubular RNLS expression in DN and its correlation with DN-associated renal tubular injury. Conditional permanent renal tubular epithelial rat-cell line NRK-52E was transfected with pcDNA3-RNLS plasmid or administered recombinant rat RNLS protein and high glucose (HG) dose. A total of 22 adult Sprague-Dawley rats were randomly divided into the control (CON, n = 10) or diabetic nephrology (DN, n = 12) group. Random blood glucose levels of the rats were measured by sampling of the caudal vein weekly. After 8 weeks, the rat's body weight, 24-h urinary albumin concentration, and right kidney were evaluated. Our study suggested the decreased expression levels of RNLS in renal tissue and renal tubular epithelial cells in DN rats, accompanied by renal tubulointerstitial fibrosis, apoptosis of renal tubular epithelial cells, and activation of the p38MAPK signal pathway. Reversing the low RNLS expression can reduce the level of p38MAPK phosphorylation and delay renal tubular injury. Thus, the reduction of renal tubular RNLS expression in DN mediates tubulointerstitial fibrosis and cell apoptosis via the activation of the p38MAPK signal pathway. RNLS plays a key mediating role in DN-associated tubular injury via p38MAPK, which provides new therapeutic targets and a theoretical basis for early prevention and treatment of DN.


Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Animais , Ratos , Ratos Sprague-Dawley , Rim , Sistema de Sinalização das MAP Quinases
14.
Front Endocrinol (Lausanne) ; 14: 1166820, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37529600

RESUMO

To date, the traditional open thyroid surgery via a low collar incision remains the standard approach for patients undergoing thyroidectomy. However, this conventional approach will inevitably leave patients a neck scar and even cause a variety of complications such as paresthesia, hypesthesia, and other uncomfortable sensations. With the progress in surgical techniques, especially in endoscopic surgery, and the increasing desire for cosmetic and functional outcomes, various new approaches for thyroidectomy have been developed to avoid or decrease side effects. Some of these alternative approaches have obvious advantages compared with traditional surgery and have already been widely used in the treatment of thyroid disease, but each has its limitations. This review aims to evaluate and compare the different approaches to thyroidectomy to help surgeons make the proper treatment strategy for different individuals.


Assuntos
Doenças da Glândula Tireoide , Neoplasias da Glândula Tireoide , Humanos , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia/efeitos adversos , Tireoidectomia/métodos , Doenças da Glândula Tireoide/cirurgia , Endoscopia/métodos
15.
Front Med (Lausanne) ; 10: 1169562, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37457582

RESUMO

Introduction: Coronavirus disease 2019 (COVID-19) is a global pandemic and highly contagious, posing a serious threat to human health. Colorectal cancer (CRC) is a risk factor for COVID-19 infection. Therefore, it is vital to investigate the intrinsic link between these two diseases. Methods: In this work, bioinformatics and systems biology techniques were used to detect the mutual pathways, molecular biomarkers, and potential drugs between COVID-19 and CRC. Results: A total of 161 common differentially expressed genes (DEGs) were identified based on the RNA sequencing datasets of the two diseases. Functional analysis was performed using ontology keywords, and pathway analysis was also performed. The common DEGs were further utilized to create a protein-protein interaction (PPI) network and to identify hub genes and key modules. The datasets revealed transcription factors-gene interactions, co-regulatory networks with DEGs-miRNAs of common DEGs, and predicted possible drugs as well. The ten predicted drugs include troglitazone, estradiol, progesterone, calcitriol, genistein, dexamethasone, lucanthone, resveratrol, retinoic acid, phorbol 12-myristate 13-acetate, some of which have been investigated as potential CRC and COVID-19 therapies. Discussion: By clarifying the relationship between COVID-19 and CRC, we hope to provide novel clues and promising therapeutic drugs to treat these two illnesses.

16.
Nat Metab ; 5(8): 1395-1407, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37524785

RESUMO

Wearable electronic devices are playing a rapidly expanding role in the acquisition of individuals' health data for personalized medical interventions; however, wearables cannot yet directly program gene-based therapies because of the lack of a direct electrogenetic interface. Here we provide the missing link by developing an electrogenetic interface that we call direct current (DC)-actuated regulation technology (DART), which enables electrode-mediated, time- and voltage-dependent transgene expression in human cells using DC from batteries. DART utilizes a DC supply to generate non-toxic levels of reactive oxygen species that act via a biosensor to reversibly fine-tune synthetic promoters. In a proof-of-concept study in a type 1 diabetic male mouse model, a once-daily transdermal stimulation of subcutaneously implanted microencapsulated engineered human cells by energized acupuncture needles (4.5 V DC for 10 s) stimulated insulin release and restored normoglycemia. We believe this technology will enable wearable electronic devices to directly program metabolic interventions.


