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1.
Biochem Biophys Res Commun ; 559: 183-190, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33945996

RESUMO

Oral squamous cell carcinoma (OSCC) is one of the causes of cancer-related death worldwide. The abnormal proliferation ability of OSCC has become one of the major reasons for its poor prognosis. FK-506 binding protein 11 (FKBP11) is abnormally expressed in malignant tumors and affects many biological processes. The purpose of this study is to investigate the effect of FKBP11 on cell proliferation in OSCC and explore the possible regulatory mechanism. The expression of FKBP11 was detected by western blotting (WB) and/or real-time PCR in OSCC and paracancerous normal tissues in tongue squamous cell carcinoma (TSCC) cell lines, revealing high expression in OSCC and CAL-27 cells. Furthermore, FKBP11 knockdown inhibited the proliferation of CAL-27 cells by CCK-8 and colony formation assays. G2/M arrest and induction of apoptosis were observed using flow cytometry, Hoechst 33258 and Calcein-AM/PI staining, accompanied by changes in some cell cycle- and apoptosis-related proteins, including CDK1, Cyclin B1, p21, p27, p53, Bax, Bcl-2 and Caspase-3. Additionally, the expression of these proteins can be reversed by the use of pifithrin-α (PFT-α), a p53 inhibitor. An in vivo xenograft model further confirmed that FKBP11 enhanced OSCC progression. In conclusion, FKBP11 could promote cell proliferation by regulating G2/M phase and apoptosis via the p53/p21/p27 and p53/Bcl-2/Bax pathways, respectively, which suggests that it may be a new candidate target for the treatment of OSCC.

2.
Ecotoxicol Environ Saf ; 217: 112244, 2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33933891

RESUMO

Nickel is widely spread by different anthropogenic activities and shows toxicity for plant growth and development. Whether rhizobia symbiotically fix nitrogen can eliminate or reduce nickel toxic effect on plant or not is still unknown. This study was aimed to investigate the effect of different rhizobia genus inoculation on growth, nitrogen fixing ability, metal accumulation and enzymatic antioxidative balance of Pongamia pinnnaa. Inoculation with Rhizobium pisi and Ochrobacterium pseudogrignonense increased the all the growth parameters both in 0 and 40 mg/kg nickel as comparison with control. Only shoot length increased in presence of nitrogen as compared with no supply of nitrogen. Nitrogen content also increased both in rhizobia inoculation as compared to no nitrogen supply and non-inoculation control, respectively. Nickel uptake was higher in shoots and leaves but lower in roots in case of inoculation as compared to non-inoculation control. Rhizobia inoculation improved the plant antioxidant capacity by increasing the activity of enzymatic scavengers catalase (CAT), superoxide dismutase (SOD), peroxidase (POD) and ascorbate (GR). However, 40 mg/kg of nickel adding showed mostly effect on the activity CAT, SOD, POD in leaves. All the enzymatic activity showed a significant increase in absence of nitrogen supply as compared nitrogen supply. Our results suggested that rhizobia inoculation effectively mediated nickel stress for legume plants by increasing nitrogen supplement and inducing antioxidant capacity.

3.
Sensors (Basel) ; 21(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807806

RESUMO

In this research, we propose two Particle Swarm Optimisation (PSO) variants to undertake feature selection tasks. The aim is to overcome two major shortcomings of the original PSO model, i.e., premature convergence and weak exploitation around the near optimal solutions. The first proposed PSO variant incorporates four key operations, including a modified PSO operation with rectified personal and global best signals, spiral search based local exploitation, Gaussian distribution-based swarm leader enhancement, and mirroring and mutation operations for worst solution improvement. The second proposed PSO model enhances the first one through four new strategies, i.e., an adaptive exemplar breeding mechanism incorporating multiple optimal signals, nonlinear function oriented search coefficients, exponential and scattering schemes for swarm leader, and worst solution enhancement, respectively. In comparison with a set of 15 classical and advanced search methods, the proposed models illustrate statistical superiority for discriminative feature selection for a total of 13 data sets.

