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1.
Int J Med Sci ; 17(16): 2468-2476, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33029089

RESUMO

Rationale: Coronavirus disease 2019 (COVID-19) was first announced in Wuhan, and has rapidly evolved into a pandemic. However, the risk factors associated with the severity and mortality of COVID-19 are yet to be described in detail. Methods: We retrospectively reviewed the information of 1525 cases from the Leishenshan Hospital in Wuhan. Univariate and multivariate Cox regression analyses were generated to explore the relationship between procalcitonin (PCT) level and the progression and prognosis of COVID-19. Univariate and multivariate logistic regression analyses were performed to explore the relationship between disease severity in hospitalized patients and their PCT levels. Survival curves and the cumulative hazard function for COVID-19 progression were conducted in the two groups. To further detect the relationship between the computed tomography score and survival days, curve-fitting analyses were performed. Results: Patients in the elevated PCT group had a higher incidence of severe and critical severity conditions (P < 0.001), death, and higher computed tomography (CT) scores. There was an association between elevated PCT levels and mortality in the univariate ((hazard ratio [1], 3.377; 95% confidence interval [2], 1.012-10.344; P = 0.033) and multivariate Cox regression analysis (HR, 4.933; 95% CI, 1.170-20.788; P = 0.030). Similarly, patients with elevated PCT were more likely to have critically severe disease conditions in the univariate (odds ratio [2], 7.247; 95% CI, 3.559-14.757; P < 0.001) and multivariate logistic regression analysis (OR, 10.679; 95% CI, 4.562-25.000; P < 0.001). Kaplan-Meier curves showed poorer prognosis for patients with elevated PCT (P = 0.024). The CT score 1 for patients with elevated PCT peaked at day 40 following the onset of symptoms then decreased gradually, while their total CT score was relatively stable. Conclusion: PCT level was shown as an independent risk factor of in-hospital mortality among COVID-19 patients. Compared with inpatients with normal PCT levels, inpatients with elevated PCT levels had a higher risk for overall mortality and critically severe disease. These findings may provide guidance for improving the prognosis of patients with critically severe COVID-19.


Assuntos
Betacoronavirus , Infecções por Coronavirus/etiologia , Infecções por Coronavirus/mortalidade , Pneumonia Viral/etiologia , Pneumonia Viral/mortalidade , Pró-Calcitonina/sangue , Idoso , Antibacterianos/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , China/epidemiologia , Comorbidade , Infecções por Coronavirus/diagnóstico por imagem , Infecções por Coronavirus/tratamento farmacológico , Progressão da Doença , Feminino , Hospitalização , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico por imagem , Prognóstico , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
2.
Food Funct ; 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33057520

RESUMO

Acanthopanax senticosus (Ciwujia) has broad-spectrum pharmacological activities, including osteoprotective effects. However, the mechanisms underlying these effects remain unclear. We investigated whether Acanthopanax senticosus aqueous extract (ASAE) ameliorates ovariectomy-induced bone loss in middle-aged mice through inhibition of osteoclastogenesis. In vitro, ASAE significantly suppressed the receptor activator of nuclear factor-κB ligand (RANKL)-stimulated osteoclast differentiation and formation of F-actin rings by downregulating the expression of the nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), c-Fos, and osteoclastogenesis-related marker genes and proteins, including c-Src, tartrate-resistant acid phosphatase (TRAP), cathepsin K, ß3-integrin, and matrix metallopeptidase-9 (MMP-9). This was achieved by inhibiting RANK signaling pathways, including p65, c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38 in osteoclast precursors. In vivo, ASAE markedly ameliorated bone loss in ovariectomized (OVX) middle-aged mice. ASAE significantly inhibited the serum levels of tartrate-resistant acid phosphatase 5b (TRACP-5b) and RANKL, whereas it increased those of osteocalcin, procollagen 1 N-terminal peptide (P1NP), and osteoprotegerin in OVX mice. ASAE significantly inhibited the OVX-induced expression of osteoclast-specific proteins and genes in the femur. In conclusion, ASAE prevents ovariectomy-induced bone loss in middle-aged mice by inhibiting RANKL-induced osteoclastogenesis through suppression of RANK signaling pathways and could be potentially used in mediated treatment of osteoclast-related diseases (e.g., osteoporosis).

