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1.
J Med Chem ; 2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36469401

RESUMO

Dual leucine zipper kinase (DLK) and leucine zipper-bearing kinase (LZK) are regulators of neuronal degeneration and axon growth. Therefore, there is a considerable interest in developing DLK/LZK inhibitors for neurodegenerative diseases. Herein, we use ligand- and structure-based drug design approaches for identifying novel amino-pyrazine inhibitors of DLK/LZK. DN-1289 (14), a potent and selective dual DLK/LZK inhibitor, demonstrated excellent in vivo plasma half-life across species and is anticipated to freely penetrate the central nervous system with no brain impairment based on in vivo rodent pharmacokinetic studies and human in vitro transporter data. Proximal target engagement and disease relevant pathway biomarkers were also favorably regulated in an in vivo model of amyotrophic lateral sclerosis.

2.
Cancer Manag Res ; 14: 3347-3358, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36465711

RESUMO

Purpose: The impact of primary tumour radiotherapy on the prognosis for non-small-cell lung cancer (NSCLC) with controlled malignant pleural effusion (MPE-C) (MPE-C-NSCLC) is unclear. This study aimed to analyze the efficacy and safety of primary tumor radiotherapy in patients with MPE-C-NSCLC. Patients and Methods: A total of 186 patients with MPE-C-NSCLC were enrolled and divided into two groups. The patients in the D group were treated with only drugs. Those in the RD group were treated with drugs plus primary tumour radiotherapy. The Kaplan-Meier method was used for survival analysis, and the Log rank test was used for between-group analysis and univariate prognostic analysis. The Cox proportional hazards model was used to perform multivariate analyses to assess the impacts of factors on survival. Propensity score matching (PSM) was matched based on clinical characteristics, systematic drug treatment and drug response to further adjust for confounding factors. Results: The overall survival (OS) rates at 1, 2, and 3 years for the RD group and D group were 54.4%, 26.8%, and 13.3% and 31.1%, 11.5%, and 4.4%, respectively; the corresponding MSTs were 14 months and 8 months, respectively (χ 2=15.915, p<0.001). There was a significant difference in survival by PSM (p=0.027).Before PSM, multivariate analysis showed that metastasis status (organ≤3 and metastasis≤5), primary tumour radiotherapy, chemotherapy cycles≥4, and drug best response (CR+PR) were independent predictors of prolonged OS. After PSM, primary tumour radiotherapy and drug best response (CR+PR) were independent predictors of prolonged OS were still independent predictors of prolonged OS. There were no grade 4-5 radiation toxicities. Conclusion: For MPE-C-NSCLC, the response of systemic drug treatment plays a crucial role in survival outcomes, and we also should pay attention to primary tumour radiotherapy in addition to systematic drug treatment.

3.
Cardiovasc Diabetol ; 21(1): 265, 2022 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-36461077

RESUMO

BACKGROUND: Dimethylarginine dimethylaminohydrolase (DDAH) 1 maintains the bioavailability of nitric oxide by degrading asymmetric dimethylarginine (ADMA). Here, we aimed to investigate the effect of haptoglobin (Hp) genotype on the association of ADMA and DDAH 1 polymorphism with diabetic macroangiopathy. METHODS: In stage 1, 90 Chinese participants with type 2 diabetes were enrolled to measure a panel of targeted metabolites, including ADMA, using tandem mass spectrometry (BIOCRATES AbsoluteIDQ™ p180 kit). In stage 2, an independent cohort of 2965 Chinese patients with type 2 diabetes was recruited to analyze the effect of Hp genotype on the association between DDAH 1 rs233109 and diabetic macroangiopathy. Hp genotypes were detected using a validated assay based on the TaqMan method. DDAH 1 rs233109 was genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy using the MassARRAY platform. RESULTS: In stage 1, serum ADMA levels correlated with common Hp genotypes (ß ± SE = - 0.049 ± 0.023, P = 0.035), but not with diabetic macroangiopathy (P = 0.316). In stage 2, the distribution of DDAH 1 rs233109 genotype frequencies was 15% (CC), 47% (TC), and 38% (TT), which was in Hardy-Weinberg equilibrium (P = 0.948). A significant Hp genotype by rs 233109 genotype interaction effect on diabetic macroangiopathy was found (P = 0.017). After adjusting for confounders, patients homozygous for rs233109 CC were more likely to develop diabetic macroangiopathy than those carrying TT homozygotes in the Hp 2-2 subgroup [odds ratio = 1.750 (95% confidence interval, 1.101-2.783), P = 0.018]. CONCLUSION: Hp genotype affects the association between DDAH 1 rs233109 and diabetic macroangiopathy in Chinese patients with type 2 diabetes.