Assuntos
Técnicas Biossensoriais , Dispositivos Eletrônicos Vestíveis , Animais , Camundongos , Humanos , Masculino , Modelos Animais de Doenças , Expressão Gênica , Mamíferos
17.
Nucleic Acids Res ; 51(15): e85, 2023 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-37497781

RESUMO

Synthetic biology holds great promise to improve the safety and efficacy of future gene and engineered cell therapies by providing new means of endogenous or exogenous control of the embedded therapeutic programs. Here, we focused on gluconate as a clinically licensed small-molecule inducer and engineered gluconate-sensitive molecular switches to regulate transgene expression in human cell cultures and in mice. Several switch designs were assembled based on the gluconate-responsive transcriptional repressor GntR from Escherichia coli. Initially we assembled OFF- and ON-type switches by rewiring the native gluconate-dependent binding of GntR to target DNA sequences in mammalian cells. Then, we utilized the ability of GntR to dimerize in the presence of gluconate to activate gene expression from a split transcriptional activator. By means of random mutagenesis of GntR combined with phenotypic screening, we identified variants that significantly enhanced the functionality of the genetic devices, enabling the construction of robust two-input logic gates. We also demonstrated the potential utility of the synthetic switch in two in vivo settings, one employing implantation of alginate-encapsulated engineered cells and the other involving modification of host cells by DNA delivery. Then, as proof-of-concept, the gluconate-actuated genetic switch was connected to insulin secretion, and the components encoding gluconate-induced insulin production were introduced into type-1 diabetic mice as naked DNA via hydrodynamic tail vein injection. Normoglycemia was restored, thereby showcasing the suitability of oral gluconate to regulate in situ production of a therapeutic protein.


Assuntos
Diabetes Mellitus Experimental , Gluconatos , Animais , Humanos , Camundongos , Diabetes Mellitus Experimental/genética , Proteínas de Ligação a DNA/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo , Gluconatos/metabolismo , Gluconatos/farmacologia , Regiões Promotoras Genéticas , Proteínas Repressoras/metabolismo , Fatores de Transcrição/metabolismo , Transgenes
18.
Sensors (Basel) ; 23(14)2023 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-37514616

RESUMO

Indoor localization and navigation have become an increasingly important problem in both industry and academia with the widespread use of mobile smart devices and the development of network techniques. The Wi-Fi-based technology shows great potential for applications due to the ubiquitous Wi-Fi infrastructure in public indoor environments. Most existing approaches use trilateration or machine learning methods to predict locations from a set of annotated Wi-Fi observations. However, annotated data are not always readily available. In this paper, we propose a robot-aided data collection strategy to obtain the limited but high-quality labeled data and a large amount of unlabeled data. Furthermore, we design two deep learning models based on a variational autoencoder for the localization and navigation tasks, respectively. To make full use of the collected data, a hybrid learning approach is developed to train the models by combining supervised, unsupervised and semi-supervised learning strategies. Extensive experiments suggest that our approach enables the models to learn effective knowledge from unlabeled data with incremental improvements, and it can achieve promising localization and navigation performance in a complex indoor environment with obstacles.

20.
Sci Total Environ ; 896: 165276, 2023 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-37406706

RESUMO

Miscanthus lutarioriparius grown in Dongting Lake has an annual biomass yield potential of 1 million tons. However, with the shutdown of its previous utilization for paper-making, abandoning this huge amount of biomass has caused serious economic, ecological, and social problems. Constructing an industrial cluster to continuously convert biomass into various bioproducts is a win-win measure to address this dilemma. With the increasing confirmation of the importance of biomass quality affecting the conservation process, fully understanding the biomass characteristics of Dongting Lake-grown M. lutarioriparius is crucial for building a scientific industrial cluster. The present work is designed to explore the variation in biomass quality across the entire Dongting Lake area. Results show that the biomass contented with Cd, Mn, Zn, and Cr has significant geographical differences, with a general trend of Southern Dongting Lake-grown biomass having a higher concentration than that from Eastern and Western Dongting Lake areas. Moreover, significant differences are found in terms of biomass ash content, lignin content, and the degree of polymerization of cellulose (DP). The biomass with low ash content is generally from the entire Eastern Dongting Lake area and the northern part of the Western Dongting Lake area. Virtually all Western Dongting Lake-grown biomass has a low lignin content (approximately 18 %). Regarding the spatial variation of DP, Eastern Dongting Lake-grown biomass has a higher DP (average at 585.33) than that in Southern (575.15) and then Western Dongting Lake (529.16). Based on these quality indicators, the biomass production potentials for bioethanol, biochar, and xylo-oligosaccharide were calculated and visualized. Results show that biomass from almost the entire Western and Eastern Dongting Lake area is suitable for bioethanol and xylo-oligosaccharide production, while biomass from the Southern Dongting Lake area for biochar production. These results provide scientific guidance for the future utilization of Dongting Lake-grown M. lutarioriparius biomass.


Assuntos
Monitoramento Ambiental , Lignina , Biomassa , Lignina/análise , Lagos/análise , Poaceae , China
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