3.
J Cell Commun Signal ; 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33058043

RESUMO

Due to the steadily rising morbidity and mortality, thyroid cancer remains the most commonly seen endocrine cancer. The present study attempted to investigate the mechanism from the perspective of long non-coding RNA (lncRNA) regulation. We identified 53 markedly increased lncRNAs in thyroid cancer samples according to TCGA data. Among them, high lncRNA DIO3OS expression was a risk factor for thyroid cancer patients' poorer overall survival. DIO3OS showed to be considerably increased within thyroid cancer tissue samples and cells. Knocking down DIO3OS within thyroid carcinoma cells suppressed cancer cell viability, the capacity of DNA synthesis, cell invasion, as well as cell migration; besides, proliferating markers, ki-67 and PCNA, were decreased by DIO3OS knockdown. Cancer bioinformatics analysis suggested that NF-κB2 might be related to DIO3OS function in thyroid cancer carcinogenesis. NF-κB2 was positively correlated with DIO3OS, and DIO3OS knockdown decreased NF-κB2 protein levels. Knocking down NF-κB2 within thyroid carcinoma cells suppressed cancer cell viability, the capacity of DNA synthesis, cell invasion, cell migration, and the protein levels of proliferating markers. Let-7d directly targeted DIO3OS and NF-κB2; DIO3OS knockdown upregulated let-7d expression. The overexpression of let-7d suppressed cancer cell viability, the capacity of DNA synthesis, cell invasion, cell migration, as well as the protein levels of proliferating markers. Let-7d inhibition remarkably attenuated the functions of DIO3OS knockdown in NF-κB2 expression and thyroid cancer cell phenotype. In conclusion, DIO3OS/let-7d/NF-κB2 axis regulates the viability, DNA synthesis capacity, invasion, and migration of thyroid cancer cells. The clinical application of this axis needs further in vivo and clinical investigation.

4.
Front Immunol ; 11: 1801, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33013831

RESUMO

A recently developed humanized mouse has been used to assess the immune response evoked against the isolated attenuated C9 parasite clone (C9-M; carrying a single insertion disrupting the open reading frame (ORF) of PF3D7_1305500) of Plasmodium falciparum. Significant human RBC engraftment was achieved by ameliorating the residual non-adaptive immune response using clodronate-loaded liposome treatment. Controlled reactive professional phagocytic leukocytes in immunodeficient mice allowed for sizeable human blood chimerism and injected huRBCs acted as bona fide host cells for P. falciparum. huRBC-reconstituted immunodeficient mice received infectious challenge with attenuated P. falciparum C9 parasite mutants (C9-M), complemented (C9-C), and wild type (NF54) progenitors to study the role of immune effectors in the clearance of the parasite from mouse circulation. C9-M and NF54 parasites grew and developed in the huRBC-reconstituted humanized NSG mice. Further, the presence of mutant parasites in deep-seated tissues suggests the escape of parasites from the host's immune responses and thus extended the survival of the parasite. Our results suggest an evasion mechanism that may have been employed by the parasite to survive the mouse's residual non-adaptive immune responses. Collectively, our data suggest that huRBCs reconstituted NSG mice infected with attenuated P. falciparum is a valuable tool to explore the role of C9 mutation in the growth and survival of parasite mutants and their response to the host's immune responses. This mouse might help in identifying novel chemotherapeutic targets to develop new anti-malarial drugs.

5.
Analyst ; 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33020770

RESUMO

The abnormal variation of the mucin 1 (MUC1) protein level is associated with the development of multiple cancers, and the monitoring of trace MUC1 can be useful for early disease diagnosis. Here, on the basis of the synchronization of DNA-fueled sequence recycling and dual rolling circle amplification (RCA), the establishment of a non-label and highly sensitive fluorescent aptamer-based detection strategy for the MUC1 protein biomarker is described. The target MUC1 binds the aptamer hairpin probe and causes its structure switching to release an ssDNA tail to trigger the recycling of the complex via two toehold-mediated strand displacement reactions under assistance of a fuel DNA. Such a recycling amplification leads to the formation of a partial dsDNA duplex with two primers at both ends, which cooperatively bind the circular DNA ring template to start the dual RCA to produce many G-quadruplex sequences. The protoporphyrin IX dye further associates with the G-quadruplex structures to show a dramatically elevated fluorescent signal for sensitively detecting MUC1 with a low detection limit of 0.5 pM. The established aptamer-based detecting strategy is also highly selective and can realize assay of MUC1 in diluted human serums, highlighting its potential for the detection of different protein biomarkers at low contents.

