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1.
Biochim Biophys Acta Mol Basis Dis ; : 165836, 2020 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-32413386

RESUMO

Acetylation belongs to a class of post-translational modification (PTM) processes that epigenetically regulate gene expression and gene transcriptional activity. Reversible histone acetylation on lysine residues governs the interactions between DNA and histones to mediate chromatin remodeling and gene transcription. Non-histone protein acetylation complicates cellular function whereas acetylation of key mitochondrial enzymes regulates bioenergetic metabolism. Acetylation and deacetylation of functional proteins are essential to the delicated homeostatic regulation of embryonic development, postnatal maturation, cardiomyocyte differentiation, cardiac remodeling and onset of various cardiovascular diseases including obesity, diabetes mellitus, cardiometabolic diseases, ischemia-reperfusion injury, cardiac remodeling, hypertension, and arrhythmias. Histone acetyltransferase (HATs) and histone deacetylases (HDACs) are essential enzymes mainly responsible for the regulation of lysine acetylation levels, thus providing possible drugable targets for therapeutic interventions in the management of cardiovascular diseases.

2.
Biochim Biophys Acta Rev Cancer ; 1874(1): 188366, 2020 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-32339608

RESUMO

Autophagy is an evolutionarily conserved self-cannibalization process commonly found in all eukaryotic cells. Through autophagy, long-lived or damaged organelles, superfluous proteins, and pathogens are sequestered and encapsulated into the double-membrane autophagosomes prior to fusion with lysosomes for ultimate degradation and recycling. Given that autophagy is deemed both protective and detrimental in malignancies, the clinical therapeutic utilization of autophagy modulators in cancer has attracted immense attentions over the past decades. Dependence of tumor cells on autophagy during amino acid insufficiency or deprivation has prompted us to explore the underlying autophagy regulatory mechanisms to inject amino acid degrading enzymes and enzyme-based strategies into therapeutic maneuvers of autophagy in cancer.

3.
Pharmacol Res ; 157: 104846, 2020 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-32339784

RESUMO

Doxorubicin (DOX) is one of the most effective antineoplastic drugs. However, its clinical application has been greatly limited due to the development of cardiotoxicity with DOX utilization. A number of theories have been postulated for DOX-induced cardiotoxicity with a pivotal contribution from unchecked (excess) mitophagy and mitochondrial fission. Liensinine (LIEN), a newly identified mitophagy inhibitor, strengthens the antineoplastic efficacy of DOX although its action on hearts remains elusive. This study was designed to examine the effect of LIEN on DOX-induced cardiotoxicity and the underlying mechanisms involved with a focus on mitochondrial dynamics. Our data revealed that LIEN alleviated DOX-induced cardiac dysfunction and apoptosis through inhibition of dynamin-related protein 1 (Drp1)-mediated excess (unchecked) mitochondrial fission. LIEN treatment decreased Drp1 phosphorylation at Ser616 site, inhibited mitochondrial fragmentation, mitophagy (assessed by TOM20 and TIM23), oxidative stress, cytochrome C leakage, cardiomyocyte apoptosis, as well as improved mitochondrial function and cardiomyocyte contractile function in DOX-induced cardiac injury. In DOX-challenged neonatal mouse ventricular myocytes (NMVMs), LIEN-suppressed Drp1 phosphorylation, mitochondrial fragmentation, and apoptosis were blunted by Rab7 overexpression, the effect of which was reversed by the ERK inhibitor U0126. Moreover, activation of ERK or Drp1 abolished the protective effects of LIEN on cardiomyocyte mechanical anomalies. These data shed some lights towards understanding the role of LIEN as a new protective agent against DOX-associated cardiotoxicity without compromising its anti-tumor effects.

4.
Basic Res Cardiol ; 115(3): 25, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32232579

RESUMO

Since the publication of the article, the authors found a small problem with Fig. 7e. Unfortunately, Fig. 7e did not contain the correct images. The correct images are shown below and do not change the conclusions.

