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1.
Bioorg Med Chem Lett ; 30(22): 127598, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33011288

RESUMO

SET and MYND domain-containing protein 2 (SMYD2), a lysine methyltransferase, is reported to catalyze the methylation of lysine residues on histone and non-histone proteins. As a potential target for cancer therapy, there are several SMYD2 inhibitors are reported, LLY-507 as a cell-active inhibitor exhibits submicromolar potency against SMYD2 in several cancer cell lines. To know which structural fragment of LLY-507 is suitable for chemical modification, three sites are chosen for structure-activity relationship studies (SARs). Among our focused library, compounds 43 and 44 with amide link on site C showed reasonably improved potency indicating that modification on this fragment is more flexible and introduction of electrophilic warheads in this position might provide lysine-targeting covalent inhibitors for SMYD2.

2.
Biomed Res Int ; 2020: 4107065, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33015164

RESUMO

Music intervention has been applied to improve symptoms of schizophrenic subjects as a complementary treatment in medicine. Although the psychiatric symptoms, especially for motivation and emotion, could be increased in schizophrenia, the underlying neural mechanisms remain poorly understood. We employed a longitudinal study to measure the alteration of striatum functional networks in schizophrenic subjects undergoing Mozart music listening using resting-state functional magnetic resonance imaging (fMRI). Forty-five schizophrenic inpatients were recruited and randomly assigned to two groups. Under the standard care with antipsychotic medication, one group received music intervention for 1 month and the other group is set as control. Both schizophrenic groups were compared to healthy subjects. Resting-state fMRI was acquired from schizophrenic subjects at baseline and after one-month music intervention and from healthy subjects at baseline. Striatum network was assessed through seed-based static and dynamic functional connectivity (FC) analyses. After music intervention, increased static FC was observed between pallidum and ventral hippocampus in schizophrenic subjects. Increased dynamic FCs were also found between pallidus and subregions of default mode network (DMN), including cerebellum crus and posterior cingulate cortex. Moreover, static pallidus-hippocampus FC increment was positively correlated with the improvement of negative symptoms in schizophrenic subjects. Together, these findings provided evidence that music intervention might have an effect on the FC of the striatum-DMN circuit and might be related to the remission of symptoms of schizophrenia.

3.
Bioorg Med Chem Lett ; 30(22): 127480, 2020 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-32882416

RESUMO

CBP bromodomain could recognize acetylated lysine and function as transcription coactivator to regulate transcription and downstream gene expression. Furthermore, CBP has been shown to be related to many human malignancies including acute myeloid leukemia. Herein, we identified DC-CPin734 as a potent CBP bromodomain inhibitor with a TR-FRET IC50 value of 19.5 ± 1.1 nM and over 400-fold of selectivity against BRD4 bromodomains through structure based rational drug design guided iterative chemical modification endeavoring to discover optimal tail-substituted tetrahydroquinolin derivatives. Moreover, DC-CPin734 showed potent inhibitory activity to AML cell line MV4-11 with an IC50 value of 0.55 ± 0.04 µM, and its cellular on-target effects were further evidenced by c-Myc downregulation results. In summary, DC-CPin734 showing good potency, selectivity and anti AML activity could serve as a potent and selective in vitro and in vivo probe of CBP bromodomain and a promising lead compound for future drug development.