4.
Biomed Res Int ; 2021: 6661526, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33791371

RESUMO

Background: Animal models are well established for studying the effects of alkaloids in preventing myocardial ischemia-reperfusion injury. However, few studies have investigated the therapeutic effects of alkaloids in humans. This meta-analysis and systematic review assessed the efficacy of alkaloids in attenuating infarct size in rats with myocardial ischemia-reperfusion injury. Methods: An integrated literature search including the PubMed, Embase, and Cochrane Library databases was performed to identify studies that evaluated the therapeutic effects of alkaloids on myocardial ischemia-reperfusion injury in rats. The main outcome was infarct size, and SYRCLE's risk of bias tool was used to assess the quality of the studies. Results: 22 studies were brought into the meta-analysis. Compared with the effects of vehicle, alkaloids significantly reduced infarct size (standardized mean difference (SMD) = -0.45; 95% confidence interval (CI) = -0.64 to - 0.26). In subgroup analyses, isoquinoline alkaloids (SMD = -0.43; 95%CI = -0.70 to - 0.16) significantly reduced infarct size versus the control. Conclusion: Isoquinoline alkaloids can potentially alleviate myocardial ischemia-reperfusion injury. This meta-analysis and systematic review supply a reference for research programs aiming to develop alkaloid-based clinical drugs. This trial is registered with CRD42019135489.

5.
Zhongguo Dang Dai Er Ke Za Zhi ; 23(4): 420-424, 2021 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-33840417

RESUMO

Compared with adults, children tend to have lower incidence rate, hospitalization rate, and mortality rate of coronavirus disease 2019 (COVID-19), while the cause of such age-based differences in disease severity remains unclear. An investigation of pathogenesis in children may help to analyze the therapies for the high-risk population. Human angiotensin-converting enzyme Ⅱ is the main receptor of severe acute respiratory syndrome coronavirus 2 and can limit pulmonary capillary leakage and inflammation mediated by angiotensin 2 and exert a protective effect against acute lung injury. Its expression decreases with age. Regular vaccination and frequent upper respiratory virus infection in children can lead to regular immune activation, and its combination with strong innate immunity can help to achieve virus clearance in the early stage of infection in children with COVID-19. Meanwhile, there are strong regeneration and repair abilities of alveolar epithelial cells in children, which may help with the early recovery of infection. In addition, risk factors, such as underlying cardiopulmonary diseases, obesity, and smoking, are relatively uncommon in children. Social factors, including home quarantine and timely closure of schools, may help to reduce the infection rate in children. However, children with immunodeficiency are a high-risk population and should be closely monitored. Further studies are needed to investigate the immune and protection mechanisms against COVID-19 in children.


Assuntos
Adulto , Criança , Humanos , Inflamação , Pulmão , Fatores de Risco
6.
BMJ Open ; 11(4): e045192, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33795307

RESUMO

INTRODUCTION: Childhood overweight and obesity (OWO) is a primary global health challenge. Childhood OWO prevention is now a public health priority in China. The Sino-Canadian Healthy Life Trajectories Initiative (SCHeLTI), one of four trials being undertaken by the international HeLTI consortium, aims to evaluate the effectiveness of a multifaceted, community-family-mother-child intervention on childhood OWO and non-communicable diseases risk. METHODS AND ANALYSIS: This is a multicentre, cluster-randomised, controlled trial conducted in Shanghai, China. The unit of randomisation is the service area of Maternal Child Health Units (N=36). We will recruit 4500 women/partners/families in maternity and district level hospitals. Participants in the intervention group will receive a multifaceted, integrated package of health promotion interventions beginning in preconception or in the first trimester of pregnancy, continuing into infancy and early childhood. The intervention, which is centred on a modified motivational interviewing approach, will target early-life maternal and child risk factors for adiposity. Through the development of a biological specimen bank, we will study potential mechanisms underlying the effects of the intervention. The primary outcome for the trial is childhood OWO (body mass index for age ≥85th percentile) at 5 years of age, based on WHO sex-specific standards. The study has a power of 0.8 (α=0.05) to detect a 30% risk reduction in the proportion of children with OWO at 5 years of age, from 24.4% in the control group to 17% in the intervention group. Recruitment was launched on 30 August 2018 for the pilot study and 10 January 2019 for the formal study. ETHICS AND DISSEMINATION: The study has been approved by the Medical Research Ethics Committee of the International Peace Maternity and Child Health Hospital in Shanghai, China, and the Research Ethics Board of the Centre Intégré Universitaire de Santé et Services Sociaux de l'Estrie-CHUS in Sherbrooke, Canada. Data sharing policies are consistent with the governance policy of the HeLTI consortium and government legislation. TRIAL REGISTRATION NUMBER: ChiCTR1800017773. PROTOCOL VERSION: November 11, 2020 (Version #5).