Assuntos
Complicações do Diabetes , Diabetes Mellitus Tipo 2 , Doenças Vasculares , Humanos , Haptoglobinas/genética , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Genótipo
4.
J Mol Cell Biol ; 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36352530

RESUMO

Previous studies have indicated an association of fat mass and obesity-associated (FTO) with nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease worldwide. This study aimed to decipher the complex role of FTO in hepatic lipid metabolism. We found that a decrease in N6-methyladenosine (m6A) RNA methylation in the liver of mice fed with high-fat diet (HFD) was accompanied by an increase in FTO expression. Overexpression of FTO in the liver promoted triglyceride accumulation by upregulating the expression of lipogenic genes. Mechanistical studies revealed that FTO could stabilize the mRNAs of sterol regulatory element binding transcription factor 1 (SREBF1) and carbohydrate responsive element binding protein (ChREBP), two master lipogenic transcription factors, by demethylating m6A sites. Knockdown of either SREBF1 or ChREBP attenuated the lipogenic effect of FTO, suggesting that they are bona fide effectors for FTO in regulating lipogenesis. Insulin could stimulate FTO transcription through a mechanism involving the action of intranuclear insulin receptor beta, while knockdown of FTO abrogated the lipogenic effect of insulin. Inhibition of FTO by entacapone decreased the expression of SREBF1, ChREBP, and downstream lipogenic genes, ameliorating liver steatosis in HFD-fed mice. Thus, our study established a critical role of FTO in both the insulin-regulated hepatic lipogenesis and the pathogenesis of NAFLD and provided a potential strategy for treating NAFLD.

5.
J Asian Nat Prod Res ; : 1-8, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36355831

RESUMO

Two new dihydro-ß-agarofuran sesquiterpenes chiapen T (1) and chiapen U (2), along with chiapen A (3), 1ß-hydroxy-2ß,6α,12-triacetoxy-8ß-(ß-nicotinoyloxy)-9ß-(benzoyloxy)-ß-dihydroagarofuran (4), wilforlide B (5), 3-hydroxy-2-oxo-3-friedelen-29-oic acid (6), epikatonic acid (7), 22-epi-maytenfolic acid (8), maytenoic acid (9), wilforic acid F (10), wilforic acid B (11), were reported for the first time from the Celastrus angulatus. The structures of all the compounds were elucidated by HR-ESI-MS, 1 D and 2 D NMR spectra, as well as single-crystal X-ray diffraction analyses. Compounds 1 and 2 were examined for anti-inflammatory activity, respectively. None of them showed potent activity.

6.
Ophthalmic Res ; 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36380650

RESUMO

INTRODUCTION: The purpose of this study was to establish a novel and reversible experimental ocular hypertension primate model by blocking Schlemm's canal. METHODS: A model was induced in adult cynomolgus monkeys (n=4) by blocking Schlemm's canal with an inserted microcatheter (200 µm diameter); it was removed 6 weeks later from one monkey to reverse the elevated intraocular hypertension. All animals were monitored for 11 months; weekly measurements of intraocular pressure and biweekly examinations with spectral domain optical coherence tomography and disc photography were performed. Histopathology of the eye and retinal ganglion cell counts were completed at the end of the study. RESULTS: The intraocular pressure of the blocked eyes was significantly higher than that of the contralateral eyes at 1 month after the blockage (P <0.001); the mean intraocular pressure was similar to the contralateral eye from 1 week to 11 months after the microcatheter was removed in monkey A (P=0.170). The mean intraocular pressure of the blocked eyes of the remaining monkeys was significantly higher than that of the contralateral eyes throughout the follow-up period (P <0.001). The fundus imaging showed decreases in the retinal nerve fibre layer thickness, and localised defects were observed in two blocked eyes. A histological examination demonstrated that the number of retinal ganglion cells in blocked eyes of monkeys A, B, and C was significantly decreased compared with the control. CONCLUSION: Schlemm's canal blockage alone in the monkey model produces sustained elevation of intraocular pressure, which present a novel animal model for studying the pathogenesis of glaucoma.

