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2.
Sci Total Environ ; 927: 172236, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38582123

RESUMO

Pindolol (PIN) is a commonly used ß-blocker drug and has been frequently detected in various natural waters. Comprehensive understanding of its environmental photochemical transformation is necessary to assess its environmental risk. In this study, the photodegradation kinetics and mechanisms of PIN in both freshwater and coastal water were investigated for the first time. The photodegradation experiments were carried out by steady-state photochemical experiment under simulated sunlight irradiation. The results showed that the photodegradation rate of PIN in the freshwater of the Pearl River estuary was significantly faster than that in its downstream coastal water. In river water, PIN can undergo both direct photolysis and indirect photolysis induced by riverine dissolved organic matter (DOM) mainly through excited triplet-state of DOM and singlet oxygen, while direct photolysis dominated its degradation in coastal water. The promotion effect was found to be much greater for Suwannee River Natural Organic Matter (SRNOM) than that of the sampled riverine DOM, due to its high steady-state concentrations of reactive species. Interestingly, coastal DOM in northern and southern China were found to have similar promotion effects on PIN photodegradation for the first time, but both less than that of riverine DOM. A total of seven degradation products of PIN resulting from hydroxylation, hydrogen abstraction and cleavage of ether bond were identified. Biological toxicity of one products were found to be higher than that of PIN. These results are of significance for knowing the persistence and ecological risk of PIN in natural waters.

3.
Sensors (Basel) ; 24(5)2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38474958

RESUMO

We review dielectric resonator antenna (DRA) designs. This review examines recent advancements across several categories, specifically focusing on their applicability in array configurations for millimeter-wave (mmW) bands, particularly in the context of 5G and beyond 5G applications. Notably, the off-chip DRA designs, including in-substrate and compact DRAs, have gained prominence in recent years. This surge in popularity can be attributed to the rapid development of cost-effective multilayer laminate manufacturing techniques, such as printed circuit boards (PCBs) and low-temperature co-fired ceramic (LTCC). Furthermore, there is a growing demand for DRAs with beam-steering, dual-band functions, and on-chip alignment availability, as they offer versatile alternatives to traditional lossy printed antennas. DRAs exhibit distinct advantages of lower conductive losses and greater flexibility in shapes and materials. We discuss and compare the performances of different DRA designs, considering their material usage, manufacturing feasibility, overall performance, and applications. By exploring the pros and cons of these diverse DRA designs, this review provides valuable insights for researchers in the field.

4.
Cancer Lett ; 588: 216747, 2024 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-38403110

RESUMO

Cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (CDK4/6i) have rapidly received Food and Drug Administration (FDA) approval as a new type of therapy for patients with advanced hormone receptor-positive breast cancer. However, with the widespread application of CDK4/6i, drug resistance has become a new challenge for clinical practice and has greatly limited the treatment effect. Here, the whole microenvironment landscape of ER+ breast cancer tumors was revealed through single-cell RNA sequencing, and a specific subset of cancer-associated fibroblasts (CD63+ CAFs) was identified as highly enriched in CDK4/6i resistant tumor tissues. Then, we found that CD63+ CAFs can distinctly promote resistance to CDK4/6i in breast cancer cells and tumor xenografts. In addition, it was discovered that miR-20 is markedly enriched in the CD63+ CAFs-derived exosomes, which are used to communicate with ER+ breast cancer cells, leading to CDK4/6i resistance. Furthermore, exosomal miR-20 could directly target the RB1 mRNA 3'UTR and negatively regulate RB1 expression to decrease CDK4/6i sensitivity in breast cancer cells. Most importantly, we designed and synthesized cRGD-miR-20 sponge nanoparticles and found that they can enhance the therapeutic effect of CDK4/6i in breast cancer. In summary, our findings reveal that CD63+ CAFs can promote CDK4/6i resistance via exosomal miR-20, which induces the downregulation of RB1 in breast cancer cells, and suggest that CD63+ CAFs may be a novel therapeutic target to enhance CDK4/6i sensitivity.


