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1.
Behav Neurol ; 2021: 5533827, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33859767

RESUMO

There are nearly 50 million Alzheimer's disease (AD) patients worldwide, 90% of whom develop behavioral and psychological symptoms of dementia (BPSD), which increase the mortality rate of patients, and impose an economic and care burden on families and society. As a neurotransmitter and neuromodulator, serotonin is involved in the regulation of psychoemotional, sleep, and feeding functions. Accumulating data support the importance of serotonin in the occurrence and development of BPSD. Studies have shown that reduction of serotonin receptors can increase depression and mental symptoms in AD patients. At present, there is no drug treatment for AD approved by the US Food and Drug Administration. Among them, agomelatine, as a new type of antidepressant, can act on serotonin 2 receptors to improve symptoms such as depression and anxiety. At present, research on BPSD is still in the preliminary exploratory stage, and there are still a lot of unknowns. This review summarizes the relationship between serotonin 2 receptors, agomelatine, and BPSD. It provides a new idea for the study of the pathogenesis and treatment of BPSD.

2.
Clin Transl Med ; 11(3): e374, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33783987

RESUMO

Prolonged pressure overload triggers cardiac hypertrophy and frequently leads to heart failure (HF). Vascular endothelial growth factor-C (VEGF-C) and its receptor VEGFR-3 are components of the central pathway for lymphatic vessel growth (also known as lymphangiogenesis), which has crucial functions in the maintenance of tissue fluid balance and myocardial function after ischemic injury. However, the roles of this pathway in the development of cardiac hypertrophy and dysfunction during pressure overload remain largely unknown. Eight- to 10-week-old male wild-type (WT) mice, VEGFR-3 knockdown (VEGFR-3f/- ) mice, and their WT littermates (VEGFR-3f/f ) were subjected to pressure overload induced by transverse aortic constriction (TAC) for 1-6 weeks. We found that cardiac lymphangiogenesis and the protein expression of VEGF-C and VEGFR-3 were upregulated in the early stage of cardiac hypertrophy but were markedly reduced in failing hearts. Moreover, TAC for 6 weeks significantly reduced cardiac lymphangiogenesis by inhibiting activation of VEGFR-3-mediated signals (AKT/ERK1/2, calcineurin A/NFATc1/FOXc2, and CX43), leading to increased cardiac edema, hypertrophy, fibrosis, apoptosis, inflammation, and dysfunction. These effects were further aggravated in VEGFR-3f/- mice and were dose-dependently attenuated by delivery of recombinant VEGF-C156S in WT mice. VEGF-C156s administration also reversed pre-established cardiac dysfunction induced by sustained pressure overload. Thus, these results demonstrate, for the first time, that activation of the VEGF-C-VEGFR-3 axis exerts a protective effect during the transition from cardiac hypertrophy to HF and highlight selective stimulation of cardiac lymphangiogenesis as a potential new therapeutic approach for hypertrophic heart diseases.

3.
Sci Rep ; 11(1): 404, 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33432117

RESUMO

Up-regulation of long non-coding RNAs (lncRNAs), colon-cancer associated transcript (CCAT) 1 and 2, was associated with worse prognosis in colorectal cancer (CRC). Nevertheless, their role in predicting metastasis in early-stage CRC is unclear. We measured the expression of CCAT1, CCAT2 and their oncotarget, c-Myc, in 150 matched mucosa-tumour samples of early-stage microsatellite-stable Chinese CRC patients with definitive metastasis status by multiplex real-time RT-PCR assay. Expression of CCAT1, CCAT2 and c-Myc were significantly up-regulated in the tumours compared to matched mucosa (p < 0.0001). The expression of c-Myc in the tumours was significantly correlated to time to metastasis [hazard ratio = 1.47 (1.10-1.97)] and the risk genotype (GG) of rs6983267, located within CCAT2. Expression of c-Myc and CCAT2 in the tumour were also significantly up-regulated in metastasis-positive compared to metastasis-negative patients (p = 0.009 and p = 0.04 respectively). Nevertheless, integrating the expression of CCAT1 and CCAT2 by the Random Forest classifier did not improve the predictive values of ColoMet19, the mRNA-based predictor for metastasis previously developed on the same series of tumours. The role of these two lncRNAs is probably mitigated via their oncotarget, c-Myc, which was not ranked high enough previously to be included in ColoMet19.