6.
Artigo em Inglês | MEDLINE | ID: mdl-33023179

RESUMO

In many developing countries, the existence of the uncertified recycler seriously hinders the healthy development of the waste electrical and electronic equipment (WEEE or e-waste) recycling industry. As a result, how the government can regulate the uncertified recycler to improve environment and public health during the recycling processes has become a critical issue. To help tackle this issue, we build an evolutionary game model to study the interactions between the government and the uncertified recycler. We conduct stability analysis of each participant and obtain four asymptotically stable states. Furthermore, we conduct numerical simulations for comparative analysis based on the current situation of the Chinese e-waste recycling industry. Our results are as follows. First, there exist multiple asymptotically stable states for the government and the uncertified recycler, namely (no-governance, maintaining status quo), (governance, maintaining status quo), (governance, industrial upgrading), and (no-governance, industrial upgrading). Then, we verify the validity of the evolutionary game model through numerical simulations and find that penalty, supervision cost, additional investment cost, and financial subsidy can significantly influence the behavioral strategy of the government and the uncertified recycler. Finally, we find that the government should adopt the reward-penalty-supervision mechanism to promote the healthy development of the e-waste recycling industry and protect the environment and public health. Specifically, first, the government's subsidy for the uncertified recycler has upper and lower limits. Exceeding the upper limit will result in an excessive financial burden to the government, while falling below the lower limit will hinder the uncertified recycler from technology upgrading. Second, the government should strengthen the supervision of the uncertified recycler and increase the punishment for violations. Third, the government should focus on controlling the supervision cost. Fourth, according to the asymptotically stable state (no-governance, industrial upgrading), the government should prepare to withdraw from the market when the uncertified recycler chooses industrial upgrading.

7.
Cell Mol Life Sci ; 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33051777

RESUMO

Heparanase is the predominant enzyme that cleaves heparan sulfate, the main polysaccharide in the extracellular matrix. While the role of heparanase in sustaining the pathology of autoimmune diabetes is well documented, its association with metabolic syndrome/type 2 diabetes attracted less attention. Our research was undertaken to elucidate the significance of heparanase in impaired glucose metabolism in metabolic syndrome and early type 2 diabetes. Here, we report that heparanase exerts opposite effects in insulin-producing (i.e., islets) vs. insulin-target (i.e., skeletal muscle) compartments, sustaining or hampering proper regulation of glucose homeostasis depending on the site of action. We observed that the enzyme promotes macrophage infiltration into islets in a murine model of metabolic syndrome, and fosters ß-cell-damaging properties of macrophages activated in vitro by components of diabetogenic/obese milieu (i.e., fatty acids). On the other hand, in skeletal muscle (prototypic insulin-target tissue), heparanase is essential to ensure insulin sensitivity. Thus, despite a deleterious effect of heparanase on macrophage infiltration in islets, the enzyme appears to have beneficial role in glucose homeostasis in metabolic syndrome. The dichotomic action of the enzyme in the maintenance of glycemic control should be taken into account when considering heparanase-targeting strategies for the treatment of diabetes.