5.
Ecotoxicol Environ Saf ; 197: 110622, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32311616

RESUMO

Sperm morphology and performance traits are key determinants of male fertilization success, particularly when females copulate with multiple males. Such sperm traits have been reported to be influenced by environmental pollutants in various animals; however, such studies remain rare in free-living birds exposed to heavy metal pollution. In the present study, we selected tree sparrow (Passer montanus) as the study object to explore the effect of long-term environmental heavy metal pollution on sperm morphology (assessed mainly by using the dimensions of different sperm components and the sperm abnormality rates) and sperm performance (indicated by sperm velocity), and to elucidate potential relationships between variations in sperm morphology and performance. Sperm ATP concentration was also assessed considering sperm morphology and performance could be linked via energy availability. According to our results, tree sparrows from heavy metal polluted area (1) accumulated cadmium at a higher level in their testes; (2) produced longer sperm with lower abnormality rates, in addition to sperm with longer flagella and smaller head/flagellum ratios; (3) their sperm swam faster compared to those from the relatively unpolluted area, while no differences were observed in sperm ATP concentrations. We also found that the levels of lead and cadmium in testes affected the sperm nucleus length, and the level of copper in testes was negatively related to the proportions of abnormal sperm. Furthermore, the present study showed that sperm velocity was negatively correlated with sperm head lengths, head/flagellum ratios and ATP concentrations. Our study results reveal that sperm morphology and performance in tree sparrows show positive variations to maximize male fertility ability under long-term environmental heavy metal pollution, where males increase sperm flagellum lengths to decrease head/flagellum ratios, as opposed to varying sperm energy production, to achieve higher sperm velocity.

6.
Environ Pollut ; 263(Pt B): 114396, 2020 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-32222667

RESUMO

Genetic diversity is the bedrock of evolution. The "Genetic Erosion" hypothesis posits that environmental pollution could cause reduced genetic diversity. To explore the effects of heavy metal pollution on genetic diversity in natural populations, we selected an area with more than sixty years of heavy metal contamination (Baiyin, BY) and a relatively unpolluted one (Liujiaxia, LJX), and tree sparrow (Passer montanus) as study models. Five tree sparrow populations were sampled in BY at sites differing in heavy metal pollution level. Lower genetic diversity based on seven microsatellite loci was observed in the five tree sparrow populations from BY compared with those from LJX. Analysis of molecular variance indicated no significant genetic differentiation between BY and LJX. However, the observed heterozygosity and allelic richness were negatively correlated to the lead and cadmium concentrations in the primary feathers of tree sparrow. Our results indicated the genetic diversity might have a negative response to long-term environmental heavy metal pollution in tree sparrow, supporting the "Genetic Erosion" hypothesis. Therefore, the findings shed lights on the possible effects of heavy metal pollution on genetic diversity of wild bird populations.

7.
Arch Toxicol ; 94(4): 1203-1213, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32112223

RESUMO

Polymorphisms in arsenic (+ 3 oxidation state) methyltransferase (AS3MT) have been shown to be related to interindividual variations in arsenic metabolism and to influence adverse health effects in acute promyelocytic leukemia (APL) patients treated with arsenic trioxide (As2O3). The occurrence of hyperleukocytosis with As2O3 treatment seriously affects the early survival rate of APL patients, but no definite explanation for such a complication has been clearly established. To clarify the causes of this situation, AS3MT polymorphisms 14215 (rs3740390), 14458 (rs11191439), 27215 (rs11191446), and 35991 (rs10748835) and profiles of plasma arsenic metabolites were evaluated in a group of 54 newly diagnosed APL patients treated with single-agent As2O3. High-performance liquid chromatography-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS) was used to determine the concentrations of plasma arsenic metabolites. Plasma arsenic methylation metabolism capacity was evaluated by the percentage of inorganic arsenic (iAs), monomethylarsonic acid (MMA), dimethylarsinic acid (DMA), primary methylation index (PMI, MMA/iAs), and secondary methylation index (SMI, DMA/MMA). The results showed that APL patients who developed hyperleukocytosis had a higher plasma iAs%, but a lower MMA% and PMI than those who did not develop hyperleukocytosis during As2O3 treatment. In addition, patients with the AS3MT 14215 (rs3740390) CC genotype had significantly higher plasma iAs% and incidence of hyperleukocytosis, but lower PMI than patients with the CT + TT genotype. Conversely, we did not observe statistically significant associations between the occurrence of hyperleukocytosis and AS3MT 14458 (rs11191439), 27215 (rs11191446), and 35991 (rs10748835) polymorphisms in our study subjects. These results indicated that AS3MT 14215 (rs3740390) might be used as an indicator for predicting the occurrence of hyperleukocytosis in APL patients treated with As2O3.