4.
Front Cell Dev Biol ; 8: 594683, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33251220

RESUMO

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia and is a major cause of stroke and heart failure. We and others have found that gallic acid (GA) plays a beneficial role in cardiac hypertrophic remodeling and hypertension. However, the effect of GA on angiotensin II (Ang II)-induced AF and atrial remodeling as well as the underlying mechanisms remain unknown. AF was induced in mice by Ang II infusion (2000 ng/kg/min) for 3 weeks. Blood pressure was measured using the tail-cuff method. Atrial volume was evaluated by echocardiography. Atrial remodeling was studied using hematoxylin and eosin, Masson's trichrome, and immunohistochemical staining. Atrial oxidative stress was assessed by dihydroethidium staining. The gene expression of fibrotic and inflammatory markers and protein levels of signaling mediators were measured by quantitative real-time PCR and western blot analysis. In mice, GA administration significantly attenuated Ang II-induced elevation of blood pressure, AF incidence and duration, atrial dilation, fibrosis, inflammation, and oxidative stress compared with the vehicle control. Furthermore, GA downregulated Ang II-induced activity and expression of immunoproteasome subunits (ß2i and ß5i), which reduced PTEN degradation and led to the inactivation of AKT1 and downstream signaling mediators. Importantly, blocking PTEN activity by VO-Ohpic markedly reversed the GA-mediated protective effects on Ang II-induced AF and atrial remodeling. Therefore, our results provide novel evidence that GA exerts a cardioprotective role by inhibiting immunoproteasome activity, which attenuates PTEN degradation and activation of downstream signaling, and may represent a promising candidate for treating hypertensive AF.

5.
Front Cell Dev Biol ; 8: 592048, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33195259

RESUMO

Macrophage polarization and inflammation are key factors for the onset and progression of atherosclerosis. The immunoproteasome complex consists of three inducible catalytic subunits (LMP2, LMP10, and LMP7) that play a critical role in the regulation of these risk factors. We recently demonstrated that the LMP7 subunit promotes diet-induced atherosclerosis via inhibition of MERTK-mediated efferocytosis. Here, we explored the role of another subunit of LMP10 in the disease process, using ApoE knockout (ko) mice fed on an atherogenic diet (ATD) containing 0.5% cholesterol and 20% fat for 8 weeks as an in vivo atherosclerosis model. We observed that ATD significantly upregulated LMP10 expression in aortic lesions, which were primarily co-localized with plaque macrophages. Conversely, deletion of LMP10 markedly attenuated atherosclerotic lesion area, CD68+ macrophage accumulation, and necrotic core expansion in the plaques, but did not change plasma metabolic parameters, lesional SM22α+ smooth muscle cells, or collagen content. Myeloid-specific deletion of LMP10 by bone marrow transplantation resulted in similar phenotypes. Furthermore, deletion of LMP10 remarkably reduced aortic macrophage infiltration and increased M2/M1 ratio, accompanied by decreased expression of pro-inflammatory M1 cytokines (MCP-1, IL-1, and IL-6) and increased expression of anti-inflammatory M2 cytokines (IL-4 and IL-10). In addition, we confirmed in cultured macrophages that LMP10 deletion blunted macrophage polarization and inflammation during ox-LDL-induced foam cell formation in vitro, which was associated with decreased IκBα degradation and NF-κB activation. Our results show that the immunoproteasome subunit LMP10 promoted diet-induced atherosclerosis in ApoE ko mice possibly through regulation of NF-κB-mediated macrophage polarization and inflammation. Targeting LMP10 may represent a new therapeutic approach for atherosclerosis.