Assuntos
Neoplasias da Mama , Fibroblastos Associados a Câncer , MicroRNAs , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Fibroblastos Associados a Câncer/metabolismo , Quinase 4 Dependente de Ciclina , Proliferação de Células , MicroRNAs/metabolismo , Quinase 6 Dependente de Ciclina , Microambiente Tumoral , Tetraspanina 30/metabolismo
5.
Front Immunol ; 15: 1321946, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38361930

RESUMO

HER2 overexpression/amplification is a prevalent driver in various types of cancer, including gastric cancer (GC). Limited options are available for patients with HER2-positive metastatic gastric cancer, particularly those who do not respond to the standard therapy of HER2 antibody trastuzumab combined with chemotherapy. Previous research suggests that combining a PD-1 inhibitor with radiotherapy and granulocyte macrophage-colony stimulating factor (PRaG regimen) may enhance the antitumor effects in patients with chemotherapy-resistant metastatic solid tumors. In this case study, we presented a potential treatment strategy of a patient having HER2-positive and PD-L1-negative gastric adenocarcinoma. The patient showed rapid tumor progression even after surgery and multiple trastuzumab plus chemotherapy treatments. To address this, we employed a novel anti-HER2 antibody called RC48 in combination with PRaG regimen therapy (PRaG3.0). The patient demonstrated a positive response after two treatment cycles and achieved a progression-free survival time of 6.5 months. This case highlights the potential of four-combination therapies for treating refractory, multiorgan, HER2-positive, PD-L1-negative metastatic gastric cancer. Additionally, varying radiation doses in targeting dual foci is critical to enhance tumor immunotherapy.


Assuntos
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/etiologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Antígeno B7-H1 , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Trastuzumab/uso terapêutico , Granulócitos , Macrófagos
6.
J Vis Exp ; (203)2024 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-38345232

RESUMO

Tuina, as an external treatment method of traditional Chinese medicine, has been proven to have an analgesic effect on peripheral neuropathic pain (pNP) in clinical and basic research. However, the optimal time point for the analgesic effect of tuina may vary according to different injury sensations, affecting the exploration of the initiation mechanism of tuina analgesia. The research used minor chronic constriction injury (minor CCI) model rats to simulate pNP and used the intelligent tuina manipulation simulator to simulate the three methods (point-pressing, plucking, and kneading) and three acupoints (Yinmen BL37, Chengshan BL57, and Yanglingquan GB34) for performing tuina therapy. The study evaluated the changes in pain within 24 h and the optimal time point for the efficacy of tuina analgesia in rats with minor CCI models by testing cold sensitivity threshold (CST), mechanical withdrawal threshold (MWT), and thermal withdrawal latency (TWL). Furthermore, the study evaluated IL-10 and TNF-α expression changes through Elisa detection. The results show that tuina has both immediate and sustained analgesic effects. For the three different injury sensitivity thresholds of CST, MWT, TWL, and two cytokines of IL-10 and TNF-α, the analgesic efficacy of tuina within 24 h after intervention is significantly different at different time points.


Assuntos
Interleucina-10 , Neuralgia , Ratos , Animais , Ratos Sprague-Dawley , Interleucina-10/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo , Neuralgia/terapia , Analgésicos/farmacologia , Analgésicos/uso terapêutico
7.
BMC Neurol ; 24(1): 30, 2024 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-38233767