7.
Neoplasma ; 2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33884883

RESUMO

Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1) has been shown to promote various tumors, but its role in colon cancer (CRC) has not been clearly illuminated. The aim of this study was to investigate the effects of SPOCK1 interference on the proliferation, migration and EMT of CRC cells. First, we analyzed the expression of SPOCK1 in various CRC datasets. Then, we investigated the correlation between SPOCK1 and prognosis in CRC patients. We overexpressed SPOCK1 and knocked down SPOCK1 expression in HCT-116 and SW480 cells, respectively. Then, cell proliferation was assayed with a CCK-8 assay, and cell migration was evaluated with a Transwell migration assay. NF-κB and EMT-related proteins were studied by western blotting. The results indicated that the mRNA levels of SPOCK1 were relatively high in CRC tissues and that high expression of SPOCK1 was negatively correlated with patient prognosis. With SPOCK1 overexpression in HCT-116 cells, cell proliferation and migration were increased, while SPOCK1 knockdown had the opposite effects. With SPOCK1 overexpression in HCT-116 cells, the expression levels of NF-κB and EMT-related proteins were elevated, while SPOCK1 knockdown produced the opposite results. In conclusion, our study demonstrates that SPOCK1 may activate the NF-κB/Snail signaling cascade to promote the proliferation and migration of CRC cells. SPOCK1 may serve as a new prognostic indicator and potential therapeutic target in CRC.

8.
Artigo em Inglês | MEDLINE | ID: mdl-33899319

RESUMO

Copper-alumanyl complexes, [LCu-Al(SiN Dipp )], where L = carbene = NHC iPr (N,N'-di-isopropyl-4,5-dimethyl-2-ylidene) and Me2 CAAC (1-(2,6-di-isopropylphenyl)-3,3,5,5-tetramethyl-pyrrolidin-2-ylidene) and featuring unsupported Al-Cu bonds, have been prepared. Divergent reactivity observed with carbodiimides and CO 2 implies an ambiphilicity in the Cu-Al interaction that is dependent on the identity of the carbene co-ligand.

9.
Toxicol Sci ; 2021 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-33895847

RESUMO

Long noncoding RNA maternally expressed gene 3 (MEG3) involves in fibrotic diseases, but its role in nickel oxide nanoparticles (NiO NPs)-induced pulmonary fibrosis remains unclear. The present study aimed to explore the relationships among MEG3, transforming growth factor-ß1 (TGF-ß1) and phosphoinositide 3-kinase (PI3K)/AKT pathway in NiO NPs-induced pulmonary fibrosis. Wistar rats were intratracheally instilled with NiO NPs twice a week for 9 weeks, and human lung adenocarcinoma epithelial cells (A549 cells) were exposed to NiO NPs for 24 hours. The pathological alterations and increased hydroxyproline indicated that NiO NPs caused pulmonary fibrosis in rats. The up-regulated type I collagen (Col-I) suggested that NiO NPs induced collagen deposition in A549 cells. Meanwhile, NiO NPs could significantly down-regulate MEG3, up-regulate TGF-ß1 and activate PI3K/AKT signaling pathway both in vivo and in vitro. However, we found that the PI3K/AKT pathway activated by NiO NPs could be suppressed by 10 µM TGF-ß1 inhibitor (SB431542) in A549 cells. The protein markers (Col-I, Fibronectin and alpha-smooth muscle actin) of collagen deposition up-regulated by NiO NPs were reduced by 10 µM PI3K inhibitor (LY294002). Furthermore, we further found that overexpressed MEG3 inhibited the expression of TGF-ß1, resulting in the inactivation of PI3K/AKT pathway and the reduction of collagen formation. In summary, our results validated that MEG3 could arrest NiO NPs-induced pulmonary fibrosis via inhibiting TGF-ß1-mediated PI3K/AKT pathway.