4.
Psychol Med ; : 1-11, 2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32880241

RESUMO

BACKGROUND: Neuroimaging characteristics have demonstrated disrupted functional organization in schizophrenia (SZ), involving large-scale networks within grey matter (GM). However, previous studies have ignored the role of white matter (WM) in supporting brain function. METHODS: Using resting-state functional MRI and graph theoretical approaches, we investigated global topological disruptions of large-scale WM and GM networks in 93 SZ patients and 122 controls. Six global properties [clustering coefficient (Cp), shortest path length (Lp), local efficiency (Eloc), small-worldness (σ), hierarchy (ß) and synchronization (S) and three nodal metrics [nodal degree (Knodal), nodal efficiency (Enodal) and nodal betweenness (Bnodal)] were utilized to quantify the topological organization in both WM and GM networks. RESULTS: At the network level, both WM and GM networks exhibited reductions in Eloc, Cp and S in SZ. The SZ group showed reduced σ and ß only for the WM network. Furthermore, the Cp, Eloc and S of the WM network were negatively correlated with negative symptoms in SZ. At the nodal level, the SZ showed nodal disturbances in the corpus callosum, optic radiation, posterior corona radiata and tempo-occipital WM tracts. For GM, the SZ manifested increased nodal centralities in frontoparietal regions and decreased nodal centralities in temporal regions. CONCLUSIONS: These findings provide the first evidence for abnormal global topological properties in SZ from the perspective of a substantial whole brain, including GM and WM. Nodal centralities enhance GM areas, along with a reduction in adjacent WM, suggest that WM functional alterations may be compensated for adjacent GM impairments in SZ.

5.
Epilepsy Behav ; 112: 107379, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32920374

RESUMO

OBJECTIVE: Only a few heritable SCN8A variants have been described in patients with a mild phenotype of epilepsy. Here, we describe a Chinese family with a novel inherited SCN8A variant and investigate changes in spontaneous cerebral activity during the resting-state in magnetic resonance imaging (MRI)-negative patients with epilepsy and their unaffected siblings. METHODS: A gene panel targeting 535 epilepsy genes was performed on the proband and his parents. The identified variant was confirmed in other affected members by Sanger sequencing. Resting-state functional MRI (fMRI) data were gathered from the family (4 affected individuals and 3 unaffected siblings) and 72 healthy controls (HCs). Functional connectivity density (FCD) was used to assess whether distant or local functional network changes occurred in patients with epilepsy. RESULTS: A heterozygous missense variant (c.4568C>A; p.A1523D) in SCN8A was identified in the Chinese family, with a total of 7 members who presented with a mild phenotype (childhood seizures and normal cognition). All patients remained seizure-free, and one patient remained seizure-free without medication. Increased FCD values in the thalamocortical network and basal ganglia network were observed in both patients with epilepsy and their unaffected siblings compared with the HCs. Direct comparison between SCN8A variant patients and unaffected siblings showed that more serious and distributed abnormal changes occurred in the mesial frontal regions of patients with epilepsy. CONCLUSIONS: We identified a novel SCN8A variant with a mild familial epilepsy phenotype. A similar pattern of FCD alterations in patients and their unaffected siblings might represent an endophenotype of benign epilepsy associated with the SCN8A inherited variant, and more extensive alterations in mesial frontal regions may help us to further understand the pathogenesis of SCN8A-related mild epilepsy.

6.
IEEE Trans Biomed Eng ; PP2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32976091

RESUMO

GOAL: Idiopathic generalized epilepsy (IGE) represents generalized spike-wave discharges (GSWD) and distributed changes in thalamocortical circuit. The purpose of this paper is to investigate how the ongoing alpha oscillation acts upon the local temporal dynamics and spatial hyperconnectivity during epileptic state. METHODS: We evaluated the spatiotemporal regulation of alpha oscillations in epileptic state based on simultaneous EEG-fMRI recordings in 45 IGE patients. The alpha-BOLD temporal consistency, as well as the effect of alpha power windows on dynamic functional connectivity strength (dFCS) was analyzed. Then, stable synchronization networks during GSWD were constructed, and the spatial covariation with alpha-based network integration was investigated. RESULTS: Increased temporal covariation was demonstrated between alpha power and BOLD fluctuations in thalamus and distributed cortical regions in IGE. High alpha power had inhibition effect on dFCS in healthy controls, while in epilepsy, high alpha windows arose along with the enhancement of dFCS in thalamus, caudate and some default mode network (DMN) regions. Moreover, synchronization networks in GSWD-before, GSWD-onset and GSWD-after stages were demonstrated, and the connectivity strength in prominent hub nodes (precuneus, thalamus) was associated with the spatially disturbed alpha-based network integration. CONCLUSION: The results indicated the spatiotemporal regulation of alpha in epilepsy by means of increased power and decreased coherence communication. It provided links between alpha rhythm and the altered temporal dynamics, as well as the hyperconnectivity in thalamus-DMN circuit. SIGNIFICANCE: The combination between neural oscillations and epileptic representations may be of clinical importance in terms of seizure prediction and non-invasive interventions.