9.
Sci Total Environ ; 721: 137674, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32163734

RESUMO

Anthropogenic metal pollution is known to adversely affect bird reproduction; however, few systematic studies are available on the effects of metal pollution on breeding performance and parental investment in a common resident songbird, the tree sparrow (Passer montanus). We conducted this study in two sites, a long-term heavy metal polluted site (Baiyin [BY]) and a relatively unpolluted site at approximately 110 km distance (Liujiaxia [LJX]), to assess the potential effects of environmental metal contamination on breeding parameters (clutch size, hatching success, fledging success, and growth of nestlings) and parental investment. The results showed smaller clutch size, lower fledging success, and differences in incubation behaviors of tree sparrows in BY than in LJX. Although there was no difference in parental body condition (residual body mass) between the two study sites, the parents responded differently with respect to reproduction due to varying metal levels in their habitats and bodies. Higher Cd levels in the primary feathers of females in BY were associated with lower clutch sizes. Parental investment including incubation duration and feeding rates showed no significant difference between the two sites during the incubation and nestling periods, but the frequencies of incubation visits were higher in BY. Parental behavior during the incubation period was also negatively affected by the parental Pb and Cd levels. Although the nestling growth patterns were relatively similar between the two sites, the nestlings were smaller, had lower body weight, and fledged later and fledging rate was also lower in BY than in LJX. Metal concentrations were higher in nestling organs and feces in BY. Taken together, metal pollution might adversely affect nestling growth condition. Our results suggest a negative response in the reproduction of tree sparrows to long-term environmental metal pollution.

10.
Toxicol Lett ; 326: 1-10, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32142837

RESUMO

Our previous study demonstrated that cadmium (Cd) is an effective inducer of mitophagy, which is mainly mediated by PINK1/Parkin pathway. However, the role of other mitophagy pathways in Cd-induced mitophagy remains elusive. The present study employed HeLa cells, lacking fully functional Parkin, as a cell model to study Parkin-independent mitophagy pathway induced by Cd. Our results showed that BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like (Bnip3L/NIX), an outer mitochondrial membrane mitophagy receptor, could provide an alternate pathway for Cd-induced mitophagy in HeLa cells. Specifically, 10 µM Cd for 12 h induced mitophagy in GM00637 and HeLa cells which was assessed by mitochondrial fusion to lysosomes and decreased expression of mitochondrial markers such as COX-IV and HSP60. Notably, in GM00637 cells, Cd-induced mitophagy was predominantly mediated by PINK1/Parkin pathway as evinced by translocation of Parkin to mitochondria. Interestingly, in HeLa cells, significant increase in NIX expression was occurred and mitophagy was induced under Cd exposure, suggesting NIX compensates lost role of Parkin in Cd-induced mitophagy in HeLa cells. These results were verified by knocking down NIX using siRNA in HeLa cells, which lead to abolished mitophagy process. Moreover, NIX phosphorylation at serine-81 significantly increased in cells treated with Cd implying that phosphorylation of NIX plays an important role in NIX-mediated mitophagy. These findings reveal a novel mechanism of Cd toxicity and suggest a compensatory role of NIX in Cd-induced mitophagy.