6.
Aging (Albany NY) ; 12(21): 21959-21970, 2020 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-33161394

RESUMO

BACKGROUND: The association between cigarette smoking and multiple system atrophy (MSA) has been debated. We conducted a systematic review and a meta-analysis to investigate this link. RESULTS: We identified 161 articles from database searching and bibliographic review. Five case-control studies satisfied the inclusion and exclusion criteria, and 435 and 352 healthy controls and MSA patients were examined. The prevalence of MSA amongst ever smokers was lower compared to never smokers (aOR=0.57; 95% CI, 0.29-1.14), although this result did not reach statistical significance. This was also observed for current and former smokers, with a stronger association for current smokers (aOR=0.63 vs aOR=0.96). CONCLUSIONS: There is a suggestion that smoking protects against MSA. Prospective studies in larger patient cohorts are required to further evaluate the cause-effect relationship and functional studies in cellular and animal models will provide mechanistic insights on their potential etiologic links. METHODS: PubMed and Cochrane Library were searched from inception to July 7, 2019 to identify case-control studies that analyzed smoking as an environmental risk or protective factor for MSA. Two authors independently extracted data and performed risk-of-bias and quality assessment. The random-effects model was assumed to account for between-study variance when pooling the crude and adjusted odds ratios.

7.
Front Physiol ; 11: 560170, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33013481

RESUMO

Background/Aim: The proliferation and migration of lymphatic endothelial cells (LECs) is essential for lymphatic vessel growth (also known as lymphangiogenesis), which plays a crucial role in regulating the tissue fluid balance and immune cell trafficking under physiological and pathological conditions. Several growth factors, such as VEGF-C, can stimulate lymphangiogenesis. However, the effects of angiotensin II (Ang II) on the proliferation and migration of mouse LECs and the underlying potential mechanisms remain unknown. Methods: Wild-type mice were infused with Ang II (1,000 ng/kg/min) for 1-2 weeks. Murine LECs were stimulated with Ang II (500 nM) or saline for 12-48 h. Cell proliferation was determined with 5-bromo-2-deoxyuridine (BrdU) incorporation assays, while cell migration was assessed by scratch wound healing and transwell chamber assays. The gene expression profiles were obtained by time series microarray and real-time PCR analyses. Results: Ang II treatment significantly induced lymphangiogenesis in the hearts of mice and the proliferation and migration of cultured LECs in a time-dependent manner. This effect was completely blocked by losartan, an angiotensin II type 1 receptor (AT1R) antagonist. The microarray results identified 1,385 differentially expressed genes (DEGs) at one or more time points in the Ang II-treated cells compared with the control saline-treated cells. These DEGs were primarily involved in biological processes and pathways, including sensory perception of smell, the G protein coupled receptor signaling pathway, cell adhesion, olfactory transduction, Jak-STAT, alcoholism, RIG-I-like receptor and ECM-receptor interaction. Furthermore, these DEGs were classified into 16 clusters, 7 of which (Nos. 13, 2, 8, 15, 7, 3, and 12, containing 586 genes) were statistically significant. Importantly, the Ang II-induced alterations the expression of lymphangiogenesis-related genes were reversed by losartan. Conclusion: The results of the present indicate that Ang II can directly regulate the proliferation and migration of LECs through AT1R in vivo and in vitro, which may provide new potential treatments for Ang II-induced hypertension and cardiac remodeling.

8.
BMJ Open ; 10(9): e039422, 2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-32998928

RESUMO

INTRODUCTION: Diabetes has an increasing worldwide prevalence. It is known to be a predisposing factor for postoperative complications. Preoperative glycaemic control strategies should be pursued as glycaemic control could serve as a modifiable risk factor. Glycated haemoglobin (HbA1c), a marker of 3-month average glycaemic control, has been shown in meta-analyses to predict postoperative complications in cardiothoracic, bariatric and orthopaedic surgery. However, there is no meta-analysis in the major abdominal surgery population, in whom morbidity may be higher due to the nature of the surgery. Understanding the association between HbA1c and postoperative complications could help in preoperative risk prognostication, counselling and glycaemic target selection. The aim of this systematic review and meta-analysis is to evaluate all evidence on the association between preoperative HbA1c and postoperative complications in elective major abdominal surgery, and to investigate the threshold HbA1c level before postoperative complication rates increase. METHODS AND ANALYSIS: This review will be performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines. PubMed, Embase, Cochrane Central Register of Controlled Trials, Google Scholar and China National Knowledge Infrastructure will be searched for all original studies. Study selection, data extraction, risk of bias and quality assessment will be conducted by two independent reviewers. The primary outcome is the association between preoperative HbA1c and major postoperative complications (Clavien Dindo 3-5), and the secondary outcome is the association between HbA1c and overall postoperative complications. Data management and synthesis will be performed using Microsoft Excel and Stata to derive pool estimates. ETHICS AND DISSEMINATION: No ethics approval is required as only secondary data will be used. Findings will be disseminated through peer-reviewed journals and conference presentations. PROSPERO REGISTRATION NUMBER: CRD42020167347.