10.
Nanomaterials (Basel) ; 11(3)2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33803940

RESUMO

Two-dimensional layered material Molybdenum disulfide (MoS2) exhibits a flat surface without dangling bonds and is expected to be a suitable surface-enhanced Raman scattering (SERS) substrate for the detection of organic molecules. However, further fabrication of nanostructures for enhancement of SERS is necessary because of the low detection efficiency of MoS2. In this paper, period-distribution Si/MoS2 core/shell nanopillar (NP) arrays were fabricated for SERS. The MoS2 thin films were formed on the surface of Si NPs by sulfurizing the MoO3 thin films coated on the Si NP arrays. Scanning electron microscopy, Raman spectroscopy, and X-ray photoelectron spectroscopy were performed to characterize Si/MoS2 core-shell nanostructure. In comparison with a bare Si substrate and MoS2 thin film, the use of Si/MoS2 core-shell NP arrays as SERS substrates enhances the intensity of each SERS signal peak for Rhodamine 6G (R6G) molecules, and especially exhibits about 75-fold and 7-fold enhancements in the 1361 cm-1 peak signal, respectively. We suggest that the Si/MoS2 core-shell NP arrays with larger area could absorb more R6G molecules and provide larger interfaces between MoS2 and R6G molecules, leading to higher opportunity of charge transfer process and exciton transitions. Therefore, the Si/MoS2 core/shell NP arrays could effectively enhance SERS signal and serve as excellent SERS substrates in biomedical detection.

11.
Can J Cardiol ; 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33838228

RESUMO

BACKGROUND: Downregulation of claudin-5 in the heart is associated with the end-stage heart failure. However, the underlying mechanism of claudin-5 is unclear. Here we investigated the molecular actions of claudin-5 in perspective of mitochondria in cardiomyocytes to better understand the role of claudin-5 in cardioprotection during ischemia. METHODS AND RESULTS: Claudin-5 was detected in the murine heart tissue and the neonatal rat cardiomyocytes (NRCM). Its protein level was severely decreased after myocardial ischemia/reperfusion (I/R; 30 min/24 h) or hypoxia/reoxygenation (H/R; 24 h/4 h). Claudin-5 was present in the mitochondria of NRCM as determined by confocal microscopy. H/R-induced downregulation of claudin-5 was accompanied by mitochondrial fragmentation. The protein level of mitofusin 2 (Mfn2) was dramatically decreased while the expression of dynamin-related protein (Drp) 1 was significantly increased after H/R. H/R-induced mitochondrial swelling and fission were observed by transmission electron microscope (TEM). Overexpression of claudin-5 by adenoviral infection reversed these structural disintegration of mitochondria. The mitochondria-centered intrinsic pathway of apoptosis triggered by H/R and indicated by the expression of cytochrome c and cleaved caspase 3 in the cytoplasm of NRCMs was also reduced by overexpressing claudin-5. Overexpression of claudin-5 in mouse heart also significantly decreased cleaved caspase 3 expression and the infarct size in ischemic heart with improved systolic function. CONCLUSION: We demonstrated for the first time the presence of claudin-5 in the mitochondria in cardiomyocytes and provided the firm evidence for the cardioprotective role of claudin-5 in the preservation of mitochondrial dynamics and cell fate against hypoxia- or ischemia-induced stress.