Assuntos
Cádmio/toxicidade , Células HeLa/efeitos dos fármacos , Proteínas de Membrana/farmacologia , Proteínas de Membrana/uso terapêutico , Mitofagia/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas/farmacologia , Proteínas Proto-Oncogênicas/uso terapêutico , Proteínas Supressoras de Tumor/farmacologia , Proteínas Supressoras de Tumor/uso terapêutico , Ubiquitina-Proteína Ligases/toxicidade , Humanos , Doença de Parkinson/fisiopatologia
11.
Sci Total Environ ; 710: 136300, 2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-31923672

RESUMO

Inhalable pollutants are inducing factors of lung diseases and have been widely studied. Previous studies described imbalances in pulmonary microbial communities and representatively predominant microorganisms in clinical specimens of individuals with lung diseases. However, the direct effect of inhalable pollutants on pulmonary microorganisms has not been determined to date. Cadmium is a common inhalable pollutant from manufacturing activities, and its effect on pulmonary microorganisms was investigated in this study. Such techniques as optical respiratory plethysmography, high-throughput pulmonary histological assessment and differential centrifugation were used to characterize pulmonary microenvironments, and high-throughput sequencing was used to analyze pulmonary microbial diversity. We found variations in pulmonary microenvironmental factors, such as air supply level, nutrition and inflammatory stress. Under inhalable cadmium exposure at different doses, pulmonary microorganisms were differentially subjected and sensitive to various microenvironmental stresses (e.g., inflammation, pH, ventilation, nutrition and related changes of lung tissue structure) and might participate in microenvironmental remodeling, such as pneumonia and pulmonary fibrosis. Inflammatory stress and Lactobacillus were the main microenvironmental factor and susceptible microorganism, respectively. The various pulmonary microenvironments influenced the metabolisms of pulmonary microbial communities, presenting differences in microbial collinearities, gene function levels and metabolic pathway levels among groups.


Assuntos
Pulmão , Microbiota , Aerossóis , Animais , Cádmio , Exposição por Inalação , Camundongos
12.
Acta Trop ; 204: 105343, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31954135

RESUMO

The odorant receptors (ORs) play a critical role for mosquitoes in the identification of blood-feeding hosts and other physiological processes. The OR8 subfamily in mosquitoes has been shown to be strongly involved in the detection the mammalian host associated odor, 1-octen-3-ol. CquiOR114/117 has been shown to be an orthologous OR8 in Culex quinquefasciatus Say. In this study, the expression of CquiOR114/117 in the different developmental stages of Cx. quinquefasciatus was detected by the amplification of CquiOR114/117 with real-time fluorescence quantitative polymerase chain reaction (PCR). RNA interference (RNAi) technology was used to interfere with the expression of CquiOR114/117 in females to observe the blood-feeding behavior change. The results showed that the expression level of CquiOR114/117 in the egg-to-pupa stage was significantly lower than that in the adult stage and that the expression level of the female mosquitoes peaked on the third day after emergence. The expression of CquiOR114/117 was significantly decreased in the 2-6 days after the injection of dsRNA compared with the control groups. The analysis of the blood-feeding behavior showed a significant positive correlation between CquiOR114/117 expression and the engorgement rate of the mosquitoes. CquiOR114/117 is speculated to have an effect on the blood-feeding behavior of Cx. quinquefasciatus.

