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AIM: To investigate the association between circulating ß-hydroxybutyric acid (ßOHB) and diabetic kidney disease (DKD) risk in patients with type 2 diabetes (T2D). MATERIALS AND METHODS: A total of 1388 patients with T2D were recruited. Participants were divided into high and normal ßOHB groups. Participants in the normal ßOHB group were divided into four subgroups according to ßOHB quartile (Q). The relationships of ßOHB with DKD and DKD subtype were analysed using chi-square and binary logistic regression. Restricted cubic splines were used to explore the non-linear correlation between ßOHB concentration and DKD risk in the total population. RESULTS: A higher prevalence of DKD was detected in the high compared with the normal ßOHB group (43.3% vs. 33.3%, P = .041). Participants in the Q4 group (ßOHB, 0.12-0.30 mM) had the lowest prevalence of DKD (P = .001). In the binary logistic regression model, the multivariable-adjusted odds ratios (ORs) (95% confidence intervals [CIs]) for DKD risk were 2.30 (1.62-3.26) for Q1, 1.80 (1.23-2.62) for Q2 and 1.63 (1.10-2.41) for Q3 relative to Q4 (P < .001). Restricted cubic spline analyses suggested a J-shaped association of circulating ßOHB concentration with DKD risk. DKD risk was lowest at a serum ßOHB concentration of 0.183 mM (OR, 0.63; 95% CI, 0.52-0.77). CONCLUSIONS: A J-shaped relationship between circulating ketone level and DKD risk in patients with T2D was determined. Circulating ßOHB in the range of 0.12-0.30 mM was associated with a lower risk of DKD. Further studies are warranted to verify the causality and to elucidate the underlying mechanisms.
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Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/etiologia , Estudos Transversais , Cetonas , Fatores de Risco , Ácido 3-HidroxibutíricoRESUMO
Previous studies have suggested that phthalates are associated with birth weight. However, most phthalate metabolites have not been fully explored. Therefore, we conducted this meta-analysis to assess the relationship between phthalate exposure and birth weight. We identified original studies that measured phthalate exposure and reported its association with infant birth weight in relevant databases. Regression coefficients (ß) with 95% confidence intervals (CIs) were extracted and analyzed for risk estimation. Fixed-effects (I2 ≤ 50%) or random-effects (I2 > 50%) models were adopted according to their heterogeneity. Overall summary estimates indicated negative associations of prenatal exposure to mono-n-butyl phthalate (pooled ß = -11.34 g; 95% CI: -20.98 to -1.70 g) and mono-methyl phthalate (pooled ß = -8.78 g; 95% CI: -16.30 to -1.27 g). No statistical association was found between the other less commonly used phthalate metabolites and birth weight. Subgroup analyses indicated that exposure to mono-n-butyl phthalate was associated with birth weight in females (ß = -10.74 g; 95% CI: -18.70 to -2.79 g). Our findings indicate that phthalate exposure might be a risk factor for low birth weight and that this relationship may be sex specific. More research is needed to promote preventive policies regarding the potential health hazards of phthalates.
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Background/aim: Hepatocellular carcinoma (HCC) ranks among the most prevalent malignancies worldwide and the third leading cause of cancer-related death. The TRIM (tripartite motif-containing) protein family members had been reported to be involved in carcinogenesis and tumor progression. Here we aimed to explore the expression profile of TRIM6 in HCC and investigate its clinical significance as well as underlying mechanisms. Materials and methods: We retrospectively enrolled 138 HCC patients that underwent surgical resection in our hospital and tested protein expression level of TRIM6 through immunohistochemical staining. The correlation between TRIM6 and patients' characteristics was assessed by Chi-square test. Log-rank test and Cox hazard regression test were conducted for univariate and multivariate survival analyses, respectively. Two human HCC cell lines, Huh7 and Hep3B, were subjected for knockdown and overexpression assays, followed by phonotype tests including proliferation and invasion. Nude mice were used to generate xenograft model to validate our findings in vivo. Results: TRIM6 was highly expressed in HCC specimen compared to nontumorous liver tissues. Higher TRIM6 expression was correlated with larger tumor size, later tumor stage, and worse prognosis. According to the cellular experiments, TRIM6-knockdown resulted in decreased expression of cyclin B1, c-Myc, Snail, MMP2, and VEGF-A. Consistently, TRIM6-knockdown led to impaired HCC proliferation, invasion, and angiogenesis. In contrast, TRIM6 overexpression showed opposite effects. Finally, the oncogenic role of TRIM6 in HCC was validated by in vivo mice experiments. Conclusion: TRIM6 can serve as a novel prognostic factor for HCC, which functions by multiple signaling pathways.