12.
Brain ; 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33876820

RESUMO

The unc-13 homolog B (UNC13B) gene encodes a presynaptic protein, mammalian uncoordinated 13-2 (Munc13-2), that is highly expressed in the brain-predominantly in the cerebral cortex-and plays an essential role in synaptic vesicle priming and fusion, potentially affecting neuronal excitability. However, the functional significance of UNC13B mutation in human disease is not known. In this study we screened for novel genetic variants in a cohort of 446 unrelated cases (families) with partial epilepsy without acquired causes by trio-based whole-exome sequencing. UNC13B variants were identified in 12 individuals affected by partial epilepsy and/or febrile seizures from eight unrelated families. The eight probands all had focal seizures and focal discharges in EEG recordings, including two patients who experienced frequent daily seizures and one who showed abnormalities in the hippocampus by brain MRI; however, all of the patients showed favorable outcome without intellectual or developmental abnormalities. The identified UNC13B variants included one nonsense variant, two variants at or around a splice site, one compound heterozygous missense variant, and four missense variants that cosegregated in the families. The frequency of UNC13B variants identified in the present study was significantly higher than that in a control cohort of Han Chinese and controls of the East Asian and all populations in the Genome Aggregation Database. Computational modeling, including hydrogen bond and docking analyses, suggested that the variants lead to functional impairment. In Drosophila, seizure rate and duration were increased by Unc13b knockdown compared to wild-type flies, but these effects were less pronounced than in sodium voltage-gated channel alpha subunit 1 (Scn1a) knockdown Drosophila. Electrophysiologic recordings showed that excitatory neurons in Unc13b-deficient flies exhibited increased excitability. These results suggest that UNC13B is potentially associated with epilepsy. The frequent daily seizures and hippocampal abnormalities but ultimately favorable outcome under antiepileptic therapy in our patients indicate that partial epilepsy caused by UNC13B variant is a clinically manageable condition.

13.
Inflammation ; 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33877484

RESUMO

In recent decades when biological agents have flourished, a part of patients suffering from inflammatory bowel disease (IBD) have received the treatment of tumor necrosis factor inhibitors or IL-1 antibodies. This study aims to investigate the anti-colitis effects of bispecific antibody (FL-BsAb1/17) targeting IL-1ß and IL-17A comparing with TNF-α soluble receptor medicine etanercept. IBD model in mice was established by drinking 3% DSS (dextran sulfate sodium salt). On the first day of drinking DSS, treatments with etanercept (5 mg/kg) or different doses of FL-BsAb1/17 (1 mg/kg, 5 mg/kg, and 10 mg/kg) were started by intraperitoneal injection every other day. The results demonstrated that FL-BsAb1/17 treatment was more effective than etanercept at the same dose (5 mg/kg) in relieving the typical symptom of ulcerative colitis induced by DSS (such as the severity score and intestinal shortening), and down-regulating the expression of inflammatory factors (IL-17A, IL-6, IL-12, IL-22, IL-1ß, IL-23, TNF-α) in the serum and colon. FL-BsAb1/17 could also reduce the degree of intestinal fibrosis. The same dose of FL-BsAb1/17 (5 mg/kg) performed better than etanercept in down-regulating MDA and up-regulating SOD (superoxide dismutase), CAT (catalase), and T-AOC (total antioxidant capacity) in serum. Both FL-BsAb1/17 and etanercept could reduce the transcription of Bax and increase the transcription of Bcl-2 and slow down apoptosis in colitis colon tissue. We conclude that the blocking of IL-1ß and IL-17A can inhibit DSS-induced ulcerative colitis and FL-BsAb1/17 may have potential to become a new dual-target candidate for colitis treatment.

14.
Ageing Res Rev ; 69: 101347, 2021 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-33905953

RESUMO

Parkinson's disease (PD) is a complicated neurodegenerative disease attributed to multifactorial changes. However, its pathological mechanism remains undetermined. Accumulating evidence has revealed the emerging functions of gut microbiota and microbial metabolites, which can affect both the enteric nervous system and the central nervous system via the microbiota-gut-brain axis. Accordingly, intestinal dysbiosis might be closely associated with PD. This review explores alterations to gut microbiota, correlations with clinical manifestations of PD, and briefly probes the underlying mechanisms. Next, the highly controversial roles of microbial metabolites including short-chain fatty acids (SCFAs), H2 and H2S are discussed. Finally, the pros and cons of the current treatments for PD, including those targeting microbiota, are assessed. Advancements in research techniques, further studies on levels of specific strains and longitudinal prospective clinical trials are urgently needed for the identification of early diagnostic markers and the development of novel therapeutic approaches for PD.

