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1.
Sci Rep ; 11(1): 13778, 2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215839

RESUMO

Patients requiring low-dose warfarin are more likely to suffer bleeding due to overdose. The goal of this work is to improve the feedforward neural network model's precision in predicting the low maintenance dose for Chinese in the aspect of training data construction. We built the model from a resampled dataset created by equal stratified sampling (maintaining the same sample number in three dose-groups with a total of 3639) and performed internal and external validations. Comparing to the model trained from the raw dataset of 19,060 eligible cases, we improved the low-dose group's ideal prediction percentage from 0.7 to 9.6% and maintained the overall performance (76.4% vs. 75.6%) in external validation. We further built neural network models on single-dose subsets to invest whether the subsets samples were sufficient and whether the selected factors were appropriate. The training set sizes were 1340 and 1478 for the low and high dose subsets; the corresponding ideal prediction percentages were 70.2% and 75.1%. The training set size for the intermediate dose varied and was 1553, 6214, and 12,429; the corresponding ideal prediction percentages were 95.6, 95.1%, and 95.3%. Our conclusion is that equal stratified sampling can be a considerable alternative approach in training data construction to build drug dosing models in the clinic.

2.
Dig Dis Sci ; 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34241753

RESUMO

BACKGROUND: The predictors of persistent virological suppression after clinical relapse remain unclear. AIMS: To investigate the predictors of retreatment or persistent virological suppression after clinical relapse in chronic hepatitis B (CHB) patients who discontinued entecavir or tenofovir disoproxil fumarate (TDF). METHODS: A total of 243 hepatitis B e antigen-negative CHB patients without cirrhosis who experienced clinical relapse after entecavir or TDF cessation were enrolled. RESULTS: Of the 243 CHB patients, 192 received retreatment and 51 did not receive retreatment after clinical relapse. Of the 51 patients without retreatment, 23 achieved persistent virological suppression (persistent HBV DNA < 2000 IU/mL at least 2 years) and 10 experienced hepatitis B surface antigen (HBsAg) loss. The Cox regression analysis showed that short consolidation duration, short duration of the first clinical relapse from the end of treatment (EOT), and high bilirubin and HBV DNA levels at the first clinical relapse were independent predictors of retreatment. Long duration of the first clinical relapse from the EOT and low HBsAg levels at the first clinical relapse were independent factors of patients with persistent virological suppression. The rates of persistent virological suppression at the first clinical relapse among patients with HBsAg < 100 and ≥ 100 IU/mL were 44.4% (12/27) and 5.1% (11/216) (P < 0.001), respectively. Baseline HBsAg levels and no retreatment requirement were independent factors associated with HBsAg loss. CONCLUSIONS: The HBsAg of 100 IU/mL at the first clinical relapse could predict persistent virological suppression after clinical relapse in patients who discontinued entecavir or TDF therapy.

3.
EMBO Rep ; : e51978, 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34232545

RESUMO

Zika virus (ZIKV) infection during pregnancy is linked to various developmental brain disorders. Infants who are asymptomatic at birth might have postnatal neurocognitive complications. However, animal models recapitulating these neurocognitive phenotypes are lacking, and the circuit mechanism underlying behavioral abnormalities is unknown. Here, we show that ZIKV infection during mouse pregnancy induces maternal immune activation (MIA) and leads to autistic-like behaviors including repetitive self-grooming and impaired social memory in offspring. In the medial prefrontal cortex (mPFC), ZIKV-affected offspring mice exhibit excitation and inhibition imbalance and increased cortical activity. This could be explained by dysregulation of inhibitory neurons and synapses, and elevated neural activity input from mPFC-projecting ventral hippocampus (vHIP) neurons. We find structure alterations in the synaptic connections and pattern of vHIP innervation of mPFC neurons, leading to hyperconnectivity of the vHIP-mPFC pathway. Decreasing the activity of mPFC-projecting vHIP neurons with a chemogenetic strategy rescues social memory deficits in ZIKV offspring mice. Our studies reveal a hyperconnectivity of vHIP to mPFC projection driving social memory deficits in mice exposed to maternal inflammation by ZIKV.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34236165