7.
Trials ; 23(1): 933, 2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36348365

RESUMO

BACKGROUND: Acute pancreatitis (AP) is a common digestive disease with increased incidence globally but without internationally licenced pharmacological therapy. Moderately severe and severe acute pancreatitis (MSAP/SAP) contributes predominately for its morbidities and mortality and has been managed in West China Hospital for decades using the traditional Chinese medicinal formula chaiqin chengqi decoction (CQCQD). The current study tests whether the early administration of CQCQD will result in improved clinical outcomes in predicted MSAP/SAP patients. METHODS: This is a single-centre, randomised, controlled, double-blind pragmatic clinical trial. AP patients aged 18-75 admitted within 72 h of onset will be assessed at admission for enrolment. We excluded the predicted mild acute pancreatitis (Harmless Acute Pancreatitis Score > 2 at admission) and severe organ failure (Sequential Organ Failure Assessment [SOFA] score of respiratory, cardiovascular, or renal systems > 3) at admission. Eligible patients will be randomly allocated on a 1:1 basis to CQCQD or placebo control administration based on conventional therapy. The administration of CQCQD and placebo is guided by the Acute Gastrointestinal Injury grade-based algorithm. The primary outcome measure will be the duration of respiratory failure (SOFA score of respiratory system ≥ 2) within 28 days after onset. Secondary outcome measures include occurrence of new-onset any organ failure (SOFA score of respiratory, cardiovascular, or renal system ≥ 2) and new-onset persistent organ failure (organ failure lasts > 48 h), dynamic surrogate biochemical markers and clinical severity scores, gut-centred treatment modalities, local complications status, intensive care need and duration, surgical interventions, mortality, and length of hospital stay. Follow-up will be scheduled on 6, 12, and 26 weeks after enrolment to assess AP recurrence, local complications, the requirement for surgical interventions, all-cause mortality, and patient-reported outcomes. DISCUSSION: The results of this study will provide high-quality evidence to appraise the efficacy of CQCQD for the early management of AP patients. TRIAL REGISTRATION: Chictr.org.cn Registry ( ChiCTR2000034325 ). Registered on 2 July, 2020.


Assuntos
Medicamentos de Ervas Chinesas , Pancreatite , Humanos , Doença Aguda , Medicamentos de Ervas Chinesas/efeitos adversos , Pulmão , Pancreatite/diagnóstico , Pancreatite/tratamento farmacológico , Pancreatite/complicações , Ensaios Clínicos Controlados Aleatórios como Assunto , Ensaios Clínicos Pragmáticos como Assunto
8.
Cell Biochem Biophys ; 2022 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-36445617

RESUMO

Muscarinic acetylcholine receptor subtype 3 (M3 receptor) is a G Protein-Coupled Receptor (GPCR) that mediates many important physiological functions. Currently, most M3 receptor drugs also have high affinity for other subtypes of muscarinic acetylcholine receptors (mAChRs) and produce the risk of side effects. Therefore, in order to find M3 receptor drugs with high specificity, high activity and low side effects, we established a cell model and method for efficient and sensitive screening of M3 receptor based on calcium-activated chloride channels (CaCCs), and this method is also suitable for the screening of other GPCR drugs. This screening model consists of Fischer rat thyroid follicular epithelial (FRT) cells that endogenously express M3 receptors, CaCCs, and the indicator YFP-H148Q/I152L. We verified that the model can sensitively detect changes in intracellular Ca2+ concentration using fluorescence quenching kinetics experiments, confirmed the screening function of the model by applying available M3 receptor drugs, and also evaluated the good performance of the model in high-throughput screening.

9.
ISA Trans ; 2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36446687

RESUMO

This paper is concentrated on the fixed/preassigned-time (FXT/PAT) synchronization of multilayered networks, in which the self-dynamics of nodes are heterogeneous and the synchronized state can be an arbitrary prescribed smooth orbit. Above all, the original network is augmented by involving the synchronized state as a virtual node, it is allowed to remove the topological connectivity limitations and reduce the conservatism of the synchronization conditions. Subsequently, several continuous control protocols have been developed to achieve FXT synchronization and some effective criteria are established by utilizing the theorem of FXT stability. Additionally, the relationship is revealed between the estimation of the synchronized time and the layer parameter. Moreover, the PAT synchronization is investigated for a preassigned synchronized time by proposing two control schemes with finite control gains. Eventually, the developed control designs and criteria are validated by some numerical simulations.