13.
Acta Physiol (Oxf) ; 228(4): e13439, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31900976

RESUMO

AIM: To explore the role of the histidine triad nucleotide-binding 2 (HINT2) protein in heart failure. METHODS: Neonatal mouse ventricle myocytes (NMVMs) and myocardial infarction-induced heart failure mice were used for in vitro or in vivo experiments. Adenovirus (ADV) and adeno-associated virus serum type 9 (AAV9) vectors were used to regulate HINT2 expression. The expression of HINT2 was determined by quantifying the mRNA and protein levels. Cell survival was analysed using the CCK-8 kit and TUNEL staining. Mitochondrial function was determined by the mitochondrial membrane potential and oxygen consumption rates. AAV9-HINT2 was injected 24 h post-myocardial infarction following which transthoracic echocardiography and histological analyses were performed after 4 weeks. Positron emission tomography tomography-computed tomography (PET/CT) and targeted metabolomics analyses were used to explore the metabolic status in vivo. NAD levels were measured using a colorimetric kit. Computer-simulated rigid body molecular docking was performed using AUTODOCK4. Molecule binding kinetics assays were performed using biolayer interferometry. RESULTS: HINT2 was down-regulated in NMVMs in hypoxia. ADV-HINT2-induced HINT2 overexpression improved NMVM survival after exposure to hypoxia. Mitochondrial function was preserved in the ADV-HINT2 group under hypoxic conditions. In vivo experiments showed that cardiac function and metabolic status was preserved by HINT2 overexpression. HINT2 overexpression restored mitochondrial NAD levels; this was dependent on nicotinamide mononucleotide (NMN). Using computer-simulated molecular docking analysis and biolayer interferometry, we observed that HINT2 potentially binds and associates with NMN. CONCLUSION: HINT2 overexpression protects cardiac function in adult mice after myocardial infarction by maintaining mitochondrial NAD homeostasis.

14.
Theranostics ; 10(1): 384-397, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31903127

RESUMO

Bax inhibitor-1 (BI1) conveys anti-apoptotic signals for mitochondria while prohibitin 2 (PHB2) is implicated in sustaining mitochondrial morphology and function. However, their regulatory roles in acute kidney injury (AKI) are largely unknown. Methods: In human patients with AKI, levels of BI1 in urine and plasma were determined using ELISA. An experimental model of AKI was established using ATP depletion-mediated metabolic stress and ischemia-reperfusion injury (IRI) in primary tubule cells and BI1 transgenic mice, respectively. Western blots, ELISA, qPCR, immunofluorescence, RNA silencing, and domain deletion assay were employed to evaluate the roles of BI1 and PHB2 in the preservation of mitochondrial integrity. Results: Levels of BI1 in urine and plasma were decreased in patients with AKI and its expression correlated inversely with renal function. However, reconstitution of BI1 in a murine AKI model was capable of alleviating renal failure, inflammation and tubular death. Further molecular scrutiny revealed that BI1 preserved mitochondrial genetic integrity, reduced mitochondrial oxidative stress, promoted mitochondrial respiration, inhibited excessive mitochondrial fission, improved mitophagy and suppressed mitochondrial apoptosis. Intriguingly, levels of the mitochondria-localized PHB2 were sustained by BI1 and knockdown of PHB2 abolished the mitochondrial- and renal- protective properties of BI1. Furthermore, BI1 promoted PHB2 retention within mitochondria through direct interaction with cytoplasmic PHB2 to facilitate its mitochondrial import. This was confirmed by the observation that the C-terminus of BI1 and the PHB domain of PHB2 were required for the BI1-PHB2 cross-linking. Conclusion: Our data have unveiled an essential role of BI1 as a master regulator of renal tubule function through sustaining mitochondrial localization of PHB2, revealing novel therapeutic promises against AKI.

15.
Acta Biochim Biophys Sin (Shanghai) ; 52(1): 1-8, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31897470

RESUMO

Dementia, a devastating neurological disorder commonly found in the elderly, is characterized by severe cognitive and memory impairment. Ample clinical and epidemiological evidence has depicted a close association between dementia and heart failure. While cerebral blood under perfusion and neurohormonal activation due to the dampened cardiac pump function contribute to the loss of nutrient supply and neuronal injury, Alzheimer's disease (AD), the most common type of dementia, also provokes cardiovascular function impairment, in particular impairment of diastolic function. Aggregation of amyloid-ß proteins and mutations of Presenilin (PSEN) genes are believed to participate in the pathological changes in the heart although it is still debatable with regards to the pathological cue of cardiac anomalies in AD process. In consequence, reduced cerebral blood flow triggered by cardiac dysfunction further deteriorates vascular dementia and AD pathology. Patients with atrial fibrillation, heart failure, and other cardiac anomalies are at a higher risk for cognitive decline and dementia. Conclusion: Due to the increased incidence of dementia and cardiovascular diseases, the coexistence of the two will cause more threat to public health, warranting much more attention. Here, we will update recent reports on dementia, AD, and cardiovascular diseases and discuss the causal relationship between dementia and heart dysfunction.