9.
J Cell Mol Med ; 24(19): 11272-11282, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32812337

RESUMO

Atrial fibrillation (AF) is associated with inflammation and oxidative stress. Recently, we demonstrated that the chemokine-receptor CXCR2 plays a critical role in the recruitment of monocytes/macrophages and the development of hypertension and cardiac remodelling. However, the role of CXCR2 in the pathogenesis of hypertensive AF remains unclear. AF was induced in Wistar-Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) administered with the CXCR2 inhibitor SB225002. Atrial remodelling, pathological changes and electrophysiology were examined. Our results showed that the chemokine CXCL1 and its receptor CXCR2 were markedly increased in atrial tissue of SHRs compared with WKYs. The administration of SB225002 to SHRs significantly reduced the elevation of blood pressure, AF inducibility and duration, atrial remodelling, recruitment of macrophages, superoxide production and conduction abnormalities compared with vehicle treatment. The administration of SB225002 to SHRs also reversed pre-existing AF development, atrial remodelling, inflammation and oxidative stress. These effects were associated with the inhibition of multiple signalling pathways, including TGF-ß1/Smad2/3, NF-κB-P65, NOX1, NOX2, Kir2.1, Kv1.5 and Cx43. In conclusion, this study provides new evidence that blocking CXCR2 prevents and reverses the development of AF in SHRs, and suggests that CXCR2 may be a potential therapeutic target for hypertensive AF.

10.
Front Pharmacol ; 11: 1121, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32848742

RESUMO

Hypertension is a major cause of heart attack and stroke. Our recent study revealed that gallic acid (GA) exerts protective effects on pressure overload-induced cardiac hypertrophy and dysfunction. However, the role of GA in angiotensin II (Ang II)-induced hypertension and vascular remodeling remains unknown. C57BL/6J mice were subjected to saline and Ang II infusion. Systolic blood pressure was measured using a tail-cuff system. Vascular remodeling and oxidative stress were examined by histopathological staining. Vasodilatory function was evaluated in the aortic ring. Our findings revealed that GA administration significantly ameliorated Ang II-induced hypertension, vascular inflammation, and fibrosis. GA also abolished vascular endothelial dysfunction and oxidative stress in Ang II-infused aortas. Mechanistically, GA treatment attenuated Ang II-induced upregulation of the immunoproteasome catalytic subunits ß2i and ß5i leading to reduction of the trypsin-like and chymotrypsin-like activity of the proteasome, which suppressed degradation of endothelial nitric oxide synthase (eNOS) and reduction of nitric oxide (NO) levels. Furthermore, blocking eNOS activity by using a specific inhibitor (L-N G-nitroarginine methyl ester) markedly abolished the GA-mediated beneficial effect. This study identifies GA as a novel immunoproteasome inhibitor that may be a potential therapeutic agent for hypertension and vascular dysfunction.