11.
Biomaterials ; 291: 121909, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36401954

RESUMO

Degradable heart occluders are a promising replacement for currently clinically used non-degradable ones without concerns about the complications caused by the persistent residue of a foreign implant. However, the inherent mechanical properties of degradable occluders are poor and decline with material degradation, leading to a preference for a long degradation period upon designing a degradable heart occluder. This configuration can lower the risk of occluder dislodgement but reduce the benefits of degradable implants over their non-degradable counterparts due to a longer retention of foreign materials in the human body. Here, we fabricated a fully degradable ventricular septum defect (VSD) occluder consisting of polydioxanone (PDO) fiber and poly-L-lactic acid (PLLA) membrane featuring an auto-locking function. The degradable occluder showed an excellent shape recovery effect after transcatheter delivery and anchored securely to a heart defect as evidenced by in vitro and in vivo experiments. The degradable occluder could warrant robust fixation ability during the first 3-months of implantation within which tissue reconstruction was accomplished and be completely absorbed within 12 months. Benefitting from these merits, the degradable occluder displayed desired occlusion and no complications after being implanted in the VSD sites of canines during a 24-months follow-up. Compared with traditional non-degradable occluders, our degradable occluder could provide a potentially superior approach for rapidly repairing the congenital VSD without interfering with the normal development and physiological function of the heart.


Assuntos
Corpos Estranhos , Comunicação Interventricular , Humanos , Animais , Cães , Comunicação Interventricular/cirurgia , Coração , Regeneração
12.
Artigo em Inglês | MEDLINE | ID: mdl-36430016

RESUMO

Stabilization technology is widely used in the remediation of heavy metal-contaminated farmland soil. However, the evaluation method for the remediation effect is not satisfactory. To scientifically evaluate the remediation effect, this study constructed a comprehensive evaluation system by bibliometric analysis and an analytic hierarchy process (AHP). Ultimately, 16 indicators were selected from three aspects of the soil, crops, and amendment. The 16 indicators are divided into three groups, namely indicators I that can be evaluated according to the national standards of China, indicators II that can be evaluated according to the classification management of farmland and Indicators III that are the dynamic change indicators without an evaluation criterion. Comprehensive scores for 16 indicators were calculated using three response models, respectively. According to the difference between the scores before and after the remediation, the remediation effect is divided into five levels, which are excellent, good, qualified, poor, and very poor. This study provides a theoretical basis and insightful information for a farmland pollution remediation and a sustainable utilization.


Assuntos
Recuperação e Remediação Ambiental , Metais Pesados , Processo de Hierarquia Analítica , Poluição Ambiental , Solo
13.
J Inflamm Res ; 15: 6357-6371, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36424918

RESUMO

Purpose: To explore the effect of PD-1 inhibitors combined with irradiation on myocardial injury and the changes of HMGB1-associated inflammatory markers. Methods: Four groups of five mice were used, each groupformed by randomly dividing 20 mice (group A control; group B PD-1 inhibitors; group C Irradiation; group D PD-1 inhibitors+irradiation; n = 5 for each). The mice were treated with either PD-1 inhibitors or a 15 Gy dose of single heart irradiation, or both. Hematoxylin-eosin staining assessed the morphology and pathology of heart tissue; Masson staining assessed heart fibrosis; Tunel staining evaluated heart apoptosis; flow cytometry detected CD3+, CD4+, and CD8+ T lymphocytes in heart tissues; enzyme linked immunosorbent assay evaluated IL-1ß, IL-6, and TNF-ɑ of heart tissue; Western blot and quantitative real-time PCR (qPCR) detected the expression of protein and mRNA of HMGB1, TLR-4, and NF-κB p65 respectively. Results: The degree of heart injury, collagen volume fraction (CVF) and apoptotic index (AI) in groups B, C, and D were higher than group A, but the differences between the CVF and AI of group A and group B were not statistical significance (P>0.05). Similarly, the absolute counts and relative percentage of CD3+ and CD8+ T lymphocytes and the concentrations of IL-1ß, IL-6, and TNF-α in heart tissue with group D were significantly higher than the other groups (P<0.05). In addition, compared with group A, the expression of protein and mRNA of HMGB1 and NF-κB p65 in other groups were higher, and the differences between each group were statistically significant while TLR4 was not. In addition, interaction by PD-1 inhibitors and irradiation was found in inflammatory indicators, especially in the expression of the HMGB1 and CD8+ T lymphocytes. Conclusion: PD-1 inhibitors can increase the expression of HMGB1-associated inflammatory cytokines and aggravate radiation-induced myocardial injury.