Assuntos
Doença de Alzheimer/epidemiologia , Doença de Alzheimer/metabolismo , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Envelhecimento/metabolismo , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Doenças Cardiovasculares/genética , Comorbidade , Modelos Animais de Doenças , Humanos , Camundongos , Pessoa de Meia-Idade , Mutação , Presenilinas/genética , Fatores de Risco
16.
Basic Res Cardiol ; 115(2): 11, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31919590

RESUMO

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a novel inducer to promote mitochondrial apoptosis and suppress tumor growth in a variety of cells although its role in cardiovascular diseases remains obscure. This study was designed to examine the role of DNA-PKcs in cardiac ischemia reperfusion (IR) injury and mitochondrial damage. Cardiomyocyte-specific DNA-PKcs knockout (DNA-PKcsCKO) mice were subjected to IR prior to assessment of myocardial function and mitochondrial apoptosis. Our data revealed that IR challenge, hypoxia-reoxygenation (HR) or H2O2-activated DNA-PKcs through post-transcriptional phosphorylation in murine hearts or cardiomyocytes. Mice deficient in DNA-PKcs in cardiomyocytes were protected against cardiomyocyte death, infarct area expansion and cardiac dysfunction. DNA-PKcs ablation countered IR- or HR-induced oxidative stress, mPTP opening, mitochondrial fission, mitophagy failure and Bax-mediated mitochondrial apoptosis, possibly through suppression of Bax inhibitor-1 (BI-1) activity. A direct association between DNA-PKcs and BI-1 was noted where DNA-PKcs had little effect on BI-1 transcription but interacted with BI-1 to promote its degradation. Loss of DNA-PKcs stabilized BI-1, thus offering resistance of mitochondria and cardiomyocytes against IR insult. Moreover, DNA-PKcs ablation-induced beneficial cardioprotection against IR injury was mitigated by concurrent knockout of BI-1. Double deletion of DNA-PKcs and BI-1 failed to exert protection against global IR injury and mitochondrial damage, confirming a permissive role of BI-1 in DNA-PKcs deletion-elicited cardioprotection against IR injury. DNA-PKcs serves as a novel causative factor for mitochondrial damage via suppression of BI-1, en route to the onset and development of cardiac IR injury.

17.
Int J Obes (Lond) ; 44(1): 267-268, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31776436

RESUMO

The authors found a critical mistake in the assembly of Fig. 2; in Fig. 2A the right two images were erroneously duplicated. The authors have re-analysed all the data, checked for accuracy and provided the updated Fig. 2 here. Nothing is affected with regards to data summary and conclusion.

18.
J Cancer Res Clin Oncol ; 146(2): 485-492, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31686248

RESUMO

PURPOSE: Early death (ED) is the main cause of acute promyelocytic leukemia (APL) treatment failure, and the ED rate is higher for elderly patients than that for young ones. To date, no studies have been found focusing on ED in elderly patients with APL. METHODS: This study retrospectively analyzed the clinical data of 409 consecutive patients with APL (139 patients ≥ 50 years old, 270 patients < 50 years old). All patients received arsenic trioxide alone as induction therapy. The baseline clinical characteristics and ED occurrence and predictors between elderly and young patients with APL were compared and analyzed. RESULTS: The clinical features of elderly patients at admission were not significantly different from those of young ones. The ED rate of elderly patients was significantly greater than that of young patients (23.74% vs 11.85%, P = 0.0018). Hemorrhage is the main cause of ED in elderly patients, followed by infection and differentiation syndrome. From the 15th to 30th days of treatment, elderly patients had a higher mortality rate than that of young patients (7.83% vs 2.06%, P = 0.009). Male, white blood cell (WBC) count > 10 × 109/L, fibrinogen < 1.0 g/L and low albumin levels were independent risk factors for ED in elderly patients, while ED was only correlated with WBC count, fibrinogen and creatinine levels in young patients. CONCLUSION: The results of this study may help design more rational treatment plans for elderly patients with APL based on early mortality risk to reduce the ED rate.