7.
Stem Cells Int ; 2020: 8811963, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32963548

RESUMO

Chondrogenesis and subsequent osteogenesis of mesenchymal stem cells (MSCs) and angiogenesis at injured sites are crucial for bone fracture healing. Amygdalin, a cyanogenic glycoside compound derived from bitter apricot kernel, has been reported to inhibit IL-1ß-induced chondrocyte degeneration and to stimulate blood circulation, suggesting a promising role of amygdalin in fracture healing. In this study, tibial fractures in C57BL/6 mice were treated with amygdalin. Fracture calluses were then harvested and subjected to radiographic, histological, and biomechanical testing, as well as angiography and gene expression analyses to evaluate fracture healing. The results showed that amygdalin treatment promoted bone fracture healing. Further experiments using MSC-specific transforming growth factor- (TGF-) ß receptor 2 conditional knockout (KO) mice (Tgfbr2Gli1-Cre ) and C3H10 T1/2 murine mesenchymal progenitor cells showed that this effect was mediated through TGF-ß/Smad signaling. We conclude that amygdalin could be used as an alternative treatment for bone fractures.

8.
Acta Pharmacol Sin ; 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796956

RESUMO

Grincamycins (GCNs) are a class of angucycline glycosides isolated from actinomycete Streptomyces strains that have potent antitumor activities, but their antitumor mechanisms remain unknown. In this study, we tried to identify the cellular target of grincamycin B (GCN B), one of most dominant and active secondary metabolites, using a combined strategy. We showed that GCN B-selective-induced apoptosis of human acute promyelocytic leukemia (APL) cell line NB4 through increase of ER stress and intracellular reactive oxygen species (ROS) accumulation. Using a strategy of combining phenotype, transcriptomics and protein microarray approaches, we identified that isocitrate dehydrogenase 1(IDH1) was the putative target of GCN B, and confirmed that GCNs were a subset of selective inhibitors targeting both wild-type and mutant IDH1 in vitro. It is well-known that IDH1 converts isocitrate to 2-oxoglutarate (2-OG), maintaining intracellular 2-OG homeostasis. IDH1 and its mutant as the target of GCN B were validated in NB4 cells and zebrafish model. Knockdown of IDH1 in NB4 cells caused the similar phenotype as GCN B treatment, and supplementation of N-acetylcysteine partially rescued the apoptosis caused by IDH1 interference in NB4 cells. In zebrafish model, GCN B effectively restored myeloid abnormality caused by overexpression of mutant IDH1(R132C). Taken together, we demonstrate that IDH1 is one of the antitumor targets of GCNs, suggesting wild-type IDH1 may be a potential target for hematological malignancies intervention in the future.

