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1.
Ultrason Sonochem ; 79: 105772, 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34624663

RESUMO

In this study, daidzein microparticles (DMP) were prepared using an improved ultrasound-assisted antisolvent precipitation method. Preliminary experiments were conducted using six single-factor experiments, and principal component analysis (PCA) was adopted to obtain the three staple elements of the ultrasonic power, solution concentration, and nozzle diameter. The response surface Box-Behnken (BBD) design was used to optimize the level of the above factors. The optimal preparation conditions of the DMP were obtained as follows: the flow rate was 4 mL/min, the concentration of the daidzein solution was 16 mg/mL, the ratio of antisolvent to solvent (liquid-to-liquid ratio) was 9, the nozzle diameter was 300 µm, the ultrasonic power was 180 W (665 W/L), and the system speed was 760 r/min. The minimum average particle size of DMP was 181 ± 2 nm. The properties of daidzein particles before and after preparation were analyzed via scanning electron microscopy, X-ray diffraction analysis, Differential scanning calorimetry and Fourier transform infrared spectroscopy, no obvious change in its chemical structure was observed, but crystallinity was reduced. Compared with daidzein powder, DMP has a higher solubility and stronger antioxidant capacity. The above results indicate that the improved method of ultrasonication combined with antisolvent can reduce the size of daidzein particles and has a great potential in practical production.

2.
Medicine (Baltimore) ; 100(37): e27220, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34664859

RESUMO

ABSTRACT: The visualization of intrahepatic hepatitis B virus (HBV) DNA by in situ hybridization (ISH) has uncovered some interesting aspects of HBV life cycle at the single-cell level. In the current study, we intend to evaluate the reliability and robustness of this assay in the real-world clinical scenario and its relationship with currently available clinical biomarkers in chronic hepatitis B (CHB) patients.In this cross-sectional study, 94 CHB patients and 10 patients with non-HBV related liver diseases were enrolled. Liver biopsies and routine histopathology analysis were performed. Intrahepatic HBV DNA and viral antigens (HBsAg and HBcAg) were detected by ISH and immunohistochemistry (IHC), respectively. The basic biochemical and virological parameters such as alanine transaminase, serum HBV DNA, and serum HBsAg were measured.The HBV DNA-ISH assay showed 55.8% (53/94 cases) positive rate in CHB patients, no false positive was found in non-HBV related hepatitis. The IHC of HBsAg and HBcAg showed a positive rate of 94.7% (89/94 cases) and 19.5% (17/87 cases), respectively. Quantification of HBV DNA-ISH signal showed a significant correlation with serum HBV DNA (rs = 0.6223, P < .0001). In addition, the staining pattern of HBV DNA in situ in the context of collagen deposition informed the histopathological progression of chronic liver disease.The application of this ISH assay in evaluating intrahepatic viral replication in real-world CHB patients showed favorable performance. It can be a complementation to conventional liver histopathology examination and IHC detection of viral antigens. This methodology provides an intuitive assessment of virological and pathological state of CHB patients, and further supports clinical diagnosis and management.

3.
Chemosphere ; : 132605, 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34678346

RESUMO

Trapa japonica was observed to have inhibiting effects and could be used as a potential environment-friendly control strategy for cyanobacterial blooms in freshwater. However, the changes and effecting mechanisms in eukaryotic and prokaryotic communities by T. japonica are not yet clear. In this study, the effects of T. japonica on microbial communities were assessed in Lake Qionghai and Lake Erhai by 18S rRNA and 16S rRNA amplicon sequencing, respectively. The results showed that T. japonica can improve biodiversity and change the microbial community structures to varying degrees in both lakes. The alpha diversity indexes of microbial communities (e.g., Shannon, Sobs, Ace and Chao 1) were higher in the water inhabited by T. japonica (TJ group) than the water uninhabited by T. japonica (control) (P < 0.05). The PCoA results suggested that the microbial community compositions differed between the two groups (PERMANOVA P = 0.001). In Lake Qionghai, the relative abundances of dominant taxa and nutrients level showed little differences between the two groups. These may result from the homogenous water condition in Lake Qionghai. While the genera Cyanobium_PCC-6307, the majority of Cyanobacteria, decreased significantly in TJ group than control according to 16S rRNA gene sequencing. In Lake Erhai, environmental variables were distinctly affected by T. japonica, which was found to drive Cryptophyceae to become the main taxa through taxonomic analysis of 18S rRNA. Based on 16S rRNA gene sequencing, T. japonica reduced the relative abundance of Cyanobacteria, such as Planktothrix_NIVA-CYA_15 and Cyanobium_PCC-6307, by enriching cyanobactericidal bacteria and growth-inhibiting bacteria (e.g., Limnohabitans and Flavobacterium) and changing environmental parameters. Our results revealed that T. japonica acts in shaping microbial communities in lakes on the community level, shedding new lights on eutrophication mitigation, one of the most serious global ecological problems we are facing.