8.
Hua Xi Kou Qiang Yi Xue Za Zhi ; 38(5): 537-540, 2020 Oct 01.
Artigo em Chinês | MEDLINE | ID: mdl-33085238

RESUMO

OBJECTIVE: To study the stress distribution under dynamic loading in the presence or absence of an abutment buffer layer by using three-dimensional finite element analysis. METHODS: A three-dimensional solid geometric model of an implant in a human mandible was established on the basis of CT scan data. A buffer-free abutment prosthesis and a buffer-abutment abutment prosthesis were installed above the implant. The buffer layer was made of high-density polyethylene. A vertical load of 200 N and a horizontal load of 100 N (45°) were concentrated on the centers of the implant restorations of the two groups. Stresses on the implant neck and body, abutment neck and body, central bolt neck and body, and bone interface were compared via three-dimensional finite element analysis. RESULTS: Stresses on the implant neck and body, abutment neck and body, central bolt neck and body, and bone interface on the abutment with a buffer layer were significantly lower than those on the abutment without a buffer layer. CONCLUSIONS: The increase in the buffer layer of the abutment neck significantly reduced stress on the implant neck, abutment, central bolt neck, and bone interface.


Assuntos
Dente Suporte , Implantes Dentários , Análise do Estresse Dentário , Análise de Elementos Finitos , Humanos , Estresse Mecânico
9.
J Int Med Res ; 48(10): 300060520961675, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33026276

RESUMO

OBJECTIVE: Polymorphisms in the tumor necrosis factor superfamily 15 (TNFSF15) gene contribute to susceptibility to inflammatory bowel disease (IBD). However, associations between TNFSF15 rs6478109, rs7869487, and rs7865494 polymorphisms and IBD remain unclear. METHODS: Eligible articles were retrieved from the PubMed, EMBASE, Web of Science, and CNKI databases through 20 March 2020. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the relationships of TNFSF15 polymorphisms with IBD susceptibility. RESULTS: Under the recessive model, TNFSF15 rs6478109 was associated with IBD risk (OR = 0.56; 95% CI: 0.35, 0.92). Stratification analyses based on the type of disease-Crohn's disease (CD) or ulcerative colitis (UC)-revealed a significant association under the allelic and recessive models between TNFSF15 rs6478109 and CD (allelic model: OR = 0.84, 95% CI: 0.71, 0.99; recessive model: OR = 0.44, 95% CI: 0.22, 0.87) but not UC. Stratification by ethnicity indicated a significantly decreased risk of IBD in Asian populations with TNFSF15 rs6478109 under the recessive model (OR = 0.56, 95% CI: 0.35, 0.92). CONCLUSIONS: Our meta-analysis suggested that under the allelic and recessive models, the TNFSF15 rs6478109 polymorphism was likely protective for CD but not UC in the Asian population.

10.
Cancer Biol Ther ; 21(10): 891-898, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33026965

RESUMO

BACKGROUND: Antibodies against epidermal growth factor receptor (EGFR), panitumumab, a fully human monoclonal antibody, and cetuximab, a human/mouse chimeric monoclonal antibody, have shown clinical efficacy in metastatic colorectal cancer (mCRC). In the phase 3 noninferiority ASPECCT (ClinicalTrials.gov, NCT01001377) study, panitumumab was demonstrated to be noninferior to cetuximab and provided a similar overall survival benefit for patients with chemotherapy-refractory wild-type KRAS exon 2 mCRC. However, some patients eventually develop resistance to anti-EGFR therapy. EGFR p.S492R mutation was previously identified as conferring resistance to cetuximab, but not to panitumumab. METHODS: This biomarker study analyzed plasma samples from ASPECCT collected at both baseline and posttreatment. RESULTS: No EGFR p.S492R mutations were identified at baseline; however, after treatment the EGFR p.S492R mutation was detected in 1% of patients treated with panitumumab versus 16% of those treated with cetuximab, supporting that, in a large population, this mutation is more likely to be induced by cetuximab than by panitumumab. There were, however, no significant differences in progression-free survival or overall survival between patients who were wild-type compared with those with the S492R mutation within the cetuximab arm or the overall population. CONCLUSIONS: These results may support targeting treatment to small patient subgroups based on the presence of emerging EGFR mutations and provide a molecular rationale for rechallenging with a different anti-EGFR agent in patients who develop resistance. Prospective studies are needed to evaluate the efficacy of panitumumab in the EGFR p.S492R mutant population.