RESUMO

Exosomes, which can transfer and deliver information about the original cell, are considered to be ideal candidates for early cancer diagnosis and evaluation of therapeutic efficacy due to their high abundance and stability. However, the highly expressed proteins on the surface of exosomes are usually associated with a variety of cancers; it is difficult to distinguish them by a single marker. Herein, a controlled self-assembly of gold nanorod (AuNR) arrays was prepared to construct a surface-enhanced Raman spectroscopy (SERS) sensor for the specific detection of exosomes secreted by SK-Br-3 cells based on a designed colocalization-dependent system (Co-DNA-Locker) and ratiometric strategy. After the exosomes are captured in the sensing array by the EpCAM aptamer modified on the surface of AuNRs, the DNA logic process occurs because the other two proteins, CD63 and HER2, are expressed simultaneously on the surface of exosomes secreted by SK-Br-3 cells, and the SERS signal intensity of the Rhodamine 6G (R6G) tagged on the terminal of DNA TE increased with an increase in the concentration of the exosomes, while the SERS signal intensity of Cy5 linked on the terminal of the EpCAM aptamer, which acts as an internal standard, remains stable. The AuNRs are uniformly arranged in a hexagonal shape, and the dense "hot spots" produce "hot surfaces," which greatly improve the sensitivity and uniformity of detection. In the presence of target exosomes, the DNA colocalization three-signal input switch and the ratiometric strategy realize the specific and accurate detection of exosomes. This sensing strategy achieves a wide detection range (1.0 × 104-5.0 × 106 particles/mL) and a lower detection limit (5.3 × 103 particles/mL), without using any signal amplification mechanism, demonstrating promising applications in health care monitoring and clinical diagnostics.

5.
Clin Lab ; 67(7)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34258971

RESUMO

BACKGROUND: The aim of this study was to evaluate the accuracy of three combination staining approaches, each composed of pancytokeratin immunostaining with an elastic-fiber staining method of choice, in diagnosing visceral pleural invasion (VPI) in lung adenocarcinoma patients. METHODS: Tissue samples were resected from 23 lung adenocarcinoma patients, for whom neither hematoxylin and eosin nor Gomori's aldehyde-fuchsin (GAF) staining accurately detected the presence of VPI. Three slices were prepared from each sample and examined by immunohistochemical staining of cytokeratin AE1/AE3 and one of the following methods for elastic-fiber staining, including Victoria blue (VB), GAF, or Weigert's resorcin-fuchsin (WRF). The staining scores and slider view time were compared among the three staining protocols with tumor extension beyond the elastic layer of the visceral pleura as the diagnostic criterion for VPI. RESULTS: Conclusive diagnoses were achieved for all 23 tissue samples stained with VB, 18 with GAF, and 17 with WRF. VB staining was the fastest of the three methods, and produced significantly brighter, clearer color, and better contrast between the elastic fibers and tumor cells, thus facilitating slide review. CONCLUSIONS: The combination of VB elastic fiber and cytokeratin AE1/AE3 staining is a user-friendly, fast, and highly effective method that produces bright stains, favorable color contrast against the background, and high tumor localization accuracy. Hence, this method can improve the accuracy of VPI diagnosis and the corresponding staging of lung adenocarcinoma. We recommend the combined use of VB and pancytokeratin immunostaining when VPI is suspected.

6.
Zhongguo Zhen Jiu ; 41(7): 799-804, 2021 Jul 12.
Artigo em Chinês | MEDLINE | ID: mdl-34259416

RESUMO

The survey is conducted prior to the development of international standard, Guideline for Clinical Practice of Acupuncture-Moxibustion: Migraine (Guideline) to determine the international demand. The survey includes 5 aspects, i.e. the application status of acupuncture and moxibustion abroad and the demand for the development of international standards, the priority of diseases developed by international standards, the necessity of the transformation of international standards from domestic standards, the key clinical problems to be solved by international standards, and the correlation between professional level and demand intention. The survey results show that the international demand of the Guideline is definite. Regarding the application range of acupuncture-moxibustion and the key clinical questions, the special consideration should be taken to the differences in the demands of the practitioners from different countries during the development of standard.

7.
Inorg Chem ; 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34259522

RESUMO

The rational design of multifunctional inorganic pigments relies on the manipulation of ionic valence and local surroundings of a chromophore in structurally and chemically habitable hosts. To date, the development of environmentally benign and intense violet/purple pigments is still a challenge. Here we report a family of A3-xMnxTeO6 and A3-2xMnxLixTeO6 (A = Zn, Mg; x = 0.01-0.15) pigments colored by site-selective Mn2+O4 yellow and Mn3+O5-6 violet chromophores. Zn2.9Mn0.1TeO6 is intense bright yellow, comparable with commercial BiVO4, and has better near-infrared reflectivity (∼89%) in comparison to commercial TiO2. The codoped Li+ "activator" generates holes and charge-balanced Mn3+ (Mn3+O5-6), realizing a color transformation from yellow to the bright violet pigments of A3-2xMnxLixTeO6. The most vivid Mg2.8Mn0.1Li0.1TeO6 is probably the best violet pigment known to date, exhibits excellent chemical and thermodynamic stability, and demonstrates pressure-dependent stability up to 5-7 GPa, before a (reversible) phase transition to pink. Theoretical calculations revealed the correlation between site-preference occupancy and chromophore motifs and predicted a wide color gamut of pigments in Zn3TeO6-hosted 3d transition-metal ions other than manganese.