4.
Front Neurol ; 12: 680474, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34531812

RESUMO

The Rey-Osterrieth Complex Figure (ROCF) test is a commonly used neuropsychological assessment tool. It is widely used to assess the visuo-constructional ability and visual memory of neuropsychiatric disorders, including copying and recall tests. By drawing the complex figure, the functional decline of a patient in multiple cognitive dimensions can be assessed, including attention and concentration, fine-motor coordination, visuospatial perception, non-verbal memory, planning and organization, and spatial orientation. This review first describes the different versions and scoring methods of ROCF. It then reviews the application of ROCF in the assessment of visuo-constructional ability in patients with dementia, other brain diseases, and psychiatric disorders. Finally, based on the scoring method of the digital system, future research hopes to develop a new digital ROCF scoring method combined with machine learning algorithms to standardize clinical practice and explore the characteristic neuropsychological structure information of different disorders.

5.
Front Surg ; 8: 726067, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34568419

RESUMO

Objective: The present study aimed to explore the application value of magnetic resonance imaging (MRI) histograms with multiple sequences in the preoperative differential diagnosis of endometrial stromal sarcoma (ESS) and degenerative hysteromyoma (DH). Methods: The clinical and preoperative MRI data of 20 patients with pathologically confirmed ESS and 24 patients with pathologically confirmed DH were retrospectively analyzed, forming the two study groups. Mazda software was used to select the MRI layer with the largest tumor diameter in T2WI, the apparent diffusion coefficient (ADC), and enhanced T1WI (T1CE) images. The region of interest (ROI) was outlined for gray-scale histogram analysis. Nine parameters-the mean, variance, kurtosis, skewness, 1st percentile, 10th percentile, 50th percentile, 90th percentile, and 99th percentile-were obtained for intergroup analysis, and the receiver operating curves (ROCs) were plotted to analyze the differential diagnostic efficacy for each parameter. Results: In the T2WI histogram, the differences between the two groups in seven of the parameters (mean, skewness, 1st percentile, 10th percentile, 50th percentile, 90th percentile, and 99th percentile) were statistically significant (P < 0.05). In the ADC histogram, the differences between the two groups in three of the parameters (skewness, 10th percentile, and 50th percentile) were statistically significant (P < 0.05). In the T1CE histogram, no significant differences were found between the two groups in any of the parameters (all P > 0.05). Of the nine parameters, the 50th percentile was found to have the best diagnostic efficacy. In the T2WI histogram, ROC curve analysis of the 50th percentile yielded the best area under the ROC curve (AUC; 0.742), sensitivity of 70%, and specificity of 83.3%. In the ADC histogram, ROC curve analysis of the 50th percentile yielded the best area under the ROC curve (AUC; 0.783), sensitivity of 81%, and specificity of 76.9%. Conclusion: The parameters of the mean, 10th percentile and 50th percentile in the T2WI histogram have good diagnostic efficacy, providing new methods and ideas for clinical diagnosis.

6.
Neurobiol Stress ; 15: 100396, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34568523

RESUMO

Adenosine deaminase acting on RNA1 (ADAR1) is a newly discovered epigenetic molecule marker that is sensitive to environmental stressors. A recent study has demonstrated that ADAR1 affects BDNF expression via miR-432 and is involved in antidepressant action. However, the detailed molecular mechanism is still unclear. We have uncovered a new molecular mechanism showing the involvement of miR-432 and circ_0000418 in mediating the antidepressant action of ADAR1. We demonstrate that the ADAR1 inducer (IFN-γ) alleviates the depressive-like behaviors of BALB/c mice treated with chronic unpredictable stress (CUS) exposure. Moreover, both in vivo and in vitro studies show that ADAR1 differently impacts miR-432 and circ_0000418 expressions. Furthermore, the in vitro results demonstrate that circ_0000418 oppositely affects BDNF expression. Together, our results indicate that ADAR1 affects CUS-induced depressive-like behavior and BDNF expression by acting on miR-432 and circ_0000418. Elucidation of this new molecular mechanism will not only provide insights into further understanding the important role of ADAR1 in stress-induced depressive-like behavior but also suggest a potential therapeutic strategy for developing novel anti-depressive drugs.