11.
Zhongguo Dang Dai Er Ke Za Zhi ; 22(10): 1092-1099, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33059806

RESUMO

OBJECTIVE: To study the association of maternal diabetes mellitus (DM), uncoupling protein 2 (UCP2) gene polymorphisms, and their interaction with the risk of congenital heart disease (CHD) in offspring. METHODS: A hospital-based case-control study was conducted. A total of 464 mothers of children with CHD alone who were diagnosed in Hunan Children's Hospital from March 2018 to August 2019 were enrolled as the case group. A total of 504 mothers of healthy children who were hospitalized during the same period and did not have any deformity were enrolled as the control group. A questionnaire survey was performed to collect the information on exposure. Venous blood samples (5 mL) were collected from the mothers to detect UCP2 gene polymorphisms. A multivariate logistic regression analysis was used to investigate the association of maternal DM, UCP2 gene polymorphisms, and their interaction with CHD in offspring. RESULTS: After control for confounding factors, the multivariate logistic regression analysis showed that mothers with gestational DM (OR=2.96, 95%CI: 1.57-5.59), a history of gestational DM (OR=3.16, 95%CI: 1.59-6.28), and pregestational DM (OR=4.52, 95%CI: 2.41-8.50) significantly increased the risk of CHD in offspring (P<0.05). The polymorphisms of the UCP2 gene at rs659366 (T/C vs C/C: OR=1.49, 95%CI: 1.02-2.16; T/T vs C/C: OR=2.77, 95%CI: 1.67-4.62) and rs660339 (A/A vs G/G: OR=2.19, 95%CI: 1.34-3.58) were significantly associated with risk of CHD in offspring (P<0.05). The interaction analysis showed an interaction between the polymorphisms of the UCP2 gene at rs659366 and rs660339 and maternal DM in the development of CHD (P<0.05). CONCLUSIONS: Maternal DM, UCP2 gene polymorphisms, and their interaction are associated with the development of CHD in offspring.

12.
Sci Rep ; 10(1): 18039, 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33093478

RESUMO

What determines the functional organization of cortex? One hypothesis is that innate connectivity patterns, either structural or functional connectivity, set up a scaffold upon which functional specialization can later take place. We tested this hypothesis by asking whether the visual word form area (VWFA), an experience-driven region, was already functionally connected to proto language networks in neonates scanned within one week of birth. Using the data from the Human Connectone Project (HCP) and the Developing Human Connectome Project (dHCP), we calculated intrinsic functional connectivity during resting-state functional magnetic resonance imaging (fMRI), and found that neonates showed similar functional connectivity patterns to adults. We observed that (1) language regions connected more strongly with the putative VWFA than other adjacent ventral visual regions that also show foveal bias, and (2) the VWFA connected more strongly with frontotemporal language regions than with regions adjacent to these language regions. These data suggest that the location of the VWFA is earmarked at birth due to its connectivity with the language network, providing evidence that innate connectivity instructs the later refinement of cortex.

13.
Aging (Albany NY) ; 122020 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-33099538

RESUMO

Osteoarthritis (OA) is one of the most painful and widespread chronic degenerative joint diseases and is characterized by destructed articular cartilage and inflamed joints. Previously, our findings indicated that circular RNA ciRS-7 (ciRS-7)/microRNA 7 (miR-7) axis is abnormally expressed in OA, and regulates proliferation, inflammatory responses, and apoptosis of interleukin-1ß (IL-1ß)-stimulated chondrocytes. However, its underlying role in OA remains unknown. In this study, we first validated cartilage degradation and defection of autophagy in samples of OA patients. IL-1ß initially stimulated autophagy of chondrocytes, and ultimately significantly suppressed autophagy. Upregulated ciRS-7/down-regulated miR-7 aggravated IL-1ß-induced cartilage degradation, and restrained autophagy in vitro. Gene sequencing and bioinformatics analysis performed on a control group, IL-1ß group, and IL-1ß+miR-7-mimics group demonstrated that seven of the most significant mRNA candidates were enriched in the interleukin-17 (IL-17) signaling pathway. Increased IL-17A levels were also observed by qRT-PCR and ELISA. In addition, it was revealed that the ciRS-7/miR-7 axis ameliorated cartilage degradation and defection of autophagy by PI3K/AKT/mTOR activation in IL-1ß-induced chondrocytes. Furthermore, an OA model was established in rats with medial meniscus destabilization. miR-7-siRNA-expressing lentiviruses alleviated surgical resection-induced cartilage destruction of OA mice, whereas miR-7 mimics worsened the effects. Thus, these findings revealed that the mechanism of the ciRS-7/miR-7 axis involved regulating OA progression and provided valuable directions for OA treatment.