8.
J Cancer Educ ; 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34260015

RESUMO

This study investigated the knowledge, thoughts, and attitudes of oncology nurses in China regarding fertility preservation for male cancer patients of childbearing age, and for offering counseling or oncofertility services for the men in their care. Data was collected from 18 oncology nurses in Southwest China through voluntary self-report and in-depth interviews. The qualitative interview data were analyzed using a descriptive phenomenology method based on the lived experience of the nurses. The interviewees commonly reported 6 main concerns regarding fertility preservation (FP): their insufficient knowledge and inadequate nursing education; the importance of offering such services to cancer patients; legal vulnerability if FP information is withheld from patients; the role of the nurse in counseling; and barriers to discussing FP in practice. Nurses had a positive attitude toward FP, but most had no practical role in routinely informing male patients of their options, and the nurses believed that discussion of FP was outside their scope of practice. This study offers insight into the perceptions of oncology nurses in a developing country regarding the provision of FP services for adult male cancer patients. These results lead us to recommend that local fertility nurses should be given new training regarding FP. Furthermore, nurse-led clinics are desirable. Future research should focus on the effectiveness of nurse participation in FP counseling and referral, and how to improve the professional confidence of oncology nurses for addressing FP issues.

9.
Plant Biotechnol J ; 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34260132

RESUMO

With the increasing availability of massive transcriptome data in plants, it is possible to construct a comprehensive database with multiple transcriptome data and online imputation tools. Online databases with integrated, multifaceted functions for exploring published RNA-seq libraries or microarrays are available for several plant species (Darwish et al., 2013; Xia et al., 2017; Zhang et al., 2020), helping researchers take advantage of the vast collection of public datasets. Brassica napus (AACC, 2n = 38) is one of the most important oil crops, originating from a spontaneous hybridization between Brassica rapa (AA, 2n = 20) and Brassica oleracea (CC, 2n = 18) (Chalhoub et al., 2014). Recently, an online transcriptome database has been built in B. napus (Chao et al., 2020). This database includes transcriptomes from different labs with various genotypes and growth conditions, which affects the usability. A database with comprehensive transcriptomes from one B. napus genotype is greatly needed.

10.
Anticancer Drugs ; 2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34261911

RESUMO

BACKGROUND: Health-related quality of life (HRQoL) is an important consideration in managing patients. Spleen aminopeptide oral lyophilized powder (SAOLP) has been used to enhance cellular immunity in a patient. This multicenter, randomized, double-blind, placebo-controlled clinical trial was designed to evaluate the safety and efficacy of SAOLP for improving HRQoL in patients with breast cancer. METHODS: Patients diagnosed with advanced breast cancer were included, and were administered SAOLP or placebo 4 mg qd for two cycles. The primary endpoint was improvement in HRQoL on day 42 measured by the EORTC QLQ-C30 and EORTC QLQ-BR23. Secondary endpoints included immunologic function, improvement in HRQoL on day 21 and 84, objective response rate, disease control rate, BMI and adverse events. RESULT: On day 42, on the EORTC QLQ-C30 or EORTC QLQ-BR23, scores on the functional scales and QoL scale were significantly higher and scores on symptom scales were significantly lower in patients who received SAOLP compared to placebo (P < 0.05). On day 84, the number of CD3, CD4 and CD8 cells were significantly higher in patients who received SAOLP. There were no significant differences in objective response rate, disease control rate or BMI. CONCLUSION: SAOLP may improve HRQoL and the immune response in patients with advanced breast cancer, represents a convenient and safe adjuvant therapy.