7.
Psychol Trauma ; 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34498899

RESUMO

OBJECTIVE: Empirically supported treatments (ESTs) have been criticized for lack of ethnoracial representation, which may limit the generalizability of findings for non-White patients. This study assessed ethnoracial representation in United States-based randomized controlled trials (RCTs) for three evidence-based treatments for posttraumatic stress disorder (PTSD)-Prolonged Exposure (PE), Cognitive Processing Therapy (CPT), and Eye-Movement Desensitization and Reprocessing (EMDR). METHOD: Representation was measured by explicit inclusion of people of color in published PTSD RCTs. Follow-up emails were sent to corresponding authors if full demographic information was not included in the reviewed manuscripts. Information concerning participant remuneration was collected for descriptive purposes. RESULTS: All three treatment modalities reported White participants as the majority in their sample. PE and CPT trials reported similar levels of ethnoracial diversity, while EMDR efficacy studies reported the least ethnoracial diversity. Across the reviewed studies, with few exceptions, we found low numbers of non-White participants in the majority of reviewed studies, which was compounded by poor or unclear methods of reporting ethnoracial information. CONCLUSIONS: This study demonstrates that the ESTs for PTSD are not adequately representative of the majority of non-White participants. Future RCTs should place a stronger emphasis on broad ethnoracial diversity in study participants to improve generalizability of findings. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

8.
Anal Chem ; 93(38): 12914-12920, 2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34523343

RESUMO

Flow battery electrodes are vital for performing redox reactions, and an in-depth understanding of reaction kinetics and spatial distribution differences in electrodes is very important for improving the efficiency of electrochemical reactions. In this study, a reflection-type phase-sensitive weak measurement imaging system was developed for the detection of flow batteries. The phase difference between two polarization components in total internal reflection caused by electrode redox processes was measured by weak value amplification. The resulting refractive index resolution of the imaging system was estimated to be 2.8-4.2 × 10-6 RIU. The real-time monitoring ability of the system was demonstrated by linear sweep voltammetry tests of vanadium redox batteries. Compared to traditional optical methods, the proposed weak measurement imaging sensor did not require coating, as it can be used in acid electrolytes of vanadium flow batteries. Meanwhile, the weak value amplification effect led to a higher resolution than the total internal reflection system shown in our previous work, thereby resulting in more accurate detection of electrochemical reactions. In sum, the proposed sensor looks very promising for the detection of electrochemical reactions in flow batteries, water splitting, electrochemical corrosion, and electrocatalysis.


Assuntos
Fontes de Energia Elétrica , Eletrólitos , Eletrodos , Oxirredução , Vanádio
9.
J Med Chem ; 64(19): 14895-14911, 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34546748

RESUMO

The major drawbacks of P-glycoprotein (P-gp) inhibitors at the clinical stage make the development of new P-gp inhibitors challenging and desirable. In this study, we reported our structure-activity relationship studies of 4-indolyl quinazoline, which led to the discovery of a highly effective and orally active P-gp inhibitor, YS-370. YS-370 effectively reversed multidrug resistance (MDR) to paclitaxel and colchicine in SW620/AD300 and HEK293T-ABCB1 cells. YS-370 bound directly to P-gp, did not alter expression or subcellular localization of P-gp in SW620/AD300 cells, but increased the intracellular accumulation of paclitaxel. Furthermore, YS-370 stimulated the P-gp ATPase activity and had moderate inhibition against CYP3A4. Significantly, oral administration of YS-370 in combination with paclitaxel achieved much stronger antitumor activity in a xenograft model bearing SW620/Ad300 cells than either drug alone. Taken together, our data demonstrate that YS-370 is a promising P-gp inhibitor capable of overcoming MDR and represents a unique scaffold for the development of new P-gp inhibitors.