Assuntos
Trióxido de Arsênio/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/mortalidade , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Adulto Jovem
19.
Br J Pharmacol ; 177(8): 1881-1897, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31877229

RESUMO

BACKGROUND AND PURPOSE: Lipopolysaccharides (LPS), an outer membrane component of Gram-negative bacteria, triggers myocardial anomalies in sepsis. Recent findings indicated a role for inflammatory cytokine MIF and its receptor, CD74, in septic organ injury, although little is known of the role of MIF-CD74 in septic cardiomyopathy. EXPERIMENTAL APPROACH: This study evaluated the impact of CD74 ablation on endotoxaemia-induced cardiac anomalies. Echocardiographic, cardiomyocyte contractile and intracellular Ca2+ properties were examined. KEY RESULTS: Our data revealed compromised cardiac function (lower fractional shortening, enlarged LV end systolic diameter, decreased peak shortening, maximal velocity of shortening/relengthening, prolonged duration of relengthening and intracellular Ca2+ mishandling) and ultrastructural derangement associated with inflammation, O2 - production, apoptosis, excess autophagy, phosphorylation of AMPK and JNK and dampened mTOR phosphorylation. These effects were attenuated or mitigated by CD74 knockout. LPS challenge also down-regulated Skp2, an F-box component of Skp1/Cullin/F-box protein-type ubiquitin ligase, while up-regulating that of SUV39H1 and H3K9 methylation of the Bcl2 protein BCLB. These effects were reversed by CD74 ablation. In vitro study revealed that LPS facilitated GFP-LC3B formation and cardiomyocyte defects. These effects were prevented by CD74 ablation. Interestingly, the AMPK activator AICAR, the autophagy inducer rapamycin and the demethylation inhibitor difenoconazole inhibited the effects of CD74 ablation against LPS-induced cardiac dysfunction, while the SUV39H1 inhibitor chaetocin or methylation inhibitor 5-AzaC ameliorated LPS-induced GFP-LC3B formation and cardiomyocyte contractile dysfunction. CONCLUSION AND IMPLICATIONS: Our data suggested that CD74 ablation protected against LPS-induced cardiac anomalies, O2 - production, inflammation and apoptosis through suppression of autophagy in a Skp2-SUV39H1-mediated mechanism.

20.
Oxid Med Cell Longev ; 2019: 9825061, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781358

RESUMO

Biological aging is an inevitable and independent risk factor for a wide array of chronic diseases including cardiovascular and metabolic diseases. Ample evidence has established a pivotal role for interrupted mitochondrial homeostasis in the onset and development of aging-related cardiovascular anomalies. A number of culprit factors have been suggested in aging-associated mitochondrial anomalies including oxidative stress, lipid toxicity, telomere shortening, metabolic disturbance, and DNA damage, with recent findings revealing a likely role for compromised mitochondrial dynamics and mitochondrial quality control machinery such as autophagy. Mitochondria undergo consistent fusion and fission, which are crucial for mitochondrial homeostasis and energy adaptation. Autophagy, in particular, mitochondria-selective autophagy, namely, mitophagy, refers to a highly conservative cellular process to degrade and clear long-lived or damaged cellular organelles including mitochondria, the function of which gradually deteriorates with increased age. Mitochondrial homeostasis could be achieved through a cascade of independent but closely related processes including fusion, fission, mitophagy, and mitochondrial biogenesis. With improved health care and increased human longevity, the ever-rising aging society has imposed a high cardiovascular disease prevalence. It is thus imperative to understand the role of mitochondrial homeostasis in the regulation of lifespan and healthspan. Targeting mitochondrial homeostasis should offer promising novel therapeutic strategies against aging-related complications, particularly cardiovascular diseases.

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