14.
Biochim Biophys Acta Mol Cell Res ; : 118895, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33096144

RESUMO

MutT Homolog 1 (MTH1) is a mammalian 8-oxodGTPase for sanitizing oxidative damage to the nucleotide pool. Nudix type 5 (NUDT5) also sanitizes 8-oxodGDP in the nucleotide pool. The role of MTH1 and NUDT5 in non-small-cell lung cancer (NSCLC) progression and metastasis remains unclear. In the present study, we reported that MTH1 and NUDT5 were upregulated in NSCLC cell lines and tissues, and higher levels of MTH1 or NUDT5 were associated with tumor metastasis and a poor prognosis in patients with NSCLC. Their suppression also restrained tumor growth and lung metastasis in vivo and significantly inhibited NSCLC cell migration, invasion, cell proliferation and cell cycle progression while promoting apoptosis in vitro. The opposite effects were observed in vitro following MTH1 or NUDT5 rescue. In addition, the upregulation of MTH1 or NUDT5 enhanced the MAPK pathway and PI3K/AKT activity. Furthermore, MTH1 and NUDT5 induce epithelial-mesenchymal transition both in vitro and in vivo. These results highlight the essential role of MTH1 and NUDT5 in NSCLC tumor tumorigenesis and metastasis as well as their functions as valuable markers of the NSCLC prognosis and potential therapeutic targets.

15.
Chemosphere ; : 128637, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33097235

RESUMO

BACKGROUND: The adverse effects of TI exposure on pregnant women are still unclear, especially regarding the risk of gestational diabetes mellitus (GDM) Objective: We explored the association between maternal urinary Tl burden and the risk of GDM. METHODS: A subsample of 1789 pregnant women were enrolled who provided spot urine samples before the diagnostic 75-g oral glucose tolerance test. Urinary Tl concentration was measured using inductively coupled plasma mass spectrometry. Logistic regression and covariance analysis were carried out to estimate the association between Tl exposure and GDM risk. RESULTS: The median of urinary Tl concentration was 0.382 µg/L or 0.525 µg/g creatinine (CC-Tl). There were 437 (24.4%) participants who were diagnosed with GDM, and the urinary CC-Tl concentrations of pregnant women with GDM were higher than that of pregnant women without GDM [0.548 (0.402, 0.788) vs 0.518 (0.356, 0.724), p = 0.014]. After adjusting for the relevant covariates, an association between urinary Tl concentrations and GDM was found. In comparison to the pregnant women in the lowest quartile of urinary CC-Tl concentration, the pregnant women in the highest quartile had a higher risk of GDM [OR (95% CI) = 1.44 (1.03, 2.02), p-trend = 0.055]. If limited to the pregnant women without family history of diabetes, the results were still robust [OR (95% CI) = 1.59 (1.11, 2.30), p-trend = 0.012]. CONCLUSION: Urinary CC-Tl concentration was associated with GDM among Chinese pregnant women. Our findings provide evidence that moderately high Tl exposure may be a novel risk factor for pregnant women health.