RESUMO

OBJECTIVE: To explore the predictive value of interleukin-6 (IL-6) combined with human neutrophil lipocalin (HNL) of stroke-associated pneumonia (SAP) in patients who were diagnosed with acute ischemic stroke (AIS). METHODS: 108patients were divided into two groups: pneumonia group (52 cases) and non-pneumonia group (56 cases), according to whether the patients developed SAP within 7 days of admission. General information was compared between the two groups, like age, gender, history of hypertension, diabetes mellitus, cardiovascular disease, dysphagia, smoking and alcoholhistory. Clinical data were recorded and compared, including lipid profile, interleukin-6 (IL-6), homocysteine (Hcy), National Institutes of Health Stroke Scale (NIHSS) score, and HNL. Multivariate Logistic regression analysis was used to screen the risk factors of AIS-AP, and the predictive value of IL-6 and HNL alone and in combination was evaluated by receiver operating characteristic curve (ROC curve). RESULTS: Logistic regression analysis showed that dysphagia (OR,0.018; 95% CI, 0.001 ~ 0.427; P = 0.013), increased NIHSS scores(OR,0.012; 95% CI, 0.000 ~ 0.434; P = 0.016), and high levels of IL-6 (OR,0.014; 95% CI, 0.000 ~ 0.695; P = 0.032)and HNL (OR,0.006; 95% CI, 0.000 ~ 0.280; P = 0.009) were independent risk factors for SAP with significant difference (all P < 0.05). According to the ROC curve analysis of IL-6, the area under the curve (AUC) was 0.881 (95% CI: 0.820 ~ 0.942), and the optimal cutoff value was 6.89 pg/mL with the sensitivity of 73.1% and specificity of 85.7%. As for the ROC curve analysis of HNL, the AUC was 0.896 (95% CI: 0.839 ~ 0.954), and the best cutoff value was 99.66ng/mL with the sensitivity of 76.9% and specificity of 89.3%. The AUC of the combination of IL-6 and HNL increased to 0.952 (95% CI: 0.914 ~ 0.989), and the sensitivity and specificity increased to 80.8% and 92.9%, respectively. CONCLUSION: In this research, the levels of IL-6 ≥ 6.89 pg/mL and HNL ≥ 99.66ng/mL were considered as risk factors for AIS patients complicated with SAP. The combined detection had higher predictive value for patients with SAP, which may help to identify who were in highrisk.


Assuntos
Transtornos de Deglutição , AVC Isquêmico , Pneumonia , Acidente Vascular Cerebral , Humanos , AVC Isquêmico/complicações , Interleucina-6 , Citocinas , Neutrófilos , Prognóstico , Curva ROC , Pneumonia/etiologia , Estudos Retrospectivos
8.
Nature ; 625(7995): 535-539, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38200315

RESUMO

The largest ever primate and one of the largest of the southeast Asian megafauna, Gigantopithecus blacki1, persisted in China from about 2.0 million years until the late middle Pleistocene when it became extinct2-4. Its demise is enigmatic considering that it was one of the few Asian great apes to go extinct in the last 2.6 million years, whereas others, including orangutan, survived until the present5. The cause of the disappearance of G. blacki remains unresolved but could shed light on primate resilience and the fate of megafauna in this region6. Here we applied three multidisciplinary analyses-timing, past environments and behaviour-to 22 caves in southern China. We used 157 radiometric ages from six dating techniques to establish a timeline for the demise of G. blacki. We show that from 2.3 million years ago the environment was a mosaic of forests and grasses, providing ideal conditions for thriving G. blacki populations. However, just before and during the extinction window between 295,000 and 215,000 years ago there was enhanced environmental variability from increased seasonality, which caused changes in plant communities and an increase in open forest environments. Although its close relative Pongo weidenreichi managed to adapt its dietary preferences and behaviour to this variability, G. blacki showed signs of chronic stress and dwindling populations. Ultimately its struggle to adapt led to the extinction of the greatest primate to ever inhabit the Earth.


Assuntos
Extinção Biológica , Fósseis , Hominidae , Animais , Cavernas , China , Dieta/veterinária , Florestas , Hominidae/classificação , Plantas , Pongo , Datação Radiométrica , Estações do Ano , Fatores de Tempo
9.
J Pain Res ; 17: 321-334, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38283563