11.
ACS Sens ; 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34264628

RESUMO

Identifying small extracellular vesicle (sEV) subpopulations based on their different molecular signatures could potentially reveal the functional roles in physiology and pathology. However, it is a challenge to achieve this aim due to the nano-sized dimensions of sEVs, low quantities of biological cargo each sEV carries, and our incomplete knowledge of identifying features capable of separating heterogeneous sEV subpopulations. Here, a sensitive, multiplexed, and nano-mixing-enhanced sEV subpopulation characterization platform (ESCP) is proposed to precisely determine the sEV phenotypic heterogeneity and understand the role of sEV heterogeneity in cancer progression and metastasis. The ESCP utilizes spatially patterned anti-tetraspanin-functionalized micro-arrays for sEV subpopulation sorting and nanobarcode-based surface-enhanced Raman spectroscopy for multiplexed read-outs. An ESCP has been used for investigating sEV phenotypic heterogeneity in terms of canonical sEV tetraspanin molecules and cancer-associated protein biomarkers in both cancer cell line models and cancer patient samples. Our data explicitly demonstrate the selective enrichment of tetraspanins and cancer-associated protein biomarkers, in particular sEV subpopulations. Therefore, it is believed that the ESCP could enable the evaluation and broader application of sEV subpopulations as potential diagnostic disease biomarkers.

12.
Artigo em Inglês | MEDLINE | ID: mdl-34264831

RESUMO

In this article, the bipartite synchronization issue is studied for a class of discrete-time coupled switched neural networks with antagonistic interactions via a distributed dynamic event-triggered control scheme. Essentially different from most current literature, the topology switching of the investigated signed graph is governed by a double-layer switching signal, which integrates a flexible deterministic switching regularity, the persistent dwell-time switching, into a Markov chain to represent the variation of transition probability. Considering the coexistence of cooperative and antagonistic interactions among nodes, the bipartite synchronization of which the dynamics of nodes converge to values with the same modulus but the opposite signs is explored. A distributed control strategy based on the dynamic event-triggered mechanism is utilized to achieve this goal. Under this circumstance, the information update of the controller presents an aperiodic manner, and the frequency of data transmission can be reduced extensively. Thereafter, by constructing a novel Lyapunov function depending on both the switching signal and the internal dynamic nonnegative variable of the triggering mechanism, the exponential stability of bipartite synchronization error systems in the mean-square sense is analyzed. Finally, two simulation examples are provided to illustrate the effectiveness of the derived results.

13.
JCI Insight ; 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34264867

RESUMO

A dynamically regulated microenvironment, which is mediated by crosstalks between adipocytes 2 and neighboring cells, is critical for adipose tissue homeostasis and function. However, information on 3 key molecules and/or signaling pathways regulating the crosstalks remains limited. In this study, we 4 identify adipocyte miR-182-5p as a crucial anti-obesity molecule that stimulates beige fat thermogenesis 5 by promoting the crosstalk between adipocytes and macrophages. miR-182-5p is highly enriched in 6 thermogenic adipocytes and its expression is markedly stimulated by cold exposure in mice. In contrast, 7 miR-182-5p expression is significantly reduced in adipose tissues of obese humans and mice. Knockout 8 of miR-185-5p decreased cold-induced beige fat thermogenesis whereas overexpression of miR-185-5p 9 increased beiging and thermogenesis in mice. Mechanistically, miR-182-5p promotes FGF21 expression 10 and secretion in adipocytes by suppressing Nr1d1 at 5'UTR, which in turn stimulates acetylcholine 11 synthesis and release in macrophages. Increased acetylcholine expression activates the nicotine 12 acetylcholine receptor in adipocytes, which stimulates PKA signaling and consequent thermogenic gene 13 expression. Our study reveals a key role of the miR-182-5p/FGF21/acetylcholine/acetylcholine receptor 14 axis that mediates the crosstalk between adipocytes and macrophages to promote beige fat 15 thermogenesis. Activation of the miR-182-5p-induced signaling pathway in adipose tissue may be an 16 effective approach to ameliorate obesity and associated metabolic diseases.

14.
Aging (Albany NY) ; 132021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34253690

RESUMO

Many aging related diseases such as cancer implicate the myofibroblast in disease progression. Furthermore genesis of the myofibroblast is associated with manifestation of cellular senescence of unclear significance. In this study we investigated the role of a common regulator, namely telomerase reverse transcriptase (TERT), in order to evaluate the potential significance of this association between both processes. We analyzed the effects of TERT overexpression or deficiency on expression of CDKN2A and ACTA2 as indicators of senescence and differentiation, respectively. We assess binding of TERT or YB-1, a repressor of both genes, to their promoters. TERT repressed both CDKN2A and ACTA2 expression, and abolished stress-induced expression of both genes. Conversely, TERT deficiency enhanced their expression. Altering CDKN2A expression had no effect on ACTA2 expression. Both TERT and YB-1 were shown to bind the CDKN2A promoter but only YB-1 was shown to bind the ACTA2 promoter. TERT overexpression inhibited CDKN2A promoter activity while stimulating YB-1 expression and activation to repress ACTA2 gene. TERT repressed myofibroblast differentiation and senescence via distinct mechanisms. The latter was associated with TERT binding to the CDKN2A promoter, but not to the ACTA2 promoter, which may require interaction with co-factors such as YB-1.

