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1.
J Environ Manage ; 301: 113882, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34638040

RESUMO

Due to its increasing demands for fossil fuels, Indonesia needs an alternative energy to diversify its energy supply. Landfill gas (LFG), which key component is methane (CH4), has become one of the most attractive options to sustain its continued economic development. This exploratory study seeks to demonstrate the added value of landfilled municipal solid waste (MSW) in generating sustainable energy, resulting from CH4 emissions in the Bantargebang landfill (Jakarta). The power generation capacity of a waste-to-energy (WTE) plant based on a mathematical modeling was investigated. This article critically evaluated the production of electricity and potential income from its sale in the market. The project's environmental impact assessment and its socio-economic and environmental benefits in terms of quantitative and qualitative aspects were discussed. It was found that the emitted CH4 from the landfill could be reduced by 25,000 Mt annually, while its electricity generation could reach one million kW â‹…h annually, savings on equivalent electricity charge worth US$ 112 million/year (based on US' 8/kW ⋅ h). An equivalent CO2 mitigation of 3.4 × 106 Mt/year was obtained. The income from its power sale were US$ 1.2 ×106 in the 1st year and 7.7 ×107US$ in the 15th year, respectively, based on the projected CH4 and power generation. The modeling study on the Bantargebang landfill using the LFG extraction data indicated that the LFG production ranged from 0.05 to 0.40 m3 per kg of the landfilled MSW. The LFG could generate electricity as low as US' 8 per kW ⋅ h. With respect to the implications of this study, the revenue not only defrays the cost of landfill's operations and maintenance (O&M), but also provides an incentive and means to further improve its design and operations. Overall, this work not only leads to a diversification of primary energy, but also improves environmental protection and the living standard of the people surrounding the plant.


Assuntos
Gases de Efeito Estufa , Eliminação de Resíduos , Eletricidade , Humanos , Indonésia , Metano/análise , Resíduos Sólidos/análise , Instalações de Eliminação de Resíduos
2.
Cancer Manag Res ; 13: 8241-8255, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34754244

RESUMO

Purpose: To evaluate the dynamics of early serum tumour markers (STMs) and the neutrophil-to-lymphocyte ratio (NLR) to predict clinical efficacy and prognosis of advanced non-small-cell lung cancer (NSCLC) patients who received programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors. Patients and Methods: We retrospectively reviewed patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors between September 2017 and August 2020. NLR and STMs were routinely measured between immunotherapy initiation and the first radiological evaluation. A combination score based on the leading STM and NLR and their dynamic changes was established. The effects of leading STM change, NLR change, and the combination score on the objective response rate (ORR), durable clinical benefit (DCB), progression-free survival (PFS), and overall survival (OS) were analysed. The accuracy of the combination score was evaluated by receiver operating characteristic (ROC) curve and the area under the curve (AUC). Results: Overall, 124 patients were included in this retrospective cohort study. The ORR was 22.8%, DCB was 54.5%, and the median OS and PFS were 21.6 and 14.9 months, respectively. Patients with low combination scores had a significantly improved ORR and DCB compared with those with intermediate or high scores (P = 0.002 for ORR, P < 0.0001 for DCB). In a multivariate model, the combination score was an independent indicator of PFS (P < 0.0001) and OS (P < 0.0001). The AUC demonstrated that the combination score (AUC = 0.706) has greater predictive power than either the posttreatment NLR (AUC = 0.668) or the leading STM change (AUC = 0.648) alone. Conclusion: An easy, cost-effective, and novel combination score based on the dynamics of an early STM and the NLR can accurately predict the clinical efficacy of PD-1/PD-L1 inhibitors and prognosis in advanced NSCLC patients.

4.
BMC Gastroenterol ; 21(1): 359, 2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34600475

RESUMO

BACKGROUND: Activation of Adenosine 5'-monophosphate-activated protein kinase/Sirtuin1 (AMPK/SIRT1) exerts an effect in alleviating obesity and gut damage. Sodium nitroprusside (SNP), a nitric oxide (NO) donor, has been reported to activate AMPK. This study was to investigate the effect of SNP on HFD induced gut dysfunction and the mechanism. METHODS: SNP was applied on lipopolysaccharide (LPS) stimulated Caco-2 cell monolayers which mimicked intestinal epithelial barrier dysfunction and HFD-fed mice which were complicated by gut dysfunction. Then AMPKα/SIRT1 pathway and gut barrier indicators were investigated. RESULTS: SNP rescued the loss of tight junction proteins ZO-1 and occludin, the inhibition of AMPKα/SIRT1 in LPS stimulated Caco-2 cell monolayers, and the effects were not shown when AMPKa1 was knocked-down by siRNA. SNP also alleviated HFD induced obesity and gut dysfunction in mice, as indicated by the decreasing of intestinal permeability, the increasing expression of ZO-1 and occludin, the decreasing levels of pro-inflammatory cytokine IL-6, and the repairing of gut microbiota dysbiosis. These effects were complicated by the increased colonic NO content and the activated AMPKα/SIRT1 signaling. CONCLUSIONS: The results may imply that SNP, as a NO donor, alleviates HFD induced gut dysfunction probably by activating the AMPKα/SIRT1 signaling pathway.