9.
Dermatol Surg ; 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32740211

RESUMO

BACKGROUND: The forehead is a challenging area for filler injection because of the risk of serious complications. Anatomy-based filler injection techniques help to avoid severe vascular complications. MATERIALS AND METHODS: Sixty-six cadaver heads were infused with adequate lead oxide contrast through the external carotid arteries, internal carotid arteries, facial artery, and superficial temporal artery. Three-dimensional computed tomography scans were reconstructed using validated algorithms. We measured the length and arc length of "beautiful" foreheads evaluated by 3 skilled surgeons. RESULTS: The frontal branch of the superficial temporal artery (FBSTA) was classified based on the main trunk as follows: Type I FBSTA (89.72%) took a sudden turn (89.56° ± 11.76°) once passing through the temporal crest, whereas Type II FBSTA (10.28%) barely turned (52.26° ± 6.81°) at the temporal crest. A total of 319 arteries passed through the midline in 48 cadaver heads. There were more superficial arteries (292 of 319) than deep arteries (27 of 319). The difference in the length and arc length of the forehead was 19.66 ± 4.35 mm. CONCLUSION: This study introduces an effective technique for forehead filler injection that minimizes the risk of filler injection and improves patient satisfaction.

10.
Biomed Pharmacother ; 130: 110581, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32745914

RESUMO

BACKGROUND: Radix Rehmanniae Praeparata (RR), the steamed roots of Rehmannia glutinosa, is a traditional Chinese medicine with the function of kidney-nourishing, and it has been safety used for centuries to treat bone-related disorders. The aim of this study is to investigate the positive effect and underlying mechanism of RR enhancing bone fracture healing in mouse model. METHODS: Ten-week-old C57BL/6J mice were subjected to a unilateral open transverse tibial fracture and provided a daily treatment of RR. Bone samples were harvested for tissue analyses including x-ray, µCT, histology, histomorphometry, biomechanical testing, immunohistochemical (IHC) and quantitative gene expression analysis. To determine the role of TGF-ß in accelerating fracture healing effect of RR, aforementioned experiments were performed on Gli1-CreER; Tgfbr2 flox/flox (Tgfbr2Gli1ER) conditional knockout mice. RESULTS: RR promoted bone fracture healing and strengthened bone intensity in wild-type and Cre- mice with the activation of TGF-ß/Smad2 signaling, on the contrary, RR failed to accelerating fracture healing in Tgfbr2Gli1ER mice. CONCLUSION: RR promotes bone fracture healing by intensify the contribution of Gli1+ cells on bone and cartilage formation mainly in TGF-ß-dependent manner. RR is an alternative option for clinical treatment of fracture.

11.
Planta ; 252(1): 13, 2020 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-32621079

RESUMO

MAIN CONCLUSION: NtALS1 is specifically expressed in glandular trichomes, and can improve the content of acylsugars in tobacco. ABTRACT: The glandular trichomes of many species in the Solanaceae family play an important role in plant defense. These epidermal outgrowths exhibit specialized secondary metabolism, including the production of structurally diverse acylsugars that function in defense against insects and have substantial developmental potential for commercial uses. However, our current understanding of genes involved in acyl chain biosynthesis of acylsugars remains poor in tobacco. In this study, we identified three acetolactate synthase (ALS) genes in tobacco through homology-based gene prediction using Arabidopsis ALS. Quantitative real-time PCR (qRT-PCR) and tissue distribution analyses suggested that NtALS1 was highly expressed in the tips of glandular trichomes. Subcellular localization analysis showed that the NtALS1 localized to the chloroplast. Moreover, in the wild-type K326 variety background, we generated two ntals1 loss-of-function mutants using the CRISPR-Cas9 system. Acylsugars contents in the two ntals1 mutants were significantly lower than those in the wild type. Through phylogenetic tree analysis, we also identified NtALS1 orthologs that may be involved in acylsugar biosynthesis in other Solanaceae species. Taken together, these findings indicate a functional role for NtALS1 in acylsugar biosynthesis in tobacco.