RESUMO

Purpose: This study aimed to investigate changes in metabolomic expression in the spinal dorsal horn (SDH) and thalamus during a Tuina session, aiming to elucidate the mechanism of immediate analgesia. Methods: The rats were randomly divided into three groups: the Sham group, the Model group, and the Tuina group. A minor chronic constriction injury (minor CCI) model was established in both the Model group and the Tuina group. The therapeutic effect of Tuina was determined using the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) tests. Differential metabolites of the SDH and thalamus were detected using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Bioinformatic analysis was performed using CV, PCA, Venn, and KEGG. Results: The therapeutic effect of MWT and TWL after instant Tuina intervention was significant. The therapeutic effect of Tuina instant was significantly better compared to the Model group. In the Veen analysis, it was found that Tuina instantly regulates 10 differential metabolites in the SDH and 5 differential metabolites in the thalamus. In the KEGG enrichment analysis, we found that differential metabolites were enriched in 43 pathways in the thalamus and 70 pathways in the SDH. Conclusion: Tuina therapy may have analgesic effects by metabolizing neurotransmitters such as 2-Picolinic Acid, 5-Hydroxy-Tryptophan Glutathione Betaine-aldehyde-chloride Leucine Lysine Methionine Sarcosine Succinic Acid Histidine Acetylcholine and 5-Hydroxyindoleacetic Acid through the cAMP pathway. It also affects pathways of neurodegeneration-multiple diseases, butanoate metabolism, tyrosine metabolism.

10.
Angew Chem Int Ed Engl ; 63(7): e202317935, 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38117662

RESUMO

An emerging class of C-C coupling transformations that furnish drug-like building blocks involves catalytic hydrocarbonation of alkenes. However, despite notable advances in the field, hydrocarbon addition to gem-difluoroalkenes without additional electronic activation remains largely unsuccessful. This owes partly to poor reactivity and the propensity of difluoroalkenes to undergo defluorinative side reactions. Here, we report a nickel catalytic system that promotes efficient 1,2-selective hydroarylation and hydroalkenylation, suppressing defluorination and providing straightforward access to a diverse assortment of prized organofluorides bearing difluoromethyl-substituted carbon centers. In contrast to radical-based pathways and reactions triggered by hydrometallation via a nickel-hydride complex, our experimental and computational studies support a mechanism in which a catalytically active nickel-bromide species promotes selective carbonickelation with difluoroalkenes followed by alkoxide exchange and hydride transfer, effectively overcoming the difluoroalkene's intrinsic electronic bias.

11.
Heliyon ; 10(1): e23313, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38148795

RESUMO

Objective: To investigate the mechanism of the six-method massage antipyretic process (SMAP) and its influence on the body's metabolic state. Methods: The random number table method was used to divide 24 New Zealand 2-month-old rabbits with qualified basal body temperature into a control group, model group and massage group (n = 8 per group). The model group and massage groups were injected with 0.5 µg/ml lipopolysaccharide (1 ml/kg) into the auricular vein, and the control group was injected with the same amount of normal saline at the same temperature. One hour after modelling, the massage group was given SMAP (opening Tianmen, pushing Kangong, rubbing Taiyang, rubbing Erhougaogu, clearing the Tianheshui and pushing the spine). The change of anal temperature 5 h after moulding was recorded to clarify the antipyretic effect. Results: After modelling, the rectal temperature of the juvenile rabbits in the three groups increased. The rectal temperature of the model group was higher than that of the control group 5 h after modelling, and the rectal temperature of the massage group was lower than that of the model group (P < 0.05). The antipyretic mechanism is related to the regulation of the synthesis of phenylalanine, tyrosine and tryptophan, as well as the pentose phosphate pathway. Compared with the model group, the plasma interleukin (IL)-1, IL-6, interferon-gamma, toll-like receptor 4, nuclear factor κB, the mechanistic target of rapamycin complex 1, indoleamine 2,3-dioxygenase 1, aryl hydrocarbon receptor, liver aspartate transaminase (AST), alanine transaminase (ALT) and l-glutamate dehydrogenase (L-GLDH) expression in the massage group were significantly decreased (P < 0.05). Compared with the model group, the massage group had significantly reduced AST, ALT and L-GLDH expression in plasma (P < 0.05). Conclusion: The mechanism of SMAP therapy is related to regulating the expression of peripheral inflammatory factors and metabolic pathways.