14.
Sensors (Basel) ; 22(21)2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36366114

RESUMO

Cutting tool wear state assessment during the manufacturing process is extremely significant. The primary purpose of this study is to monitor tool wear to ensure timely tool change and avoid excessive tool wear or sudden tool breakage, which causes workpiece waste and could even damage the machine. Therefore, an intelligent system, that is efficient and precise, needs to be designed for addressing these problems. In our study, an end-to-end improved fine-grained image classification method is employed for workpiece surface-based tool wear monitoring, which is named efficient channel attention destruction and construction learning (ECADCL). The proposed method uses a feature extraction module to extract features from the input image and its corrupted images, and adversarial learning is used to avoid learning noise from corrupted images while extracting semantic features by reconstructing the corrupted images. Finally, a decision module predicts the label based on the learned features. Moreover, the feature extraction module combines a local cross-channel interaction attention mechanism without dimensionality reduction to characterize representative information. A milling dataset is conducted based on the machined surface images for monitoring tool wear conditions. The experimental results indicated that the proposed system can effectively assess the wear state of the tool.

15.
J Am Chem Soc ; 2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36417425

RESUMO

Phosphine ligands are the most important class of ligands for cross-coupling reactions due to their unique electronic and steric properties. However, metalloproteins generally rely on nitrogen, sulfur, or oxygen ligands. Here, we report the genetic incorporation of P3BF, which contains a biocompatible borane-protected phosphine, into proteins. This step is followed by a straightforward one-pot strategy to perform deboronation and palladium coordination in aqueous and aerobic conditions. The genetically encoded phosphine ligand P3BF should significantly expand our ability to design functional metalloproteins.

16.
Leukemia ; 2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36352191

RESUMO

The patients with relapsed and refractory diffuse large B-cell lymphoma (DLBCL) have poor prognosis, and a novel and effective therapeutic strategy for these patients is urgently needed. Although ubiquitin-specific protease 1 (USP1) plays a key role in cancer, the carcinogenic effect of USP1 in B-cell lymphoma remains elusive. Here we found that USP1 is highly expressed in DLBCL patients, and high expression of USP1 predicts poor prognosis. Knocking down USP1 or a specific inhibitor of USP1, pimozide, induced cell growth inhibition, cell cycle arrest and autophagy in DLBCL cells. Targeting USP1 by shRNA or pimozide significantly reduced tumor burden of a mouse model established with engraftment of rituximab/chemotherapy resistant DLBCL cells. Pimozide significantly retarded the growth of lymphoma in a DLBCL patient-derived xenograft (PDX) model. USP1 directly interacted with MAX, a MYC binding protein, and maintained the stability of MAX through deubiquitination, which promoted the transcription of MYC target genes. Moreover, pimozide showed a synergetic effect with etoposide, a chemotherapy drug, in cell and mouse models of rituximab/chemotherapy resistant DLBCL. Our study highlights the critical role of USP1 in the rituximab/chemotherapy resistance of DLBCL through deubiquitylating MAX, and provides a novel therapeutic strategy for rituximab/chemotherapy resistant DLBCL.

17.
Nat Commun ; 13(1): 7260, 2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36434066

RESUMO

G-protein-signaling modulator 1 (GPSM1) exhibits strong genetic association with Type 2 diabetes (T2D) and Body Mass Index in population studies. However, how GPSM1 carries out such control and in which types of cells are poorly understood. Here, we demonstrate that myeloid GPSM1 promotes metabolic inflammation to accelerate T2D and obesity development. Mice with myeloid-specific GPSM1 ablation are protected against high fat diet-induced insulin resistance, glucose dysregulation, and liver steatosis via repression of adipose tissue pro-inflammatory states. Mechanistically, GPSM1 deficiency mainly promotes TNFAIP3 transcription via the Gαi3/cAMP/PKA/CREB axis, thus inhibiting TLR4-induced NF-κB signaling in macrophages. In addition, we identify a small-molecule compound, AN-465/42243987, which suppresses the pro-inflammatory phenotype by inhibiting GPSM1 function, which could make it a candidate for metabolic therapy. Furthermore, GPSM1 expression is upregulated in visceral fat of individuals with obesity and is correlated with clinical metabolic traits. Overall, our findings identify macrophage GPSM1 as a link between metabolic inflammation and systemic homeostasis.