15.
Endocrine ; 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34255273

RESUMO

PURPOSE: Sodium-glucose transporters (SGLTs) are important targets for therapeutic intervention of type 2 diabetes. This study aims to evaluate the physiological influences of diabetes mellitus and the potential impacts of metformin and fluoxetine on SGLTs expressions. METHODS: Alterations of SGLT1 and SGLT2 were measured in organs involved in glucose homeostasis (kidney, intestine, liver and pancreas) of streptozotocin (STZ) and high-fat diet (HFD) induced diabetic mice by western blotting and real-time PCR (RT-PCR) respectively. RESULTS: In kidney, duodenal segments of intestine, liver, and pancreas of HFD diabetic mice, expressions of SGLT2 were all elevated compared to control mice. The level of SGLT1 was significantly increased in intestine, but was decreased in pancreas. SGLT1 expression in kidney was unaffected, and SGLT1 was undetectable in hepatocytes. Similar results were obtained in STZ diabetic mice. More importantly, here we noticed metformin decreased levels of SGLT2 in kidney, intestine, and pancreas of HFD mice markedly. Expressions of SGLT1 in intestine and pancreas were reduced by metformin as well. In contrast, fluoxetine increased abundances of SGLT2 and SGLT1 in kidney of HFD mice, but decreased SGLT1 expression in intestine. CONCLUSIONS: The present study provided evidence that expressions of SGLT1 and SGLT2 were significantly modulated by diabetes mellitus as well as by metformin and fluoxetine, which indicated the efficacy of SGLT2 inhibitors might be impacted by these factors.

16.
Poult Sci ; 100(8): 101273, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34214744

RESUMO

Eggshell color is an important shell quality trait that influences consumer preference. It is also of particular importance with respect to sexual signaling and the physiological and mechanical properties of shell pigment. Pigments include protoporphyrin IX, biliverdin, and traces of biliverdin zinc chelates, with brown eggs being notably rich in protoporphyrin IX, the synthesis of which has a marked effect on the intensity of brown eggshell color. This pigment is initially synthesized in the eggshell gland within the oviduct of laying hens and is subsequently deposited throughout the cuticular and calcareous layers of brown eggshell. In this review, we describe the factors affecting brown eggshell color and potential targets for the regulation of pigment synthesis. Protoporphyrin IX synthesis might be compromised by synthetase-mediated pigment synthesis, the redox status of the female birds, and regulation of the nuclear transcription factors associated with δ-aminolevulinic acid synthetase1. We believe that this review will provide a valuable reference for those engaged in studying eggshell depigmentation.

17.
Neurosci Lett ; 760: 136102, 2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34237414

RESUMO

Drug addiction is underscored by the transition from experimental use to dependent use of addictive drugs. Acute use of methamphetamine (METH) causes a range of clinical symptoms, including hyperlocomotion. Dopamine D1 receptor (D1R)-mediated negative regulation of phosphorylated calcium/calmodulin-dependent protein kinase IIα (p-CaMKIIα, threonine [Thr] 286) is involved in the acute effects induced by single METH administration. Protein phosphatase 2A (PP2A) is a potential bridge that links D1R and p-CaMKIIα (Thr 286) after acute METH administration. However, the mechanisms underlying hyperlocomotion induced by single METH administration remain unclear. In this study, SCH23390 (a D1R inhibitor) and LB100 (a PP2A inhibitor) were administered to examine the involvement of D1R and PP2A signaling in acute METH-induced hyperlocomotion in mice. The protein levels of methylated PP2A-C (m-PP2A-C, leucine [Leu] 309), phosphorylated PP2A-C (p-PP2A-C, tyrosine [Tyr] 307), PP2A-C, p-CaMKIIα (Thr 286), and CaMKIIα in the prefrontal cortex (PFc), nucleus accumbens (NAc), and caudate putamen (CPu) were measured. Administration of 0.5 mg/kg SCH23390 reversed the acute METH-induced increase in protein levels of m-PP2A-C (Leu 309) and the decrease in protein levels of p-PP2A-C (Tyr 307) in the CPu, but not in the PFC and NAc. Moreover, prior administration of 0.1 mg/kg LB100 attenuated hyperlocomotion induced by single METH administration and reversed the decrease in protein levels of p-CaMKII (Thr 286) in the PFC, NAc, and CPu. Collectively, these results indicate that the D1R/PP2A/p-CaMKIIα signaling cascade in the CPu may be involved in hyperlocomotion after a single administration of METH.