15.
BMC Pregnancy Childbirth ; 21(1): 341, 2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33926401

RESUMO

BACKGROUND: Previous studies have focused on pregnancy outcomes after frozen embryo transfer (FET) performed using different endometrial preparation protocols. Few studies have evaluated the effect of endometrial preparation on pregnancy-related complications. This study was designed to explore the association between different endometrial preparation protocols and adverse obstetric and perinatal complications after FET. METHODS: We retrospectively included all FET cycles (n = 12,950) in our hospital between 2010 and 2017, and categorized them into three groups, natural cycles (NC), hormone replacement therapy (HRT) and ovarian stimulation (OS) protocols. Pregnancy-related complications and subsequent neonatal outcomes were compared among groups. RESULTS: Among all 12,950 FET cycles, the live birth rate was slightly lower for HRT cycles than for NC (HRT vs. NC: 28.15% vs. 31.16%, p < 0.001). The pregnancy loss rate was significantly higher in OS or HRT cycles than in NC (HRT vs. NC: 17.14% vs. 10.89%, p < 0.001; OS vs. NC: 16.44% vs. 10.89%, p = 0.001). Among 3864 women with live birth, preparing the endometrium using OS or HRT protocols increased the risk of preeclampsia, and intrahepatic cholestasis of pregnancy (ICP) in both singleton and multiple deliveries. Additionally, OS and HRT protocols increased the risk of low birth weight (LBW) and small for gestational age (SGA) in both singletons and multiples after FET. CONCLUSION: Compared with HRT or OS protocols, preparing the endometrium with NC was associated with the decreased risk of pregnancy-related complications, as well as the decreased risk of LBW and SGA after FET.

16.
BMC Public Health ; 21(1): 768, 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33882878

RESUMO

BACKGROUND: Childhood overweight and obesity (OWO) has become a major public concern worldwide including in Shanghai, one of the most developed areas of China. Understanding perceptions and challenges of tackling childhood OWO among caregivers of children is critical to provide services in need. METHODS: A qualitative descriptive study including in-depth interviews with seven parents and six focus group discussions with a total of 32 parents or grandparents of children zero to 6 years of age. Participants lived in three districts of Shanghai and indexed children included both those with OWO or non-OWO children. Data were analyzed using qualitative thematic analysis. RESULTS: Caregivers tended to underestimate children's weight status, and to regard chubby children as a sign of good parental care. Some caregivers even suggested that there were positive effects of childhood overweight. Caregivers identified a number of challenges to prevention of OWO in children, including difficulties in controlling dietary intake or increasing children's physical activities; discordant views between parents and grandparents, and barriers to accessing professional guidance. Caregivers desired more detailed advice regarding children's nutrition intake and physical activity, and preferred online approaches. CONCLUSIONS: Misconceptions regarding childhood overweight were found in caregivers of children in Shanghai. Professional guidance on childhood weight control for caregivers is desired via digital applications such as mobile phone applications and social media.

17.
Cancer Sci ; 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33738896

RESUMO

Drug resistance is a significant obstacle to effective cancer treatment. Drug resistance develops from initially reversible drug-tolerant cancer cells, which offer therapeutic opportunities to impede cancer relapse. The mechanisms of resistance to proteasome inhibitor (PI) therapy have been investigated intensively, however the ways by which drug-tolerant cancer cells orchestrate their adaptive responses to drug challenges remain largely unknown. Here, we demonstrated that cyclin A1 suppression elicited the development of transient PI tolerance in mixed-lineage leukemia (MLL) cells. This adaptive process involved reversible downregulation of cyclin A1, which promoted PI resistance through cell-cycle arrest. PI-tolerant MLL cells acquired cyclin A1 dependency, regulated directly by MLL protein. Loss of cyclin A1 function resulted in the emergence of drug tolerance, which was associated with patient relapse and reduced survival. Combination treatment with PI and deubiquitinating enzyme (DUB) inhibitors overcame this drug resistance by restoring cyclin A1 expression through chromatin crosstalk between histone H2B monoubiquitination and MLL-mediated histone H3 lysine 4 methylation. These results reveal the importance of cyclin A1-engaged cell-cycle regulation in PI resistance in MLL cells, and suggest that cell-cycle re-entry by DUB inhibitors may represent a promising epigenetic therapeutic strategy to prevent acquired drug resistance.