11.
Hypertension ; 76(2): 381-392, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32639881

RESUMO

Atrial fibrillation (AF) is frequently associated with increased inflammatory response characterized by infiltration of monocytes/macrophages. The chemokine receptor CXCR-2 is a critical regulator of monocyte mobilization in hypertension and cardiac remodeling, but it is not known whether CXCR-2 is involved in the development of hypertensive AF. AF was induced by infusion of Ang II (angiotensin II; 2000 ng/kg per minute) for 3 weeks in male C57BL/6 wild-type mice, CXCR-2 knockout mice, bone marrow-reconstituted chimeric mice, and mice treated with the CXCR-2 inhibitor SB225002. Microarray analysis revealed that 4 chemokine ligands of CXCR-2 were significantly upregulated in the atria during 3 weeks of Ang II infusion. CXCR-2 expression and the number of CXCR2+ immune cells markedly increased in Ang II-infused atria in a time-dependent manner. Moreover, Ang II-infused wild-type mice had increased blood pressure, AF inducibility, atrial diameter, fibrosis, infiltration of macrophages, and superoxide production compared with saline-treated wild-type mice, whereas these effects were significantly attenuated in CXCR-2 knockout mice and wild-type mice transplanted with CXCR-2-deficient bone marrow cells or treated with SB225002. Moreover, circulating blood CXCL-1 levels and CXCR2+ monocyte counts were higher and associated with AF in human patients (n=31) compared with sinus rhythm controls (n=31). In summary, this study identified a novel role for CXCR-2 in driving monocyte infiltration of the atria, which accelerates atrial remodeling and AF after hypertension. Blocking CXCR-2 activation may serve as a new therapeutic strategy for AF.

12.
Front Physiol ; 11: 625, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32581853

RESUMO

Background/Aim: Hypertensive cardiac hypertrophy is the leading cause of cardiac remodeling and heart failure. We recently demonstrated that the immunoproteasome, an inducible form of the constitutive proteasome, plays a critical role in regulating cardiovascular diseases. However, the role of the immunoproteasome LMP10 (ß2i) catalytic subunit in the regulation of angiotensin II (Ang II)-induced cardiac hypertrophic remodeling remains unclear. Methods: Wild-type (WT) and LMP10 knockout (KO) mice were infused with Ang II 1,000 ng/kg/min for 2 weeks. Blood pressure was measured using a tail-cuff system. Cardiac function and hypertrophic remodeling were examined by echocardiography and histological staining. The expression levels of genes and proteins were examined with quantitative real-time PCR and immunoblotting analysis, respectively. Results: LMP10 mRNA and protein expression was significantly increased in Ang II-stimulated hearts and primary cardiomyocytes. Moreover, Ang II infusion for 2 weeks increased systolic blood pressure, abnormal cardiac function, hypertrophy, fibrosis, and inflammation in WT mice, which were significantly reversed in KO mice. Moreover, a marked reduction in the protein levels of insulin growth factor-1 receptor (IGF1R), glycoprotein 130 (gp130), and phosphorylated AKT, mTOR, STAT3, and ERK1/2 and an increase in the LC3II/I ratio were also observed in LMP10 KO mice compared with WT mice after Ang II infusion. In vitro culture experiments confirmed that LMP10 knockdown activated autophagy and increased IGF1R and gp130 degradation, leading to the inhibition of cardiomyocyte hypertrophy. However, inhibiting autophagy with chloroquine reversed this effect. Conclusion: The results of this study indicate that LMP10 KO attenuates Ang II-induced cardiac hypertrophic remodeling via the autophagy-dependent degradation of IGF1R and gp130, and suggests that LMP10 may be a novel therapeutic target for hypertrophic heart diseases.

13.
Front Pharmacol ; 11: 885, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32595507

RESUMO

Cardiac hypertrophy without appropriate treatment eventually progresses to heart failure. Our recent data demonstrated that the immunoproteasome subunit ß5i promotes cardiac hypertrophy. However, whether ß5i is a promising therapeutic target for treating hypertrophic remodeling remains unknown. Here, we investigated the effects of PR-957, a ß5i-specific inhibitor, on angiotensin II (Ang II)-induced hypertrophic remodeling in the murine heart. The infusion of Ang II increased immunoproteasome chymotrypsin-like activity and ß5i catalytic subunit expression in the heart, whereas PR-957 treatment fully blocked the enhanced immunoproteasome activity caused by Ang II. Moreover, the administration of PR-957 significantly suppressed Ang II-induced cardiac hypertrophy, fibrosis, and inflammation. Mechanistically, PR-957 treatment inhibited phosphatase and tensin homolog on chromosome ten (PTEN) degradation, thereby inhibiting multiple signals including AKT/mTOR, ERK1/2, transforming growth factor-ß, and IKB/NF-kB. Furthermore, PTEN blocking by its specific inhibitor VO-OHpic markedly attenuated the inhibitory effect of PR-957 on Ang II-induced cardiac hypertrophy in mice. We conclude that PR-957 blocks PTEN degradation and activates its downstream mediators, thereby attenuating Ang II-induced cardiac hypertrophy. These findings highlight that PR-957 may be a potential therapeutic agent for Ang II-induced hypertrophic remodeling.