12.
ACS Nano ; 17(23): 23746-23760, 2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-37991252

RESUMO

The increasing understanding of ferroptosis has indicated its role and therapeutic potential in cancer; however, this knowledge has yet to be translated into effective therapies. Glioblastoma (GBM) patients face a bleak prognosis and encounter challenges due to the limited treatment options available. In this study, we conducted a genome-wide CRISPR-Cas9 screening in the presence of a ferroptosis inducer (RSL3) to identify the key driver genes involved in ferroptosis. We identified ALOX15, a key lipoxygenase (LOX), as an essential driver of ferroptosis. Small activating RNA (saRNA) was used to mediate the expression of ALOX15 promoted ferroptosis in GBM cells. We then coated saALOX15-loaded mesoporous polydopamine (MPDA) with Angiopep-2-modified macrophage membranes (MMs) to reduce the clearance by the mononuclear phagocyte system (MPS) and increase the ability of the complex to cross the blood-brain barrier (BBB) during specific targeted therapy of orthotopic GBM. These generated hybrid nanoparticles (NPs) induced ferroptosis by mediating mitochondrial dysfunction and rendering mitochondrial morphology abnormal. In vivo, the modified MM enabled the NPs to target GBM cells, exert a marked inhibitory effect on GBM progression, and promote GBM radiosensitivity. Our results reveal ALOX15 to be a promising therapeutic target in GBM and suggest a biomimetic strategy that depends on the biological properties of MMs to enhance the in vivo performance of NPs for treating GBM.


Assuntos
Neoplasias Encefálicas , Ferroptose , Glioblastoma , Nanopartículas , Humanos , Glioblastoma/tratamento farmacológico , Biomimética , Macrófagos , Linhagem Celular Tumoral , Neoplasias Encefálicas/tratamento farmacológico
13.
Glob Chang Biol ; 29(23): 6591-6605, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37846617

RESUMO

Orbicella faveolata, commonly known as the mountainous star coral, is a dominant reef-building species in the Caribbean, but populations have suffered sharp declines since the 1980s due to repeated bleaching and disease-driven mortality. Prior research has shown that inshore adult O. faveolata populations in the Florida Keys are able to maintain high coral cover and recover from bleaching faster than their offshore counterparts. However, whether this origin-specific variation in thermal resistance is heritable remains unclear. To address this knowledge gap, we produced purebred and hybrid larval crosses from O. faveolata gametes collected at two distinct reefs in the Upper Florida Keys, a nearshore site (Cheeca Rocks, CR) and an offshore site (Horseshoe Reef, HR), in two different years (2019, 2021). We then subjected these aposymbiotic larvae to severe (36°C) and moderate (32°C) heat challenges to quantify their thermal tolerance. Contrary to our expectation based on patterns of adult thermal tolerance, HR purebred larvae survived better and exhibited gene expression profiles that were less driven by stress response under elevated temperature compared to purebred CR and hybrid larvae. One potential explanation could be the compromised reproductive output of CR adult colonies due to repeated summer bleaching events in 2018 and 2019, as gametes originating from CR in 2019 contained less storage lipids than those from HR. These findings provide an important counter-example to the current selective breeding paradigm, that more tolerant parents will yield more tolerant offspring, and highlight the importance of adopting a holistic approach when evaluating larval quality for conservation and restoration purposes.