18.
Photochem Photobiol Sci ; 20(3): 435-449, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33721281

RESUMO

Genetically encodable proteins that photosensitize the production of singlet oxygen, O2(a1Δg), will play an increasingly important role in elucidating mechanisms of cellular processes modulated by reactive oxygen species, ROS, and changes in redox balance. In the development of such tools, it is essential to characterize the oxygen-dependent photophysics of the protein-encased chromophore. Of the O2(a1Δg)-photosensitizing systems recently developed, a protein-bound derivative of Malachite Green has several desirable features: (1) it absorbs light at wavelengths longer than those typically absorbed by endogenous molecules, and (2) the chromophore becomes a viable sensitizer only when bound to the activating protein. However, we now demonstrate that the photophysics of this Malachite Green system is not simple. Our data indicate that, with an increase in the concentration of ground-state oxygen, O2(X3Σg-), the yield of O2(a1Δg) does not increase in a proportional manner. Moreover, the lifetime of O2(a1Δg) decreases as the O2(X3Σg-) concentration is increased. One mechanism that could account for our observations involves the concomitant photo-initiated formation of O2(a1Δg) and the superoxide radical anion. We propose that the superoxide ion acts as a dynamic diffusion-dependent quencher to influence the O2(a1Δg) lifetime and as a static quencher within the protein enclosure to influence the measured O2(a1Δg) yield. Thus, in the least, caution should be exercised when using this Malachite Green system to probe mechanisms of ROS-mediated processes. Our results contribute to a better understanding of the general photophysics of protein-bound O2(a1Δg) sensitizers which, in turn, facilitates the further development of these useful mechanistic tools.

19.
J Mol Neurosci ; 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33772424

RESUMO

The pathological hallmarks of Parkinson's disease (PD), a neurodegenerative disorder, are the selective loss of dopamine neurons in the substantia nigra pars compacta (SNpc) and the presence of α-synuclein (α-syn) aggregates in the form of Lewy bodies/Lewy neurites (LBs/LNs) in neurons. Recent studies have indicated that aquaporin 4 (AQP4), as a predominant water channel protein in the brain, is involved in the progression of Parkinson's disease (PD). However, it remains unclear whether AQP4 expression affects α-syn pathology in Parkinson's disease. In this study, we established a progressive PD model by subjecting AQP4 null (AQP4+/-) mice to bilateral intrastriatal injection of α-syn preformed fibrils (PFFs) and investigated the effect of decreased AQP4 expression on the development of PD. We found that decreased expression of AQP4 accelerated pathologic deposition of α-syn and facilitated the loss of dopamine neurons and behavioral disorders. Draining of macromolecules from the brain via the glymphatic pathway was slowed due to decreased AQP4 expression. Taken together, these findings indicate that decreased AQP4 expression may aggravate PD-like pathology, possibly via impairment of the glymphatic pathway.

20.
Cell Death Differ ; 2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33731873

RESUMO

Liquid-liquid phase separation is considered a generic approach to organize membrane-less compartments, enabling the dynamic regulation of phase-separated assemblies to be investigated and pivotal roles of protein posttranslational modifications to be demonstrated. By surveying the subcellular localizations of human deubiquitylases, USP42 was identified to form nuclear punctate structures that are associated with phase separation properties. Bioinformatic analysis demonstrated that the USP42 C-terminal sequence was intrinsically disordered, which was further experimentally confirmed to confer phase separation features. USP42 is distributed to SC35-positive nuclear speckles in a positively charged C-terminal residue- and enzymatic activity-dependent manner. Notably, USP42 directs the integration of the spliceosome component PLRG1 into nuclear speckles, and its depletion interferes with the conformation of SC35 foci. Functionally, USP42 downregulation deregulates multiple mRNA splicing events and leads to deterred cancer cell growth, which is consistent with the impact of PLRG1 repression. Finally, USP42 expression is strongly correlated with that of PLRG1 in non-small-cell lung cancer samples and predicts adverse prognosis in overall survival. As a deubiquitylase capable of dynamically guiding nuclear speckle phase separation and mRNA splicing, USP42 inhibition presents a novel anticancer strategy by targeting phase separation.

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