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Carcinoma Hepatocelular , Progressão da Doença , Neoplasias Hepáticas , Proteínas com Motivo Tripartido , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Camundongos Nus , Prognóstico , Estudos Retrospectivos , Proteínas com Motivo Tripartido/metabolismo , Proteínas com Motivo Tripartido/genéticaRESUMO
Orf virus (ORFV, species Orf virus) belongs to the typical species of the Parapoxvirus genus of the family Poxviridae, which infects sheep, goats, and humans with worldwide distribution. Although outbreaks of Orf have been reported sequentially in several Chinese provinces, the epidemiology of Orf and genetic diversity of ORFV strains still needs to be further characterized. To further reveal the genomic organization of the ORFV-GZ18 and ORFV-CL18 isolates, the complete genome sequences of two recently obtained ORFV isolates were sequenced using the next-generation sequencing technology and analyzed, which had been deposited in the GenBank database under accession number MN648218 and MN648219, respectively. The complete genomic sequence of ORFV-CL18 was 138,495 bp in length, including 131 potential open reading frames (ORFs) flanked by inverted terminal repeats (ITRs) of 3481 bp at both ends, which has genomic structure typical Parapoxviruses. The overall genomic organization of the fully sequenced genome of ORFV-GZ18 was consistent with ORFV-CL18 genome, with a complete genome size of 138,446 nucleotides, containing 131 ORFs flanked by ITRs of 3469 bp. Additionally, the overall G + C contents of ORFV-GZ18 and ORFV-CL18 genome sequences were about 63.9% and 63.8%, respectively. The phylogenetic analysis showed that both ORFV-GZ18 and ORFV-CL18 were genetically closely related to ORFV-SY17 derived from sheep. In summary, the complete genomic sequences of ORFV-GZ18 and ORFV-CL18 are reported, with the hope it will be useful to investigate the host range, geographic distribution, and genetic evolution of the virus in Southern West and Northern East China.
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Ectima Contagioso , Vírus do Orf , Animais , China/epidemiologia , Genômica , Cabras , Humanos , Nucleotídeos , Vírus do Orf/genética , Filogenia , OvinosRESUMO
BACKGROUND: Sedative gastrointestinal endoscopy is extensively used worldwide. An appropriate degree of sedation leads to more acceptability and satisfaction. Artificial intelligence has rapidly developed in the field of digestive endoscopy in recent years and we have constructed a mature computer-aided diagnosis (CAD) system. This system can identify the remaining parts to be examined in real-time endoscopic procedures, which may help anesthetists use anesthetics properly to keep patients in an appropriate degree of sedation. AIMS: This study aimed to evaluate the effects of the CAD system on anesthesia quality control during gastrointestinal endoscopy. METHODS: We recruited 154 consecutive patients at Renmin Hospital of Wuhan University, including 76 patients in the CAD group and 78 in the control group. Anesthetists in the CAD group were able to see the CAD system's indications, while anesthetists in the control group could not. The primary outcomes included emergence time (from examination completion to spontaneous eye opening when doctors called the patients' names), recovery time (from examination completion to achievement of the primary recovery endpoints) and patient satisfaction scores. The secondary outcomes included anesthesia induction time (from sedative administration to successful sedation), procedure time (from scope insertion to scope withdrawal), total dose of propofol, vital signs, etc. This trial was registered in the Primary Registries of the WHO Registry Network, with registration number ChiCTR2100042621. RESULTS: Emergence time in the CAD group was significantly shorter than that in the control group (p < 0.01). The recovery time was also significantly shorter in the CAD group (p < 0.01). Patients in the CAD group were significantly more satisfied with their sedation than those in control group (p < 0.01). Vital signs were stable during the examinations in both groups. Propofol doses during the examinations were comparable between the two groups. CONCLUSION: This CAD system possesses great potential for anesthesia quality control. It can improve patient satisfaction during endoscopic examinations with sedation. TRIAL REGISTRATION: ChiCTR2100042621.