Assuntos
Antozoários , Recifes de Corais , Humanos , Animais , Antozoários/fisiologia , Temperatura Alta , Florida
14.
J Orthop Res ; 2023 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-37804208

RESUMO

The objective of this study was to measure how much of the superolateral femoral neck should be removed to reduce the incidence of wedge effect. Simulating surgery: Computed Tomography images of 131 intertrochanteric fracture patients were included, three-dimensionally reconstructed, virtually reduced and implanted with Proximal Femoral Nail Antirotation blade-Ⅱ(PFNA-Ⅱ) nail. The antero-posterior length and media-lateral width of the intersection between superolateral femoral neck and PFNA-Ⅱ nail were measured. Retrospective study: The pre- and postoperative CT of 30 patients were collected. The average varus angle of the neck-shaft angle and the correlation between the angles and the difference in the actual and estimated width of the fragments removed were measured. Models of 108 patient were selected for analysis. The average antero-posterior length and media-lateral width were 14.46 mm (14.00-14.93 mm) and 9.33 mm (8.79-9.87 mm), respectively. The AO/OTA classification was not significantly associated with the outcome, but the gender was. In the retrospective study, the mean value of the varus angles was -4.58° (SE = 6.85°), and the difference of width was strongly positively correlated with the varus angle with a correlation coefficient of 0.698. Results obtained in this study can improve the understanding of this region and help surgeons to make appropriate preoperative planning to reduce the incidence of wedge effect. Retrospective study provided effective proof of the reliability of this study.

15.
Sci Rep ; 13(1): 15179, 2023 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-37704755

RESUMO

Differentiating dry eye disease (DED) from allergic or viral conjunctivitis rapidly and accurately is important to ensure prompt diagnosis and treatment. Tear lactoferrin (LF), a multi-functional glycoprotein found in tears, decreases significantly in patients with DED, and has been considered as a DED diagnostic biomarker. Measuring tear LF level, however, takes time and requires the use of bulky instruments. Herein, a homogeneous carbon nanostructure-based aptasensor with high sensitivity and selectivity has been developed by applying fluorescence polarization (FP) technology. The FP of carbon dots (CDs) bioconjugated with LF aptamers (CDs-aptamer) is 21.2% higher than that of CDs, which can be further amplified (1.81 times) once interacting with graphene oxide nanosheets (GONS). In the presence of LF, GONS separates from CDs-aptamer because of the stronger binding affinity between CDs-aptamer to LF, resulting in the decrease of FP value. A linear relationship is observed between FP value and LF concentration in spiked tear samples from 0.66 to 3.32 mg/mL. The selectivity of the aptasensor has been investigated by measuring other proteins. The results indicate that the FP-based aptasensor is a cost-effective method with high sensitivity and selectivity in detection of tear LF.


Assuntos
Síndromes do Olho Seco , Lactoferrina , Humanos , Carbono , Polarização de Fluorescência , Oligonucleotídeos
16.
Bull Environ Contam Toxicol ; 111(3): 43, 2023 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-37715810

RESUMO

Three modified biochar (Cunninghamia lanceolata) with iron and manganese elementals (FMBCs) were successfully prepared and used to remove hexavalent chromium (Cr(VI)) from aqueous solutions. The biochar before and after decoration were characterized by advanced instruments. The adsorption capacities of modified biochar in different Cr(VI) (20 mg·L- 1, 1 mg·L- 1) solutions were 4868.28 mg·kg- 1 and 300 mg·kg- 1. The Cr(VI) removal was highest at pH 2. The possible adsorption was considered to be ion exchange adsorption, chemisorption, and electrostatic attraction. Meanwhile, interfering ions are conducive to increasing the adsorption content. FMBCs prepared at different temperatures showed different characteristics, single-use and cycle-use performance, and high and low concentration removal superiority. The result indicated that FMBCs had a promising potential as an adsorbent to remove toxic and harmful Cr(VI) from aqueous solutions.


Assuntos
Ferro , Manganês , Adsorção
18.
Curr Med Imaging ; 2023 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-37622557