14.
Hypertens Res ; 43(10): 1089-1098, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32541849

RESUMO

Cardiac remodeling is an important pathological process ultimately leading to heart failure. Ubiquitin carboxy-terminal hydrolase 1 (UCHL1) is a deubiquitinase that plays a critical role in neurodegenerative diseases and cancer. However, its role in cardiac remodeling in spontaneously hypertensive rats remains unclear. Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs) were administered the UCHL1 inhibitor LDN-57444 (20 µg/kg/day) from 2 months of age for 4 months. Blood pressure, cardiac hypertrophy, fibrosis, inflammation, and oxidative stress were evaluated by the tail-cuff system, echocardiography, and histological analysis. Gene and protein expression levels were examined by real-time PCR and immunoblotting analysis. At 6 months of age, the expression of UCHL at the mRNA and protein levels was significantly upregulated in SHRs compared with WKYs. Moreover, systolic blood pressure, cardiac performance, left ventricular (LV) hypertrophy, fibrosis, inflammation, and superoxide production were significantly increased in SHRs compared with WKYs, and these effects were markedly attenuated by LDN-57444 after 4 months of administration. These beneficial actions were possibly associated with a reduction in blood pressure and inactivation of multiple signaling pathways, including AKT, ERK1/2, STAT3, calcineurin A, TGF-ß/Smad2/3, and NF-κB. In conclusion, the results indicate that UCHL1 is involved in hypertensive cardiac remodeling in SHRs, and targeting UCHL1 activity may be a novel potential therapeutic approach for the treatment of hypertensive heart diseases.

15.
Sci Adv ; 6(16): eaax4826, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32494592

RESUMO

Pathological cardiac hypertrophy leads to heart failure (HF). The ubiquitin-proteasome system (UPS) plays a key role in maintaining protein homeostasis and cardiac function. However, research on the role of deubiquitinating enzymes (DUBs) in cardiac function is limited. Here, we observed that the deubiquitinase ubiquitin C-terminal hydrolase 1 (UCHL1) was significantly up-regulated in agonist-stimulated primary cardiomyocytes and in hypertrophic and failing hearts. Knockdown of UCHL1 in cardiomyocytes and mouse hearts significantly ameliorated cardiac hypertrophy induced by agonist or pressure overload. Conversely, overexpression of UCHL1 had the opposite effect in cardiomyocytes and rAAV9-UCHL1-treated mice. Mechanistically, UCHL1 bound, deubiquitinated, and stabilized epidermal growth factor receptor (EGFR) and activated its downstream mediators. Systemic administration of the UCHL1 inhibitor LDN-57444 significantly reversed cardiac hypertrophy and remodeling. These findings suggest that UCHL1 positively regulates cardiac hypertrophy by stabilizing EGFR and identify UCHL1 as a target for hypertrophic therapy.