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Anestesia , Anestésicos , Propofol , Inteligência Artificial , Endoscopia Gastrointestinal , Humanos , Hipnóticos e Sedativos , Satisfação do Paciente , Controle de QualidadeRESUMO
Dysregulation of cholesterol metabolism and its oxidative products-oxysterols-in the brain is known to be associated with neurodegenerative diseases. It is well-known that 27-hydroxycholesterol (27-OHC) and 24S-hydroxycholesterol (24S-OHC) are the main oxysterols contributing to the pathogenesis of Alzheimer's disease (AD). However, the molecular mechanism of how 27-OHC and 24S-OHC cause cognitive decline remains unclear. To verify whether 27-OHC and 24S-OHC affect learning and memory by regulating immune responses, C57BL/6J mice were subcutaneously injected with saline, 27-OHC, 24S-OHC, 27-OHC+24S-OHC for 21 days. The oxysterols level and expression level of related metabolic enzymes, as well as the immunomodulatory factors were measured. Our results indicated that 27-OHC-treated mice showed worse learning and memory ability and higher immune responses, but lower expression level of interleukin-10 (IL-10) and interferon (IFN-λ2) compared with saline-treated mice, while 24S-OHC mice performed better in the Morris water maze test than control mice. No obvious morphological lesion was observed in these 24S-OHC-treated mice. Moreover, the expression level of interleukin-17A (IL-17A), granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage inflammatory protein 3α (MIP-3α) were significantly decreased after 24S-OHC treatment. Notably, compared with 27-OHC group, mice treated with 27-OHC+24S-OHC showed higher brain 24S-OHC level, accompanied by increased CYP46A1 expression level while decreased CYP7B1, retinoic acid-related orphan receptor gamma t (RORγt) and IL-17A expression level. In conclusion, our study indicated that 27-OHC is involved in regulating the expression of RORγt, disturbing Th17/Treg balance-related immune responses which may be associated with the learning and memory impairment in mice. In contrast, 24S-OHC is neuroprotective and attenuates the neurotoxicity of 27-OHC.
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Interleucina-17 , Oxisteróis , Animais , Hidroxicolesteróis/metabolismo , Hidroxicolesteróis/farmacologia , Interleucina-17/genética , Camundongos , Camundongos Endogâmicos C57BL , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares , Linfócitos T Reguladores/metabolismoRESUMO
Mouse hepatitis virus A59 (MHV-A59) is a representative member of the genus betacoronavirus within the subfamily Coronavirinae, which infects the liver, brain and respiratory tract. Through different inoculation routes, MHV-A59 can provide animal models for encephalitis, hepatitis and pneumonia to explore viral life machinery and virus-host interactions. In viral replication, non-structural protein 5 (Nsp5), also termed main protease (Mpro), plays a dominant role in processing coronavirus-encoded polyproteins and is thus recognized as an ideal target of anti-coronavirus agents. However, no structure of the MHV-A59 Mpro has been reported, and molecular exploration of the catalysis mechanism remains hindered. Here, we solved the crystal structure of the MHV-A59 Mpro complexed with a Michael acceptor-based inhibitor, N3. Structural analysis revealed that the Cß of the vinyl group of N3 covalently bound to C145 of the catalytic dyad of Mpro, which irreversibly inactivated cysteine protease activity. The lactam ring of the P1 side chain and the isobutyl group of the P2 side chain, which mimic the conserved residues at the same positions of the substrate, fit well into the S1 and S2 pockets. Through a comparative study with Mpro of other coronaviruses, we observed that the substrate-recognition pocket and enzyme inhibitory mechanism is highly conservative. Altogether, our study provided structural features of MHV-A59 Mpro and indicated that a Michael acceptor inhibitor is an ideal scaffold for antiviral drugs.