10.
Artigo em Inglês | MEDLINE | ID: mdl-34477345

RESUMO

BACKGROUND: To determine the thyroid uptake rate by correcting the background and analyse its clinical significance. METHODS: The study included 161 patients with hyperthyroidism. The thyroid uptake rate was calculated by drawing a 100 pixels ROI (Region of Interest) background, above and below the thyroid and correcting the thyroid ROI for background counting. At the same time, the clinical baseline characteristic parameters such as age and thyroid volume etc. of patients with hyperthyroidism were collected. The consistency of 9mTcO4uptake rate before treatment and 131I-uptake rate after treatment, and the correlation between uptake rate of thyroid and baseline characteristic parameters were also analysed. RESULTS: The uptake rate of 99mTcO4 was found positively correlated with 3 h-RAIU, 24 h-RAIU, 3 h/24 h conversion rate, thyroid volume, 131I activity FT3 and FT4, and showed negative correlation with age, effective half-life. (P<0.05). The uptake rate of 131I was found positively correlated with 3 h-RAIU, 24 h-RAIU, 3 h/24 h conversion rate, thyroid volume, 131I activity, FT3, FT4. (P<0.05). In patients with positive thyrotrophin receptor antibody (TRAb), a significant positive correlation between uptake rate of 99mTcO4 and 131I (P<0.05) was observed. There was a high consistency between pre-treatment uptake rate of 99mTcO4 and post-treatment uptake rate of 131I (P = 0.009; W = 0.7). CONCLUSIONS: The corrected thyroid uptake rate is remarkably correlated with clinical characteristic parameters of patients, which can be used to comprehensively evaluate the comprehensive condition of patients with hyperthyroidism.

11.
Artigo em Inglês | MEDLINE | ID: mdl-34504531

RESUMO

Pulse lavage (PL) debridement and ultrasound are both known to be the treatment of biofilm-related periprosthetic joint infection (PJI). However, the efficacy of these in combination is unknown in eradicating biofilm from the orthopaedic metal implant surface. This study was conducted to understand the efficacy of PL and ultrasound in combination in eradicating bacterial biofilms on titanium alloy in vitro. Biofilms of Staphylococcus aureus strains were grown on titanium alloy coupons for 24 h. Then, the coupons were taken to each treatment group: (i) debrided with PL, (ii) exposed to ultrasound, or (iii) exposed to both. An untreated biofilm was set as a control group. Viable plate count and confocal microscopy using live/dead staining was used to measure the amount of biofilm. Viable plate count showed an approximate two-log reduction in CFU/cm2 in PL alone, from an initial cell count on the mental surface of approximately 109 CFU/cm2. The ultrasound caused an approximate seven-log reduction, and the combination group eradicated viable biofilm bacteria completely. Confocal imaging corroborated the CFU data. Our results indicate that PL and ultrasound both are remarkably in eradicating biofilm, and the combination of PL and ultrasound is more effective than alone in reducing biofilm.

12.
Foods ; 10(8)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34441574

RESUMO

Plasticizers and the water migration of edible protein films during storage can result in changes in film properties, while specific changing processes need to be further explored. In this study, glycerol-plasticized soy protein isolate (SPI) films were stored at 25 °C, 4 °C, and -18 °C for 6 weeks (relative humidity (RH), 40-50%). The glycerol migration was monitored by the glycerol migration rate and differential scanning calorimetry (DSC). Water content, low-field nuclear magnetic resonance (LF-NMR), and thermogravimetric analysis (TGA) were used to analyze the water state. The results showed that significant pores and cracks were observed after storage at 25 °C. The proportion of bound water gradually increased, and the glycerol migration rate also reached 1.3% and 0.7% at 25 °C and 4 °C, respectively. The results proved that increasing the storage temperature accelerated the loss of water and glycerol, and decreased the mechanical properties of the SPI film.

13.
Front Cardiovasc Med ; 8: 690116, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34368250

RESUMO

With improvement in living standards and average life expectancy, atherosclerotic cardiovascular disease incidences and mortality have been increasing annually. Paeonia suffruticosa, a natural herb, has been used for the treatment of atherosclerotic cardiovascular disease for thousands of years in Eastern countries. Paeonol is an active ingredient extracted from Paeonia suffruticosa. Previous studies have extensively explored the clinical benefits of paeonol. However, comprehensive reviews on the cardiovascular protective effects of paeonol have not been conducted. The current review summarizes studies reporting on the protective effects of paeonol on the cardiovascular system. This study includes studies published in the last 10 years. The biological characteristics of Paeonia suffruticosa, pharmacological mechanisms of paeonol, and its toxicological and pharmacokinetic characteristics were explored. The findings of this study show that paeonol confers protection against atherosclerotic cardiovascular disease through various mechanisms, including inflammation, platelet aggregation, lipid metabolism, mitochondria damage, endoplasmic reticulum stress, autophagy, and non-coding RNA. Further studies should be conducted to elucidate the cardiovascular benefits of paeonol.