16.
Heart Rhythm ; 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33031960

RESUMO

BACKGROUND: Recent research findings have revealed a key role of oxidative DNA damage in the pathogenesis of atrial fibrillation (AF). Therefore, the circulating oxidative DNA damage marker 8-hydroxy-2'-deoxyguanosine (8-OHdG) may represent a biomarker for staging AF and identifying patients at risk for AF recurrence and postoperative atrial fibrillation (POAF) after treatment. OBJECTIVE: The purpose of this study was to investigate whether serum levels of 8-OHdG correlate with the stage of AF, recurrence after AF treatment, and onset of POAF after cardiac surgery. METHODS: In this prospective observational study, 8-OHdG levels were detected by enzyme-linked immunosorbent assay in human serum samples. Blood samples were collected from control patients without AF history; patients with paroxysmal AF and persistent AF undergoing electrical cardioversion or pulmonary vein isolation (PVI); and patients with sinus rhythm (SR) undergoing cardiac surgery. AF recurrence was determined during 12-month follow-up. Univariate and multivariate analyses were used to identify changes in 8-OHdG levels between the groups. RESULTS: Compared to the control group, 8-OHdG levels in the patient groups gradually and significantly increased during arrhythmia progression. 8-OHdG levels in AF patients showing AF recurrence after PVI treatment were significantly increased compared to patients without AF recurrence. Moreover, in SR patients undergoing cardiac surgery, 8-OHdG levels were significantly elevated in those showing POAF compared to patients without POAF. CONCLUSION: 8-OHdG level may represent a potential diagnostic biomarker for AF staging as well as for predicting AF recurrence and POAF after treatment.

17.
Circ Res ; 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33092465

RESUMO

Rationale: Previous translational studies implicate plasma extracellular microRNA-30d (miR-30d) as a biomarker in left ventricular (LV) remodeling and clinical outcome in heart failure (HF) patients, though precise mechanisms remain obscure. Objective: To investigate the mechanism of miR-30d-mediated cardioprotection in HF. Methods and Results: In rat and mouse models of ischemic HF, we show that miR-30d gain of function (genetic, lentivirus or agomiR-mediated) improves cardiac function, decreases myocardial fibrosis, and attenuates cardiomyocyte (CM) apoptosis. Genetic or locked nucleic acid (LNA)-based knock-down of miR-30d expression potentiates pathological LV remodeling, with increased dysfunction, fibrosis, and CM death. RNA-seq of in vitro miR-30d gain and loss of function, together with bioinformatic prediction and experimental validation in cardiac myocytes and fibroblasts, were used to identify and validate direct targets of miR-30d. miR-30d expression is selectively enriched in CMs, induced by hypoxic stress and is acutely protective, targeting mitogen-associate protein kinase (MAP4K4) to ameliorate apoptosis. Moreover, miR-30d is secreted primarily in extracellular vesicles by CMs and inhibits fibroblast proliferation and activation by directly targeting integrin α5 in the acute phase via paracrine signaling to cardiac fibroblasts. In the chronic phase of ischemic remodeling, lower expression of miR-30d in the heart and plasma EVs is associated with adverse remodeling in rodent models and human subjects, and is linked to whole blood expression of genes implicated in fibrosis and inflammation, consistent with observations in model systems. Conclusions: These findings provide the mechanistic underpinning for the cardioprotective association of miR-30d in human HF. More broadly, our findings support an emerging paradigm involving intercellular communication of EV-contained miRNAs to trans regulate distinct signaling pathways across cell types. Functionally validated RNA biomarkers and their signaling networks may warrant further investigation as novel therapeutic targets in HF.

18.
Nat Commun ; 11(1): 4980, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-33020477

RESUMO

The functions of the proto-oncoprotein c-Myc and the tumor suppressor p53 in controlling cell survival and proliferation are inextricably linked as "Yin and Yang" partners in normal cells to maintain tissue homeostasis: c-Myc induces the expression of ARF tumor suppressor (p14ARF in human and p19ARF in mouse) that binds to and inhibits mouse double minute 2 homolog (MDM2) leading to p53 activation, whereas p53 suppresses c-Myc through a combination of mechanisms involving transcriptional inactivation and microRNA-mediated repression. Nonetheless, the regulatory interactions between c-Myc and p53 are not retained by cancer cells as is evident from the often-imbalanced expression of c-Myc over wildtype p53. Although p53 repression in cancer cells is frequently associated with the loss of ARF, we disclose here an alternate mechanism whereby c-Myc inactivates p53 through the actions of the c-Myc-Inducible Long noncoding RNA Inactivating P53 (MILIP). MILIP functions to promote p53 polyubiquitination and turnover by reducing p53 SUMOylation through suppressing tripartite-motif family-like 2 (TRIML2). MILIP upregulation is observed amongst diverse cancer types and is shown to support cell survival, division and tumourigenicity. Thus our results uncover an inhibitory axis targeting p53 through a pan-cancer expressed RNA accomplice that links c-Myc to suppression of p53.