18.
Cancer Cell ; 2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: covidwho-1275179

RESUMO

Patients with cancer experience a higher burden of SARS-CoV-2 infection, disease severity, complications, and mortality, than the general population. SARS-CoV-2 mRNA vaccines are highly effective in the general population; however, few data are available on their efficacy in patients with cancer. Using a prospective cohort, we assessed the seroconversion rates and anti-SARS-CoV-2 spike protein antibody titers following the first and second dose of BNT162b2 and mRNA-1273 SARS-CoV-2 vaccines in patients with cancer in US and Europe from January to April 2021. Among 131 patients, most (94%) achieved seroconversion after receipt of two vaccine doses. Seroconversion rates and antibody titers in patients with hematological malignancy were significantly lower than those with solid tumors. None of the patients with history of anti-CD-20 antibody in the 6 months before vaccination developed antibody response. Antibody titers were highest for clinical surveillance or endocrine therapy groups and lowest for cytotoxic chemotherapy or monoclonal antibody groups.

19.
Exp Cell Res ; 405(2): 112728, 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34246653

RESUMO

ATP-binding cassette (ABC) transporter C10 (ABCC10), also named multidrug resistance protein 7 (MRP7), is a member of ABC transporter superfamily and has been revealed to transport a wide range of chemotherapeutic agents including taxanes, epothilone B, Vinca alkaloids, and anthracyclines. In our previous study, a 5-cyano-6-phenylpyrimidin derivative CP55 was synthesized and found significantly reversal effect of multidrug resistance (MDR) mediated by ABCB1. In this study, we found CP55 also efficiently reversed MDR mediated by ABCC10. Our in vitro study showed that co-treatment with CP55 significantly increased the efficacy of ABCC10-substrate anticancer drugs in MDR cells overexpressing ABCC10. Furthermore, we showed that treatment with CP55 increased the intracellular accumulation of [3H]-labeled anticancer drugs and in-turn decreasing drug efflux by inhibiting the transport activity, without altering ABCC10 protein ex-pression level or cellular localization. Potential CP55-ABCC10 interactions were predicted via docking analysis using human ABCC10 homology model and obtained high docking score. Therefore, CP55 represents a promising therapeutic agent in the combinational treatment of chemo-resistant cancer related to ABCC10.

20.
BMC Cancer ; 21(1): 827, 2021 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-34273954

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is a common cause of cancer mortality worldwide. Recent studies have shown that the polytopic enzyme membrane associated ring-CH-type finger 6 (MARCH6) participates in tumorigenesis, but its function in HCC development needs to be investigated. This study aimed to explore the role of MARCH6 in HCC. METHODS: Expression of MARCH6 in human HCC samples was checked by immunohistochemical staining assay. Clinical relevance of MARCH6 and activating transcription factor 2 (ATF2) was analyzed from TCGA database. CCK-8, EdU staining, colony formation and transwell were performed to assess cell proliferation, growth and migration. Xenografted tumorigenesis was used to examine in vivo role MARCH6. Immunoblotting was applied to detect protein abundance. RESULTS: We found that MARCH6 expression was elevated in human HCC samples. Over-expression of MARCH6 was associated with poor prognosis of HCC patients. Up-expression of MARCH6 promoted cell growth and migration of HCC cells. In contrast, the HCC cell growth and migration were suppressed by MARCH6 knockdown. Furthermore, the DNA synthesis was enhanced by MARCH6. The expression of ATF2 was potentiated by MARCH6 over-expression, while it was suppressed by MARCH6 silencing. TCGA database showed positive correlation between the expression of MARCH6 and ATF2. Importantly, ATF2 expression contributed to the oncogenic function of HCC cells. CONCLUSION: Our findings suggest that MARCH6-mediated ATF2 up-regulation contributes to HCC development. MARCH6 may be a promising target for the diagnosis and treatment of HCC.

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