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Vírus da Hepatite Murina/química , Peptídeo Hidrolases/química , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Sequência de Aminoácidos , Animais , Infecções por Coronavirus/virologia , Cristalografia por Raios X , Humanos , Camundongos , Modelos Moleculares , Vírus da Hepatite Murina/efeitos dos fármacos , Vírus da Hepatite Murina/metabolismo , Peptídeo Hidrolases/metabolismo , Conformação Proteica/efeitos dos fármacos , Alinhamento de Sequência , Proteínas não Estruturais Virais/metabolismoRESUMO
Orf virus (ORFV), a typical member of the Parapoxvirus genus within the family Poxviridae, which is the causative agent of Orf, a common epitheliotropic viral disease of sheep, goats, wild ruminants, and humans. In the present study, we sequenced the complete genomic sequences of two ORFV strains (ORFV-SY17, isolated from sheep, and ORFV-NA17, isolated from goat) and conducted the comparative analysis of multiple ORFVs. The complete genomic sequence of ORFV-SY17 was at length of 140,413 bp, including 131 potential open reading frames (ORFs) flanked by inverted terminal repeats (ITRs) of 4267 bp at both ends. The ORFV-NA17 strain displayed the similar genome structure with ORFV-SY17. The whole genomic sequence of ORFV-NA17 strain was 139,287 bp in length and contained 132 ORFs flanked by ITRs of 3974 bp. The overall G+C contents of ORFV-SY17 and ORFV-NA17 genome sequences were about 63.8% and 63.7%, respectively. The ITR sequences analysis showed that ORFV-SY17 and ORFV-NA17 contained the terminal BamHI sites and conserved telomere resolution sequences at both ends of their genome. In addition, comparative analysis of ORFs among ORFV-SY17, ORFV-NA17, and other ORFV strains revealed several sequence variations caused by insertions or deletions, especially in ORFs 005 and 116, which were very likely associated with host species. Phylogenetic analysis based on the complete genome sequences revealed that ORFV-SY17 was genetically closely related to NA1/11 and HN3/12 strains derived from sheep, while ORFV-NA17 was closely related to YX strain derived from goat. The multiple alignment of deduced amino acid sequences further revealed the genetic relationship between host species and genetic variations of ORFV strains. Taken together, the availability of genomic sequences of ORFV-SY17 and ORFV-NA17 strains from Jilin Province will aid in our understanding of the genetic diversity and evolution of ORFV strains in this region and can assist in distinguishing between ORFV strains that originate in sheep and goats.
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Ectima Contagioso/virologia , Genoma Viral , Doenças das Cabras/virologia , Vírus do Orf/genética , Vírus do Orf/isolamento & purificação , Doenças dos Ovinos/virologia , Animais , China , Cabras , Humanos , Vírus do Orf/classificação , Vírus do Orf/ultraestrutura , Filogenia , Ovinos , Sequenciamento Completo do GenomaRESUMO
Researchers have shown that long noncoding RNAs (lncRNAs) are closely associated with the pathogenesis of colorectal cancer (CRC). In here, we aimed to explore the function of lncRNA MAFG-AS1 in tumorigenesis of CRC. Firstly, we found that the expression of MAFG-AS1 was upregulated in CRC tissues and positively correlated with the advanced tumor stage. A reciprocal repression was found between MAFG-AS1 and miR-147b. The expression of miR-147b was downregulated in CRC tissues and inversely correlated with MAFG-AS1. Both the low-expression of miR-147b expression and the advanced tumor stage were independent factor for poor survival probability. Furthermore, overexpression of MAFG-AS1 promoted cell proliferation, cell cycle progression, and invasion, and inhibited apoptosis, while transduction of miR-147b partially reversed the effect of MAFG-AS1 on cellular processes. Consistently, stable over-expression of MAFG-AS1 contributed to the growth of colon cancer cell xenografts in vivo. NDUFA4 was identified as a direct target of miR-147b and knockdown of NDUFA4 abolished the oncogenic role of miR-147b inhibitor. Besides, MAFG-AS1 contributed to cell glycolysis by sponging miR-147b and activation of NDUFA4, causing an upregulation of PDK1, PFK1 and PKM2. Taken together, our study suggested that MAFG-AS1 functions as a novel oncogenic lncRNA in the development of CRC by regulating miR-147b/NDUFA4.