12.
J Phys Chem Lett ; 11(15): 6463-6467, 2020 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-32697914

RESUMO

Lead-free halide double perovskites (DPs) have attracted great attention due to their stability, nontoxicity and good photophysical property. In this work, we report a new, small-bandgap Cs2CuSbCl6 DP nanocrystals (NCs) with a bandgap of 1.66 eV, which is the smallest bandgap in reported lead-free three-dimensional DP NCs. Density functional theory calculations confirm that Cs2CuSbCl6 DP has an indirect bandgap of 1.70 eV, in good agreement with the experimental result. The photophysical property of Cs2CuSbCl6 NCs is studied by the combination of femtosecond transient absorption (TA) and nanosecond TA techniques. In addition, the Cs2CuSbCl6 NCs exhibit good stability exposed in the air. These results show that these NCs will have great potential to be used as a light-absorbing material for photovoltaic applications.

13.
Brain Imaging Behav ; 2020 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-32700258

RESUMO

Basal ganglia, which include the striatum and thalamus, have key roles in motivation, emotion, motor function, also contribute to higher-order cognitive function. Previous researches have documented structural and functional alterations in basal ganglia in schizophrenia. While few studies have assessed asymmetries of these characters in basal ganglia of schizophrenia. The current study investigated this issue by using diffusion tensor imaging, anatomic T1-weight image and resting-state functional data from 88 chronic schizophrenic subjects and 92 healthy controls. The structural characteristic, including fractional anisotropy, mean diffusivity (MD) and volume, were extracted and quantified from the subregions of basal ganglia, including caudate, putamen, pallidum and thalamus, through automated atlas-based method. The resting-state functional maps of these regions were also calculated through seed-based functional connectivity. Then, the laterality indexes of structural and functional features were calculated. Compared with healthy controls, schizophrenic subjects showed increased left laterality of volume in striatum and reduced left laterality of volume in thalamus. Furthermore, the difference of laterality of subregions in thalamus is compensatory in schizophrenic subjects. Importantly, the severity of patients' positive symptom was negative corelated with reduced left laterality of volume in thalamus. Our findings provide preliminary evidence demonstrating that the possibility of aberrant laterality in neural pathways and connectivity patterns related to the basal ganglia in schizophrenia.

14.
PLoS One ; 15(6): e0234790, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555721

RESUMO

Civil aviation is a distinctive career. Pilots need to monitor the entire system in real time. However, the psychophysiological mechanism of flying is largely unknown. The human brain is a large-scale interconnected organization, and many stable intrinsic large-scale brain networks have been identified. Among them are three core neurocognitive networks: default mode network (DMN), central executive network (CEN), and salience network (SN). These three networks play a critical role in human cognition. This study aims to examine the dynamic properties of the three large-scale brain networks in civil aviation pilots. We collected resting-state functional magnetic resonance imaging data from pilots. Independent component analysis, which is a data-driven approach, was combined with sliding window dynamic functional connectivity analysis to detect the dynamic properties of large-scale brain networks. Our results revealed that pilots exhibit an increased interaction of the CEN with the DMN and the SN along with a decreased interaction within the CEN. In addition, the temporal properties of functional dynamics (number of transitions) increased in pilots compared to healthy controls. In general, pilots exhibited increased between-network functional connectivity, decreased within-network functional connectivity, and a higher number of transitions. These findings suggest that pilots might have better functional dynamics and cognitive flexibility.


Assuntos
Mapeamento Encefálico , Encéfalo/fisiologia , Adulto , Encéfalo/diagnóstico por imagem , Estudos de Casos e Controles , Análise por Conglomerados , Humanos , Imagem por Ressonância Magnética , Masculino , Pilotos , Adulto Jovem
15.
Trends Plant Sci ; 25(10): 1030-1040, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32532595

RESUMO

The development of genomics and epigenomics has allowed rapid advances in our understanding of plant biology. However, conventional bulk analysis dilutes cell-specific information by providing only average information, thereby limiting the resolution of genomic and functional genomic studies. Recent advances in single-cell sequencing technology concerning genomics and epigenomics open new avenues to dissect cell heterogeneity in multiple biological processes. Recent applications of these approaches to plants have provided exciting insights into diverse biological questions. We highlight the methodologies underlying the current techniques of single-cell genomics and epigenomics before covering their recent applications, potential significance, and future perspectives in plant biology.