14.
PLoS Pathog ; 17(8): e1009838, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34370796

RESUMO

Through evolution, Hepatitis B Virus (HBV) developed highly intricate mechanisms exploiting host resources for its multiplication within a constrained genetic coding capacity. Yet a clear picture of viral hitchhiking of cellular processes with spatial resolution is still largely unsolved. Here, by leveraging bDNA-based fluorescence in situ hybridization (FISH) combined with immunofluorescence, we developed a microscopic approach for multiplex detection of viral nucleic acids and proteins, which enabled us to probe some of the key aspects of HBV life cycle. We confirmed the slow kinetics and revealed the high variability of viral replication at single-cell level. We directly visualized HBV minichromosome in contact with acetylated histone 3 and RNA polymerase II and observed HBV-induced degradation of Smc5/6 complex only in primary hepatocytes. We quantified the frequency of HBV pregenomic RNAs occupied by translating ribosome or capsids. Statistics at molecular level suggested a rapid translation phase followed by a slow encapsidation and maturation phase. Finally, the roles of microtubules (MTs) on nucleocapsid assembly and virion morphogenesis were analyzed. Disruption of MTs resulted in the perinuclear retention of nucleocapsid. Meanwhile, large multivesicular body (MVB) formation was significantly disturbed as evidenced by the increase in number and decrease in volume of CD63+ vesicles, thus inhibiting mature virion secretion. In conclusion, these data provided spatially resolved molecular snapshots in the context of specific subcellular activities. The heterogeneity observed at single-cell level afforded valuable molecular insights which are otherwise unavailable from bulk measurements.

15.
Cancer Sci ; 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34431598

RESUMO

The Wnt/ß-catenin signaling pathway plays an important role in tissue homeostasis, and its malignant activation is closely related to the occurrence and development of many cancers, especially colorectal cancer with adenomatous polyposis coli (APC) and CTNNB1 mutations. By applying a TCF/lymphoid-enhancing factor (LEF) luciferase reporter system, the high-throughput screening of 18 840 small-molecule compounds was performed. A novel scaffold compound, C644-0303, was identified as a Wnt/ß-catenin signaling inhibitor and exhibited antitumor efficacy. It inhibited both constitutive and ligand activated Wnt signals and its downstream gene expression. Functional studies showed that C644-0303 causes cell cycle arrest, induces apoptosis, and inhibits cancer cell migration. Moreover, transcription factor array indicated that C644-0303 could suppress various tumor-promoting transcription factor activities in addition to Wnt/ß-catenin. Finally, C644-0303 suppressed tumor spheroidization in a 3-dimensional cell culture model and inhibited xenograft tumor growth in mice. In conclusion, we report a novel structural small molecular inhibitor targeting the Wnt/ß-catenin signaling pathway that has therapeutic potential for colorectal cancer treatment.

16.
Front Microbiol ; 12: 715450, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335553

RESUMO

Hepatitis B virus (HBV) infection is a global public health problem that plagues approximately 240 million people. Chronic hepatitis B (CHB) often leads to liver inflammation and aberrant repair which results in diseases ranging from liver fibrosis, cirrhosis, to hepatocellular carcinoma. Despite its narrow species tropism, researchers have established various in vivo models for HBV or its related viruses which have provided a wealth of knowledge on viral lifecycle, pathogenesis, and immunity. Here we briefly revisit over five decades of endeavor in animal model development for HBV and summarize their advantages and limitations. We also suggest directions for further improvements that are crucial for elucidation of the viral immune-evasion strategies and for development of novel therapeutics for a functional cure.