Assuntos
Neoplasias Colorretais/patologia , Progressão da Doença , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Fator de Transcrição MafG/genética , MicroRNAs/antagonistas & inibidores , RNA Longo não Codificante/fisiologia , Proteínas Repressoras/genética , Animais , Apoptose , Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Complexo IV da Cadeia de Transporte de Elétrons/antagonistas & inibidores , Glicólise , Xenoenxertos , Humanos , Camundongos , MicroRNAs/fisiologiaRESUMO
Homocysteine may be responsible for vascular endothelial cell injury, which occurs early in the pathology of cardiovascular disease. Homocysteine metabolism requires enzymatic interaction with vitamins such as folic acid, vitamin B12, and vitamin B6. We hypothesized that folic acid alleviated homocysteine-induced vascular injury by regulating the metabolic pathway of apoptosis. Human umbilical vein endothelial cells were incubated for 48 h with folic acid at the concentrations of 0-1000 nmol/L, in combination with either 1000 µmol/L homocysteine or vehicle for the first 24 h. We then assessed cell viability and apoptosis by methyl thiazolyl tetrazolium assay and flow cytometry, respectively. To further investigate how folic acid influenced cell apoptosis, we also analyzed the activities of caspase-3/7 and the mRNA and protein expressions of BCL2, BAX, TP53, CASP3, and CASP8 in human umbilical vein endothelial cells. We showed that folic acid increased cell viability and decreased apoptosis in a dose-dependent manner, and that this effect was mediated by decreased caspase-3/7 activity, upregulated BCL2/BAX ratio, and downregulated TP53, CASP3, and CASP8 expressions. Thus, we conclude that folic acid inhibits cell apoptosis and ameliorates homocysteine toxicity by regulating the expression of apoptosis-related genes in human umbilical vein endothelial cells.
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Proteínas Reguladoras de Apoptose/biossíntese , Apoptose/efeitos dos fármacos , Ácido Fólico/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Homocisteína/farmacologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/citologia , HumanosRESUMO
A microwave-irradiated solvent-free pinacol rearrangement of hydrobenzoin substrates catalyzed by a combination of N-fluorobenzenesulfonimide and FeCl3·6H2O was developed. Its selectivity was first investigated by density functional theory (DFT) calculations. Then the functional group tolerance was examined by synthesizing a series of substrates designed based on the insight provided by the DFT calculations. The application of the methodology was demonstrated by the efficient one-pot synthesis of (±)-latifine and (±)-cherylline, both are 4-aryltetrahydroisoquinoline alkaloids isolated from Amaryllidacecae plants.
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A unique approach to biaryls was developed on the basis of propargyl vinyl ethers and dienophiles substrates via a gold(I)-initiated cycloisomerization/Diels-Alder/retro-Diels-Alder cascade reaction. The scope and mechanism of the reaction were investigated on the basis of a series of synthetic substrates, control experiments, and DFT calculations.
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The pathogenesis of atherosclerosis has been partly acknowledged to result from aberrant epigenetic mechanisms. Accordingly, low folate levels are considered to be a contributing factor to promoting vascular disease because of deregulation of DNA methylation. We hypothesized that increasing the levels of folic acid may act via an epigenetic gene silencing mechanism to ameliorate atherosclerosis. Here, we investigated the atheroprotective effects of folic acid and the resultant methylation status in high-fat diet-fed ApoE knockout mice and in oxidized low-density lipoprotein-treated human umbilical vein endothelial cells. We analyzed atherosclerotic lesion histology, folate concentration, homocysteine concentration, S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), and DNA methyltransferase activity, as well as monocyte chemotactic protein-1 (MCP1) and vascular endothelial growth factor (VEGF) expression and promoter methylation. Folic acid reduced atherosclerotic lesion size in ApoE knockout mice. The underlying folic acid protective mechanism appears to operate through regulating the normal homocysteine state, upregulating the SAM: SAH ratio, elevating DNA methyltransferase activity and expression, altering MCP1 and VEGF promoter methylation, and inhibiting MCP1 and VEGF expression. We conclude that folic acid supplementation effectively prevented atherosclerosis by modifying DNA methylation through the methionine cycle, improving DNA methyltransferase activity and expression, and thus changing the expression of atherosclerosis-related genes.