16.
J Cell Mol Med ; 24(11): 6233-6241, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32343488

RESUMO

The pathogenesis of cardiac hypertrophy is tightly associated with activation of intracellular hypertrophic signalling pathways, which leads to the synthesis of various proteins. Tripartite motif 10 (TRIM10) is an E3 ligase with important functions in protein quality control. However, its role in cardiac hypertrophy was unclear. In this study, neonatal rat cardiomyocytes (NRCMs) and TRIM10-knockout mice were subjected to phenylephrine (PE) stimulation or transverse aortic constriction (TAC) to induce cardiac hypertrophy in vitro and in vivo, respectively. Trim10 expression was significantly increased in hypertrophied murine hearts and PE-stimulated NRCMs. Knockdown of TRIM10 in NRCMs alleviated PE-induced changes in the size of cardiomyocytes and hypertrophy gene expression, whereas TRIM10 overexpression aggravated these changes. These results were further verified in TRIM10-knockout mice. Mechanistically, we found that TRIM10 knockout or knockdown decreased AKT phosphorylation. Furthermore, we found that TRIM10 knockout or knockdown increased ubiquitination of phosphatase and tensin homolog (PTEN), which negatively regulated AKT activation. The results of this study reveal the involvement of TRIM10 in pathological cardiac hypertrophy, which may occur by prompting of PTEN ubiquitination and subsequent activation of AKT signalling. Therefore, TRIM10 may be a promising target for treatment of cardiac hypertrophy.

17.
J Immunol Res ; 2020: 7812709, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32258175

RESUMO

Background: Ubiquitin-like modifier activating enzyme 1 (UBA1) is the first and major E1 activating enzyme in ubiquitin activation, the initial step of the ubiquitin-proteasome system. Defects in the expression or activity of UBA1 correlate with several neurodegenerative and cardiovascular disorders. However, whether UBA1 contributes to atherosclerosis is not defined. Methods and Results: Atherosclerosis was induced in apolipoprotein E-knockout (Apoe-/-) mice fed on an atherogenic diet. UBA1 expression, detected by immunohistochemical staining, was found to be significantly increased in the atherosclerotic plaques, which confirmed to be mainly derived from lesional CD68+ macrophages via immunofluorescence costaining. Inactivation of UBA1 by the specific inhibitor PYR-41 did not alter the main metabolic parameters during atherogenic diet feeding but suppressed atherosclerosis development with less macrophage infiltration and plaque necrosis. PYR-41 did not alter circulating immune cells determined by flow cytometry but significantly reduced aortic mRNA levels of cytokines related to monocyte recruitment (Mcp-1, Vcam-1, and Icam-1) and macrophage proinflammatory responses (Il-1ß and Il-6). Besides, PYR-41 also suppressed aortic mRNA expression of NADPH oxidase (Nox1, Nox2, and Nox4) and lesional oxidative stress levels, determined by DHE staining. In vitro, PYR-41 blunted ox-LDL-induced lipid deposition and expression of proinflammatory cytokines (Il-1ß and Il-6) and NADPH oxidases (Nox1, Nox2, and Nox4) in cultured RAW264.7 macrophages. Conclusions: We demonstrated that UBA1 expression was upregulated and mainly derived from macrophages in the atherosclerotic plaques and inactivation of UBA1 by PYR-41 suppressed atherosclerosis development probably through inhibiting macrophage proinflammatory response and oxidative stress. Our data suggested that UBA1 might be explored as a potential pharmaceutical target against atherosclerosis.

18.
Arch Pathol Lab Med ; 144(11): 1397-1400, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32150458

RESUMO

CONTEXT.­: Mitotic count is an important histologic criterion for grading and prognostication in phyllodes tumors (PTs). Counting mitoses is a routine practice for pathologists evaluating neoplasms, but different microscopes, variable field selection, and areas have led to possible misclassification. OBJECTIVE.­: To determine whether 10 high-power fields (HPFs) or whole slide mitotic counts correlated better with PT clinicopathologic parameters using digital pathology (DP). We also aimed to find out whether this study might serve as a basis for an artificial intelligence (AI) protocol to count mitosis. DESIGN.­: Representative slides were chosen from 93 cases of PTs diagnosed between 2014 and 2015. The slides were scanned and viewed with DP. Mitotic counting was conducted on the whole slide image, before choosing 10 HPFs and demarcating the tumor area in DP. Values of mitoses per millimeter squared were used to compare results between 10 HPFs and the whole slide. Correlations with clinicopathologic parameters were conducted. RESULTS.­: Both whole slide counting of mitoses and 10 HPFs had similar statistically significant correlation coefficients with grade, stromal atypia, and stromal hypercellularity. Neither whole slide mitotic counts nor mitoses per 10 HPFs showed statistically significant correlations with patient age and tumor size. CONCLUSIONS.­: Accurate mitosis counting in breast PTs is important for grading. Exploring machine learning on digital whole slides may influence approaches to training, testing, and validation of a future AI algorithm.