Assuntos
Neoplasias/patologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Longo não Codificante/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Carcinogênese , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica , Proteínas Proto-Oncogênicas c-myc/genética , RNA Longo não Codificante/genética , Sumoilação , Proteína Supressora de Tumor p53/genética , Ubiquitinação
19.
Chem Commun (Camb) ; 2020 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-33103675

RESUMO

We have developed a new oxidative decarboxylation of cinnamic acids with 4-alkyl-1,4-dihydropyridines to construct C(sp3)-C(sp2) bonds in the presence of copper catalyst and dicumyl peroxide (DCP). A variety of internal alkenes have been obtained with mild conditions, broad substrate scope and excellent functional group tolerance. This method has significant potential for application by using inexpensive and stable cinnamic acids instead of alkenyl halides and nitro-olefins.

20.
J Magn Reson Imaging ; 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-33037860

RESUMO

BACKGROUND: The relationship between plaque characteristics and their predictive value for perioperative cerebral blood flow (CBF) are unknown. PURPOSE: To investigate the relationship between carotid plaque characteristics and perioperative CBF utilizing MRI. STUDY TYPE: Prospective. POPULATION: In all, 131 patients with carotid moderate-to-severe stenosis referred for carotid endarterectomy (CEA). FIELD STRENGTH/SEQUENCE: 3T, black-blood T1 - and T2 -weighted, 3D time-of-flight, and simultaneous noncontrast angiography intraplaque hemorrhage. ASSESSMENT: The relative CBF (rCBF = CBFindex-hemisphere /CBFcontralateral-hemisphere ) and the CBF difference ratio (DRCBF = [CBFpost-CEA - CBFpre-CEA ]/CBFpre-CEA ) in the middle cerebral artery territory were measured. The pre- and post-CEA CTP data were used as the assessment standard for CBF change. Carotid lipid-rich necrotic core (LRNC), intraplaque hemorrhage, calcification, fibrous cap rupture, maximum wall thickness, normalized wall index (NWI), and stenosis were determined. STATISTICAL TESTS: Pearson or Spearman correlation, Mann-Whitney U-test, and linear regression. RESULTS: Patients with LRNC had higher rCBFpre-CEA than those without (1.0 ± 0.1 vs. 0.9 ± 0.1, P < 0.05). NWI was weakly correlated with rCBFpre-CEA (r = -0.213, P < 0.05) and DRCBF (r = 0.185, P < 0.05) and marginally correlated with rCBFpost-CEA (r = 0.166, P = 0.057). LRNC was weakly correlated with rCBFpre-CEA (r = 0.179, P < 0.05). NWI was associated with rCBFpre-CEA (ß = -0.035; 95% confidence interval [CI] [-0.064, -0.006]; P < 0.05), rCBFpost-CEA (ß = 0.042; 95% CI [0.002, 0.081]; P < 0.05) and DRCBF (ß = 0.105; 95% CI [0.026, 0.185]; P < 0.05). After adjusting for confounding factors, associations of NWI with rCBFpost-CEA (ß = 0.059; 95% CI [0.016, 0.103]; P < 0.05) and DRCBF (ß = 0.110; 95% CI [0.021, 0.199]; P < 0.05) remained statistically significant, while the association between NWI and rCBFpre-CEA was no longer significant (ß = -0.026; 95% CI [-0.058, 0.006]; P = 0.112).The associations of LRNC with rCBFpre-CEA (ß = 0.057; 95% CI [-0.0006, 0.114]; P = 0.052) and DRCBF (ß = -0.157; 95% CI [-0.314, 0.001]; P = 0.051) were close to statistical significance. After adjusting for confounding factors, these associations were statistically significant (of LRNC vs. rCBFpre-CEA : ß = 0.060; 95% CI [0.003, 0.118]; P < 0.05; LRNC vs. DRCBF : ß = -0.205; 95% CI [-0.375, -0.036]; P < 0.05). DATA CONCLUSION: Carotid plaque burden and components, particularly LRNC, might be effective indicators for CBF change following CEA. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 5.

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