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Quimiocina CCL2/genética , Metilação de DNA , Ácido Fólico/uso terapêutico , Placa Aterosclerótica/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/genética , Complexo Vitamínico B/uso terapêutico , Animais , Apolipoproteínas E/genética , Suplementos Nutricionais , Ácido Fólico/administração & dosagem , Ácido Fólico/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Placa Aterosclerótica/genética , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/prevenção & controle , Regiões Promotoras Genéticas , S-Adenosil-Homocisteína/metabolismo , S-Adenosilmetionina/metabolismo , Complexo Vitamínico B/administração & dosagem , Complexo Vitamínico B/farmacologiaRESUMO
Most analytical methods for describing light propagation in turbid medium exhibit low effectiveness in the near-field of a collimated source. Motivated by the Charge Simulation Method in electromagnetic theory as well as the established discrete source based modeling, we herein report on an improved explicit model for a semi-infinite geometry, referred to as "Virtual Source" (VS) diffuse approximation (DA), to fit for low-albedo medium and short source-detector separation. In this model, the collimated light in the standard DA is analogously approximated as multiple isotropic point sources (VS) distributed along the incident direction. For performance enhancement, a fitting procedure between the calculated and realistic reflectances is adopted in the near-field to optimize the VS parameters (intensities and locations). To be practically applicable, an explicit 2VS-DA model is established based on close-form derivations of the VS parameters for the typical ranges of the optical parameters. This parameterized scheme is proved to inherit the mathematical simplicity of the DA approximation while considerably extending its validity in modeling the near-field photon migration in low-albedo medium. The superiority of the proposed VS-DA method to the established ones is demonstrated in comparison with Monte-Carlo simulations over wide ranges of the source-detector separation and the medium optical properties.
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This study was undertaken to determine and confer the cardioprotective effects of the adenosine A2 receptor (A2AR) and its impact on myocardial autophagy in the setting of reperfusion. We established a rat ischemia model by subjecting rats to 30 minutes of ischemia (I) and 120 minutes of reperfusion (R). The A2AR agonists CGS21680 (A2aAR specific) and BAY60-6583 (A2bAR specific) were administered separately and in combination 5 minutes before reperfusion (postconditioning). No visible improvements in the rats' hemodynamic changes in response to either CGS or BAY were observed compared with untreated control groups (I/R). BAY significantly reduced infarct sizes, whereas CGS did not. Electron microscopy, enzyme-linked immunosorbent assay and TUNEL apoptosis staining results demonstrated that CGS and BAY play cardioprotective roles by maintaining mitochondria structural stability, decreasing serum cardiac troponin I (cTnI) concentrations and decreasing the number of apoptotic cells. CGS21680 and BAY60-6583 slightly increased the expression (vs. I/R group) of Bcl-2 and significantly attenuated the expression of Beclin-1, LC3B, and LAMP-2, as analyzed by Western blot, compared with the I/R alone group. Notably, BAY60-6583 exerts a predominant effect on mitochondria structural stabilization, apoptotic inhibition, and attenuation of LC3B/LAMP-2 expression. No synergistic effects were observed for the 2 agonists. Our data suggest that A2AR-mediated cardioprotection is associated with Beclin-1-induced autophagy downregulation in the setting of reperfusion. A2bAR activation exerts stronger cardioprotective effects against I/R injury compared with A2aAR.