Assuntos
Diabetes Mellitus Tipo 2 , Camundongos , Animais , Diabetes Mellitus Tipo 2/metabolismo , Camundongos Endogâmicos C57BL , Macrófagos/metabolismo , Obesidade/metabolismo , Inflamação/metabolismo , Homeostase , Inibidores de Dissociação do Nucleotídeo Guanina/metabolismo
18.
Dig Dis ; 2022 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-36257291

RESUMO

BACKGROUND: Immune checkpoint inhibitors (ICIs) have improved survival outcomes and resulted in long-term responses in primary liver cancer in some patients. However, its efficacy is limited by the risk of tumor recurrence, resulting in rapid death and graft loss if patients are not selected appropriately. Therefore, it is necessary to identify patients suitable for such therapy. METHODS: 215 patients with primary liver cancer with immunotherapy were screened between August 2018 and October 2020 as a training set and our validation set were included 71 patients of hepatocellular carcinoma from Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College from May 2019 to July 2021. The primary endpoint was the disease control rate (DCR), and the secondary endpoints were overall survival (OS) and progression-free survival (PFS). RESULTS: In the traing set, Neutrophil-leukocyte ratio (NLR) >3, Alpha-fetoprotein (AFP) level >20 ng/ml, distant metastasis at baseline, and absence of combination with targeted therapy were associated with non-DCR in the training set. Moreover, NLR >3 and AFP level >20 ng/ml were also independently associated with OS. Furthermore, a hepatic immune predictive index (HIPI) based on NLR >3 and AFP level >20 ng/mL was developed and associated with worse clinical outcomes. In validation set, HIPI was associated with overall survival. CONCLUSION: Baseline hepatic immune predictive index based on NLR and AFP level is an effective indicator in ICI-treated patients with primary liver cancer. Our findings may help guide the selection and on-treatment strategies for immunotherapies for primary liver cancer patients.

19.
Phytother Res ; 2022 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-36281060

RESUMO

The treatments currently used for prostate cancer (PC) do not meet clinical needs, and thus, new therapies with greater effectiveness are urgently required. Metabolic reprogramming of tumor cells is emerging as an exciting field for cancer therapy. Although the Warburg effect is a common feature of glucose metabolism in many cancers, PC cells have a unique metabolic phenotype. Non-neoplastic prostate cells show reduced oxidative phosphorylation (OXPHOS) because large, accumulated zinc inhibits citrate oxidation. During transformation, there are low levels of zinc in PC cells, and the tricarboxylic acid (TCA) cycle is reactivated. However, metastatic PC exhibits the Warburg effect. Due to metabolic differences in prostate tissue, targeting metabolic alterations in PC cells is an attractive therapeutic strategy. In this study, we investigated the effect of juglone on energy metabolism in PC cells. We found that juglone inhibited cell proliferation and induced apoptosis. Mechanistically, we demonstrated that juglone suppressed OXPHOS and glycolysis due to its inhibition of hexokinase (HK), phosphofructokinase (PFK), and pyruvate kinase (PK) activity. Furthermore, downregulation of PFK and PK, but not HK contributed to the inhibition of these enzyme activities. The current study indicates that further development of juglone for PC treatment would be beneficial.

20.
Int J Mol Sci ; 23(20)2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36293504

RESUMO

As the most common cancer of the genitourinary system, prostate cancer (PCa) is a global men's health problem whose treatments are an urgent research issue. Treatment options for PCa include active surveillance (AS), surgery, endocrine therapy, chemotherapy, radiation therapy, immunotherapy, etc. However, as the cancer progresses, the effectiveness of treatment options gradually decreases, especially in metastatic castration-resistant prostate cancer (mCRPC), for which there are fewer therapeutic options and which have a shorter survival period and worse prognosis. For this reason, oncolytic viral therapy (PV), with its exceptional properties of selective tumor killing, relatively good safety in humans, and potential for transgenic delivery, has attracted increasing attention as a new form of anti-tumor strategy for PCa. There is growing evidence that OV not only kills tumor cells directly by lysis but can also activate anticancer immunity by acting on the tumor microenvironment (TME), thereby preventing tumor growth. In fact, evidence of the efficacy of this strategy has been observed since the late 19th century. However, subsequently, interest waned. The renewed interest in this therapy was due to advances in biotechnological methods and innovations at the end of the 20th century, which was also the beginning of PCa therapy with OV. Moreover, in combination with chemotherapy, radiotherapy, gene therapy or immunotherapy, OV viruses can have a wide range of applications and can provide an effective therapeutic result in the treatment of PCa.


Assuntos
Terapia Viral Oncolítica , Vírus Oncolíticos , Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/terapia , Imunoterapia , Microambiente Tumoral , Terapia Genética , Vírus Oncolíticos/genética
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