18.
J Control Release ; 336: 433-442, 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34197861

RESUMO

Random conjugations of chemotherapeutics to monoclonal antibodies result in heterogeneous antibody-drug conjugates (ADCs) with suboptimal pharmacological properties. We recently developed a new technology for facile generation of homogeneous ADCs by harnessing human CD38 catalytic domain and its dinucleotide-derived covalent inhibitor, termed ADP-ribosyl cyclase-enabled ADCs (ARC-ADCs). Herein we advance this technology by designing and synthesizing ARC-ADCs with customizable drug-to-antibody ratios (DARs). Through varying numbers and locations of CD38 fused to an antibody targeting human C-type lectin-like molecule-1 (hCLL-1), ARC-ADCs featuring DARs of 2 and 4 were rapidly generated via a single step with cytotoxic monomethyl auristatin F (MMAF) as payloads. In contrast to anti-hCLL-1 ARC-ADC carrying 2 drug molecules, anti-hCLL-1 ARC-ADC with a DAR of 4 shows highly potent activity in killing hCLL-1-positive acute myeloid leukemia (AML) cells both in vitro and in vivo. This work provides novel ADC candidates for combating AML and supports ARC-ADC as a general and versatile approach for producing site-specific ADCs with defined DARs.

19.
Cancer Manag Res ; 13: 5263-5273, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34239325

RESUMO

Purpose: Gastric cancer is a common tumor type associated with nutritional and immune status. The aim of the current study was to investigate the prognostic value of a preoperative prognostic nutritional index (PNI), composed of nutritional factors and immune factors in elderly patients undergoing gastric cancer surgery. Patients and Methods: A total of 454 patients undergoing gastric cancer surgery were divided into two groups based on preoperative PNI scores: ≤45.1 (n = 307) and >45.1 (n = 147). Survival analysis was performed using the Kaplan-Meier method and Log rank tests. Univariate and multivariate analyses were conducted to identify independent prognostic factors using a Cox proportional hazards model. Results: According to the X-tile program, the optimal cutoff value for predicting overall survival (OS) with the PNI was 45.1. The receiver operating characteristic analysis revealed that PNI exhibited 70.6% sensitivity and 56.5% specificity for predicting death during long-term follow-up. The cumulative incidence of postoperative 4-year mortality indicated that the risk of death increased significantly for PNI ≤45.1. In multivariate analysis, preoperative PNI was a significant independent predictor of mortality. In the age-stratified subgroup analysis, preoperative PNI was more sensitive for the old elderly subgroup than for the young elderly subgroup. Conclusion: Preoperative PNI is a sensitive and specific prognostic predictor among elderly patients undergoing gastric cancer surgery.

20.
Int J Mol Sci ; 22(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33947138

RESUMO

Ovarian clear cell carcinoma (OCCC) is a rare but chemorefractory tumor. About 50% of all OCCC patients have inactivating mutations of ARID1A, a member of the SWI/SNF chromatin-remodeling complex. Members of the SWI/SNF remodeling have emerged as regulators of the energetic metabolism of mammalian cells; however, the role of ARID1A as a modulator of the mitochondrial metabolism in OCCCs is yet to be defined. Here, we show that ARID1A loss results in increased mitochondrial metabolism and renders ARID1A-mutated cells increasingly and selectively dependent on it. The increase in mitochondrial activity following ARID1A loss is associated with increase in c-Myc expression and increased mitochondrial number and reduction of their size consistent with a higher mitochondrial cristae/outer membrane ratio. Significantly, preclinical testing of the complex I mitochondrial inhibitor IACS-010759 showed it extends overall survival in a preclinical model of ARID1A-mutated OCCC. These findings provide for the targeting mitochondrial activity in ARID1A-mutated OCCCs.


Assuntos
Adenocarcinoma de Células Claras/tratamento farmacológico , Antineoplásicos/uso terapêutico , Proteínas de Ligação a DNA/antagonistas & inibidores , Mitocôndrias/efeitos dos fármacos , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias Ovarianas/tratamento farmacológico , Oxidiazóis/uso terapêutico , Piperidinas/uso terapêutico , Fatores de Transcrição/antagonistas & inibidores , Adenocarcinoma de Células Claras/metabolismo , Adenocarcinoma de Células Claras/patologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Nus , Mitocôndrias/metabolismo , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Oxidiazóis/farmacologia , Fosforilação Oxidativa/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Piperidinas/farmacologia , Interferência de RNA , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Distribuição Aleatória , Esferoides Celulares , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Ensaios Antitumorais Modelo de Xenoenxerto
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