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Autofagia/fisiologia , Regulação para Baixo/fisiologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Receptores A2 de Adenosina/fisiologia , Agonistas do Receptor A2 de Adenosina/farmacologia , Animais , Autofagia/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
A series of novel oleanolic acid coupled 1,2,3-triazole derivatives have been designed and synthesized by employing a Cu(I) catalyzed Huisgen 1,3-dipolar cycloaddition reaction. The anti-proliferative evaluation indicated that some compounds exhibited excellent anti-cancer activity against the examined cancer cell lines. Among all derivatives, compound 3t possesses the best inhibitory activity against HT1080 cells. A series of pharmacology experiments show that compound 3t significantly induced HT1080 cell apoptosis. Therefore, this compound can serve as a promising lead candidate for further study.
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Antineoplásicos/química , Antineoplásicos/farmacologia , Desenho de Fármacos , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/farmacologia , Triazóis/química , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Técnicas de Química Sintética , Humanos , Concentração Inibidora 50 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ácido Oleanólico/síntese química , Ácido Oleanólico/química , Relação Estrutura-AtividadeRESUMO
Lowe syndrome is an X-linked disorder characterized by cataracts at birth, mental retardation and progressive renal malfunction that results from loss of function of the OCRL1 (oculocerebrorenal syndrome of Lowe) protein. OCRL1 is a lipid phosphatase that converts phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 4-phosphate. The renal pathogenesis of Lowe syndrome patients has been suggested to result from alterations in membrane trafficking, but this cannot fully explain the disease progression. We found that knockdown of OCRL1 in zebrafish caused developmental defects consistent with disruption of ciliary function, including body axis curvature, pericardial edema, hydrocephaly and impaired renal clearance. In addition, cilia in the proximal tubule of the zebrafish pronephric kidney were longer in ocrl morphant embryos. We also found that knockdown of OCRL1 in polarized renal epithelial cells caused elongation of the primary cilium and disrupted formation of cysts in three-dimensional cultures. Calcium release in response to ATP was blunted in OCRL1 knockdown cells, suggesting changes in signaling that could lead to altered cell function. Our results suggest a new role for OCRL1 in renal epithelial cell function that could contribute to the pathogenesis of Lowe syndrome.
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Túbulos Renais Proximais/ultraestrutura , Monoéster Fosfórico Hidrolases/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Padronização Corporal , Sinalização do Cálcio , Linhagem Celular , Cílios/metabolismo , Cílios/ultraestrutura , Cães , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Células Epiteliais/ultraestrutura , Túbulos Renais Proximais/citologia , Organogênese , Monoéster Fosfórico Hidrolases/genética , RNA Interferente Pequeno , Peixe-Zebra/embriologia , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genéticaRESUMO
We have efficiently synthesized albiziabioside A (1) together with its six disaccharide analogues through a linear synthesis, and evaluated their cytotoxicity against six different skin cancer cells. All of the analogues showed weak cytotoxicity, with the exception of compound 1, which exhibited strong cytotoxicity against A375 cells. Albiziabioside A can induce cell cycle arrest in both the S and G2/M phases. Moreover, albiziabioside A can induce A375 cell apoptosis via mitochondrial pathways involving a caspase cascade. These results provide for the first time a basic mechanism for the anticancer activity of 1.
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Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Melanoma/patologia , Saponinas/síntese química , Saponinas/farmacologia , Clorometilcetonas de Aminoácidos/farmacologia , Antineoplásicos/química , Apoptose/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Melanoma/genética , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Saponinas/química , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genéticaRESUMO
In terahertz inline digital holography, zero-order diffraction light and conjugate images can cause the reconstructed image to be blurred. In this paper, three phase retrieval algorithms are applied to conduct reconstruction based on the same near-field diffraction propagation conditions and image-plane constraints. The impact of different object-plane constraints on CW terahertz inline digital holographic reconstruction is studied. The results show that in the phase retrieval algorithm it is not suitable to impose restriction on the phase when the object is not isolated in the transmission-type CW terahertz inline digital holography. In addition, the effects of zero-padding expansion, boundary replication expansion, and apodization operation on reconstructed images are studied. The results indicate that the conjugate image can be eliminated, and a better reconstructed image can be obtained by adopting an appropriate phase retrieval algorithm after the normalized hologram extending to the minimum area, which meets the applicable range of the angular spectrum reconstruction algorithm by means of boundary replication.