16.
J Am Acad Dermatol ; 2020 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-32592875

RESUMO

BACKGROUND: Vascular complication from periorbital intravascular filler injection are major safety concerns. OBJECTIVE: To thoroughly describe the superior orbital vessels near the orbital rim and propose considerations for upper eyelids and forehead injections. METHODS: Fifty-one cadaver heads were infused with lead oxide contrast media through the external carotid artery, internal carotid artery, and facial and superficial temporal arteries. Computed tomography (CT) images were obtained after contrast agent injection, and 3D CT scans were reconstructed using a validated algorithm. RESULTS: Eighty-six qualified hemifaces clearly revealed the origin, depth and anastomoses of the superior orbital vessels, which consistently deployed two distinctive layers: deep and superficial. Of all hemifaces, 59.3% had deep superior orbital vessels near the orbital rim, including 44.2% with deep superior orbital arcades and 15.1% with deep superior orbital arteries, which originated from the ophthalmic artery. Additionally, 97.7% of the hemifaces had superficial superior orbital arcades, for which four origins were identified: ophthalmic artery, superior medial palpebral artery, angular artery, and anastomosis between the angular and ophthalmic arteries. LIMITATIONS: The arterial depth estimated from 3D CT needs to be confirmed by standard cadaver dissection. CONCLUSION: This study elucidated novel arterial systems and proposed considerations for upper eyelids and forehead injections.

17.
Bioorg Chem ; 101: 103962, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32480171

RESUMO

USP8, one member of deubiquitinating enzymes (DUBs) families, maintains the ubiquitination level of EGFR and regulates the downstream signaling pathways. The deregulation of USP8 has been implicated in many human diseases, especially in cancer. Therefore, USP8 has been identified as a promising target for drug design. Herein, via high throughput screening based on Ubiquitin-rhodamine-110 (Ubiquitin-Rho-110) fluorometric activity assay, we discovered a novel inhibitor DC-U43. By structure optimization, DC-U43-10 reached a half-maximal inhibitory concentration (IC50) value of 2.6 ± 1.1 µM and exhibited 10-fold selectivity against USP7. The binding between DC-U43-10 and USP8 was validated by surface plasmon resonance (SPR) assay with a KD value of 10.5 ± 3.7 µM. It also inhibited the colony formation of H1975 cells. Hence, DC-U43-10 represents a kind of USP8 inhibitors with novel scaffold and has broad prospects for being a probe for USP8-related academic and clinical research.

18.
Bioorg Chem ; 101: 103991, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32559581

RESUMO

CREB-binding protein (CBP) is a large multi-domain protein containing a HAT domain catalyzing transacetylation and a bromodomain responsible for acetylated lysine recognition. CBPs could act as transcription co-activators to regulate gene expression and have been shown to play a significant role in the development and progression of many cancers. Herein, through in silico screening two hit compounds with tetrahydroquinolin methyl carbamate scaffold were discovered, among which DC-CPin7 showed an in vitro inhibitory activity with the TR-FRET IC50 value of 2.5 ± 0.3 µM. We obtained a high-resolution co-crystal structure of the CBP bromodomain in complex with DC-CPin7 to guide following structure-based rational drug design, which yielded over ten DC-CPin7 derivatives with much higher potency, among which DC-CPin711 showed approximately 40-fold potency compared with hit compound DC-CPin7 with an in vitro TR-FRET IC50 value of 63.3 ± 4.0 nM. Notably, DC-CPin711 showed over 150-fold selectivity against BRD4 bromodomains. Moreover, DC-CPin711 showed micromolar level of anti-leukemia proliferation through G1 phase cell cycle arrest and cell apoptosis. In summary, through a combination of computational and crystal-based structure optimization, DC-CPin711 showed potent in vitro inhibitory activities to CBP bromodomain with a decent selectivity towards BRD4 bromodomains and good cellular activity to leukemia cells, which could further be applied to related biological and translational studies as well as serve as a lead compound for future development of potent and selective CBP bromodomain inhibitors.