RESUMO

PURPOSE: The diagnosis and quantification of early-stage alcoholic liver fibrosis (ALF) are vital and the objective is to establish a noninvasive PET technique to quantify the collagenogenesis of hepatic stellate cells (HSC) in an ALF mouse model. METHODS: To establish the ALF animal model, a liquid alcohol diet (8 weeks), and CCl4 were injected intraperitoneally at 5-8 weeks. A liquid scintillation counter was used to measure [3H]proline uptake by rats HSC in vitro experiment. Collagen type 1 production was tested by ELISA in a culture medium. The expression of type 1 collagen and proline transporters in ex vivo experiments was compared between ALF rats and mice. Different doses of unlabeled proline and benztropine were ex vivo quantified [3H]proline in liver tissues. Tracer uptake in different organs including the liver in ALF and control mice in vivo was quantified using [18F]fluoro-proline microPET/CT Results: The optimal dose and time of [3H]proline uptake by HSC was 19-37MBq/L and 30-90min after culture. Higher [3H]proline uptake and type 1 collagen production in HSC were found in ALF and control rats. There was a high correlation between [3H]proline uptake and type 1 collagen in ALF rats. To cut the costs of tracer usage and imaging in vivo, the mouse-to-rat model was compared. Type 1 collagen levels of ALF mice liver tissue in ex vivo were similar to ALF rats, as was proline transporter protein. Unlabeled proline of type 1 collagen and [3H]proline uptake of ALF mice was blocked by benztropine. In vivo [18F]fluoro-proline PET/CT imaging, SUVmax in the liver, normalized liver/brain and liver/thigh ratio were significantly different between ALF mice and controls and there was a strong positive correlation among these three indexes in ALF mice. CONCLUSIONS: [18F]fluoro-proline microPET/CT is feasible to quantify collagenogenesis in HSC in early-stage ALF animal models, which may be used as a promising and reliable noninvasive diagnostic technique.

19.
ACS Nano ; 17(17): 16432-16447, 2023 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-37646615

RESUMO

Radiotherapy is a mainstay of glioblastoma (GBM) treatment; however, the development of therapeutic resistance has hampered the efficacy of radiotherapy, suggesting that additional treatment strategies are needed. Here, an in vivo loss-of-function genome-wide CRISPR screen was carried out in orthotopic tumors in mice subjected to radiation treatment to identify synthetic lethal genes associated with radiotherapy. Using functional screening and transcriptome analyses, glutathione synthetase (GSS) was found to be a potential regulator of radioresistance through ferroptosis. High GSS levels were closely related to poor prognosis and relapse in patients with glioma. Mechanistic studies demonstrated that GSS was associated with the suppression of radiotherapy-induced ferroptosis in glioma cells. The depletion of GSS resulted in the disruption of glutathione (GSH) synthesis, thereby causing the inactivation of GPX4 and iron accumulation, thus enhancing the induction of ferroptosis upon radiotherapy treatment. Moreover, to overcome the obstacles to broad therapeutic translation of CRISPR editing, we report a previously unidentified genome editing delivery system, in which Cas9 protein/sgRNA complex was loaded into Angiopep-2 (Ang) and the trans-activator of the transcription (TAT) peptide dual-modified extracellular vesicle (EV), which not only targeted the blood-brain barrier (BBB) and GBM but also permeated the BBB and penetrated the tumor. Our encapsulating EVs showed encouraging signs of GBM tissue targeting, which resulted in high GSS gene editing efficiency in GBM (up to 67.2%) with negligible off-target gene editing. These results demonstrate that a combination of unbiased genetic screens, and CRISPR-Cas9-based gene therapy is feasible for identifying potential synthetic lethal genes and, by extension, therapeutic targets.


Assuntos
Vesículas Extracelulares , Glioblastoma , Glioma , Animais , Camundongos , Glioblastoma/genética , Glioblastoma/radioterapia , Sistemas CRISPR-Cas/genética , RNA Guia de Sistemas CRISPR-Cas , Vesículas Extracelulares/genética , Glutationa
20.
Cell Rep Methods ; 3(7): 100536, 2023 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-37533648

RESUMO

Li and colleagues have made a notable advancement in predicting cancer-associated thrombosis with a microfluidic device that monitors circulating platelet activity.1 This tool could improve the management of thrombotic events in patients with cancer, guiding timely treatment and potentially reducing mortality.


Assuntos
Neoplasias , Trombose , Humanos , Microfluídica , Trombose/diagnóstico , Plaquetas , Neoplasias/complicações
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