19.
Clin Exp Hypertens ; 42(6): 483-489, 2020 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-31955636

RESUMO

BACKGROUND: A blood pressure (BP) of 130-139/80-89 mmHg has been defined as stage 1 hypertension by the 2017 American College of Cardiology/American Heart Association High Blood Pressure Clinical Practice Guidelines. This study was conducted to assess the association of cardiovascular risk factors (CRFs) and newly defined stage 1 hypertension in China. METHODS: We analyzed the data of 84,489 adults with a BP of <140/90 mmHg. The 10-year cardiovascular disease (CVD) risk score was calculated using the China-PAR equation. Logistic analysis was used to assess the association between CRFs and stage 1 hypertension. RESULTS: The mean values of CRFs, the proportion of metabolic abnormalities, the prevalence of ≥2 CRFs, and the 10-year CVD risk of individuals with a BP of 130-139/80-89 mmHg were significantly higher than those of the population with a BP of <130/80 mmHg. The adjusted odds ratios (ORs) of waist circumference, fasting plasma glucose (FPG), and triglycerides were 1.362 (CI 95% = 1.081-1.715, p = .009), 1.264 (CI 95% = 1.093-1.462, p = .002), and 1.331 (CI 95% = 1.009-1.755, p = .043), respectively. Other CRFs were not significantly associated with stage 1 hypertension. CONCLUSIONS: Multidisciplinary and targeted interventions are required to manage the CRFs (especially abdominal obesity, elevated FPG, and hypertriglyceridemia) of the population with a BP of 130-139/80-89 mmHg in China.


Assuntos
Dislipidemias/epidemiologia , Hipertensão , Hiperuricemia/epidemiologia , Obesidade/epidemiologia , Doenças Cardiovasculares/epidemiologia , China/epidemiologia , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Gravidade do Paciente , Guias de Prática Clínica como Assunto , Prevalência , Projetos de Pesquisa/normas , Medição de Risco/métodos , Fatores de Risco
20.
Metab Syndr Relat Disord ; 18(3): 128-133, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31999502

RESUMO

Background: Nonobese individuals with disproportionate body fat distribution are also vulnerable to dysglycemia. This study aimed to evaluate the association between three visceral adiposity surrogates and impaired fasting glucose (IFG) in nonobese Chinese individuals. Methods: A total of 70,200 nonobese adults without diabetes were included in this analysis. Two diagnostic criteria (IFG-ADA and IFG-WHO) were used to define IFG. The values of the visceral adiposity index, lipid accumulation product index (LAP), and cardiometabolic index (CMI) were calculated. Multivariable logistic analysis was used to evaluate the association between these surrogates and IFG. Results: Among the three indicators, only LAP and CMI were positively correlated with fasting plasma glucose (all P < 0.001). After fully adjusting for confounders, only LAP and CMI exhibited significant associations with IFG. For women, the odds ratios (ORs) for IFG-ADA in the highest quartile of the LAP and CMI were 1.967 (95% confidence interval [CI]: 1.645-2.353) and 1.594 (95% CI: 1.383-1.836), respectively; and were 2.025 (95% CI: 1.597-2.567) and 2.017 (95% CI: 1.647-2.470), respectively, for IFG-WHO (all P < 0.001). For men, the ORs for IFG-ADA of the LAP and CMI were 1.503 (95% CI: 1.233-1.833) and 2.045 (95% CI: 1.752-2.388), respectively; and were 1.534 (95% CI: 1.174-2.005) and 2.541 (95% CI: 2.025-3.188), respectively, for IFG-WHO (all P < 0.001). Conclusions: The LAP and CMI, cost-effective and simple visceral adiposity surrogates, are strongly associated with IFG in nonobese Chinese individuals. These surrogates might be potential targets to monitor for the recognition and management of excess visceral adiposity in nonobese individuals with prediabetes.

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