19.
Int Immunopharmacol ; 86: 106709, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32593155

RESUMO

BACKGROUND: Tumor mutation burden (TMB) has been established as a biomarker for response to immune therapy and prognosis in various cancers. However, the association between TMB and prognosis of prostate cancer (PCa) remains unclear. This study aimed to investigate the impact of TMB in biochemical recurrence (BCR) and the immune microenvironment in high and low TMB groups. METHODS: Mutation data, gene expression, clinicopathological information were downloaded from The Cancer Genome Atlas (TCGA). Mutation types and TMB values were identified. All samples were divided into high and low TMB groups with median TMB value as the cutoff point. The BCR-free survival rates, Differentially expressed genes (DEGs) and immune cells infiltrations in different TMB groups were identified. RESULTS: The most common variant type and SNV were single nucleotide polymorphism and C > T. respectively. High TMB level was significantly associated with older age, positive lymph node, higher International Society of Urological Pathology (ISUP) grade, advanced stage and poor BCR-free survival. 132 DEGs were identified and involved in receptor ligand activity and hormone activity. High expression of six core genes UBE2C, PLK1, CDC20, BUB1, CDK1 and HJURP were associated with worse BCR-free survival. The analysis of immune cells infiltration revealed that the amount of activated CD4+ memory T cells was significantly different in high and low TMB groups. CONCLUSIONS: The current study comprehensively described the summary of mutation and TMB related DEGs in PCa. TMB was associated with BCR-free survival and the infiltration of activated CD4+ memory T cells in the immune microenvironment.

20.
Acta Pharmacol Sin ; 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32504066

RESUMO

Estrogen deficiency induces cardiac dysfunction and increases the risk of cardiovascular disease in postmenopausal women and in those who underwent bilateral oophorectomy. Previous evidence suggests that puerarin, a phytoestrogen, exerts beneficial effects on cardiac function in patients with cardiac hypertrophy. In this study, we investigated whether puerarin could prevent cardiac hypertrophy and remodeling in ovariectomized, aortic-banded rats. Female SD rats subjected to bilateral ovariectomy (OVX) plus abdominal aortic constriction (AAC). The rats were treated with puerarin (50 mg·kg-1 ·d-1, ip) for 8 weeks. Then echocardiography was assessed, and the rats were sacrificed, their heart tissues were extracted and allocated for further experiments. We showed that puerarin administration significantly attenuated cardiac hypertrophy and remodeling in AAC-treated OVX rats, which could be attributed to activation of PPARα/PPARγ coactivator-1 (PGC-1) pathway. Puerarin administration significantly increased the expression of estrogen-related receptor α, nuclear respiratory factor 1, and mitochondrial transcription factor A in hearts. Moreover, puerarin administration regulated the expression of metabolic genes in AAC-treated OVX rats. Hypertrophic changes could be induced in neonatal rat cardiomyocytes (NRCM) in vitro by treatment with angiotensin II (Ang II, 1 µM), which was attenuated by co-treatemnt with puerarin (100 µM). We further showed that puerarin decreased Ang II-induced accumulation of non-esterified fatty acids (NEFAs) and deletion of ATP, attenuated the Ang II-induced dissipation of the mitochondrial membrane potential, and improved the mitochondrial dysfunction in NRCM. Furthermore, addition of PPARα antagonist GW6471 (10 µM) partially abolished the anti-hypertrophic effects and metabolic effects of puerarin in NRCM. In conclusion, puerarin prevents cardiac hypertrophy in AAC-treated OVX rats through activation of PPARα/PGC-1 pathway and regulation of energy metabolism remodeling. This may provide a new approach to prevent the development of heart failure in postmenopausal women.

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