Assuntos
Proteínas Quinases Ativadas por AMP , Sirtuína 1 , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Células CACO-2 , Dieta Hiperlipídica , Humanos , Camundongos , Nitroprussiato/farmacologia , Transdução de Sinais , Sirtuína 1/genética , Sirtuína 1/metabolismo
5.
Signal Transduct Target Ther ; 6(1): 347, 2021 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-34564690

RESUMO

SARS-CoV-2 mutations contribute to increased viral transmissibility and immune escape, compromising the effectiveness of existing vaccines and neutralizing antibodies. An in-depth investigation on COVID-19 pathogenesis is urgently needed to develop a strategy against SARS-CoV-2 variants. Here, we identified CD147 as a universal receptor for SARS-CoV-2 and its variants. Meanwhile, Meplazeumab, a humanized anti-CD147 antibody, could block cellular entry of SARS-CoV-2 and its variants-alpha, beta, gamma, and delta, with inhibition rates of 68.7, 75.7, 52.1, 52.1, and 62.3% at 60 µg/ml, respectively. Furthermore, humanized CD147 transgenic mice were susceptible to SARS-CoV-2 and its two variants, alpha and beta. When infected, these mice developed exudative alveolar pneumonia, featured by immune responses involving alveoli-infiltrated macrophages, neutrophils, and lymphocytes and activation of IL-17 signaling pathway. Mechanistically, we proposed that severe COVID-19-related cytokine storm is induced by a "spike protein-CD147-CyPA signaling axis": Infection of SARS-CoV-2 through CD147 initiated the JAK-STAT pathway, which further induced expression of cyclophilin A (CyPA); CyPA reciprocally bound to CD147 and triggered MAPK pathway. Consequently, the MAPK pathway regulated the expression of cytokines and chemokines, which promoted the development of cytokine storm. Importantly, Meplazumab could effectively inhibit viral entry and inflammation caused by SARS-CoV-2 and its variants. Therefore, our findings provided a new perspective for severe COVID-19-related pathogenesis. Furthermore, the validated universal receptor for SARS-CoV-2 and its variants can be targeted for COVID-19 treatment.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Anticorpos Monoclonais Humanizados/farmacologia , Basigina/antagonistas & inibidores , Basigina/metabolismo , COVID-19/tratamento farmacológico , COVID-19/metabolismo , Síndrome da Liberação de Citocina/tratamento farmacológico , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Animais , Basigina/genética , COVID-19/genética , Chlorocebus aethiops , Síndrome da Liberação de Citocina/genética , Síndrome da Liberação de Citocina/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Transgênicos , SARS-CoV-2/genética , Células Vero
6.
Reprod Biomed Online ; 43(4): 598-606, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34474977

RESUMO

RESEARCH QUESTION: lncRNA IGF2-AS may be related to early pregnancy loss. Does lncRNA IGF2-AS affect trophoblast cell growth? The aim of the present study was to verify that lncRNA IGF2-AS encodes a polypeptide, IGF2-AS-168aa, and to study its role in the pathogenesis of trophoblasts. DESIGN: A small interfering RNA targeted to the IGF2-AS gene (si-IGF2-AS) was designed and transfected into JEG-3 and JAR cells for in-vitro gene silencing. Quantitative polymerase chain reaction and western blotting were used to determine lncRNA IGF2-AS levels in experimental cells. After IGF2-AS suppression, MTT assay was used to assess cell proliferation and apoptosis was determined by flow cytometry. Target gRNA IGF2-AS-gRNA was designed for knockout conducted the corresponding mRNA. HEK293T cells were transfected with the identified positive clone vectors. Finally, IGF2-AS-168aa was analysed by western blotting after the protein-coding region of the IGF2-AS gene was knocked out by CRISPR/Cas9 gene-editing technology. RESULTS: lncRNA IGF2-AS and IGF2-AS-168aa were significantly downregulated in JEG-3 and JAR cells transfected with si-IGF2-AS (lncRNA IGF2-AS: JAR: NC versus small interfering RNA (siRNA)-1: P = 0.019 NC versus siRNA-2: P = 0.013; JEG-3: NC versus siRNA-1: P = 0.001 NC versus siRNA-2: P = 0.004) (IGF2-AS-168aa: JAR: NC versus siRNA-1: P = 0.030 NC versus siRNA-2: P = 0.018; JEG-3: NC versus siRNA-1: P = 0.004 NC versus siRNA-2: P = 0.001). IGF2-AS gene was incapable of encoding IGF2-AS-168aa after the coding region was successfully knocked out in HEK293T cells. Flow cytometry and the MTT assay revealed that IGF2-AS gene silencing led to cell cycle block in the G1 phase, markedly decreasing cell proliferation and increasing apoptosis. CONCLUSION: The IGF2-AS gene encoded a peptide with a potential function in trophoblast cell cycle arrest.

7.
FASEB J ; 35(10): e21936, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34547129

RESUMO

Lipopolysaccharide (LPS)-stimulated macrophages express an aconitate decarboxylase (IRG1, also called ACOD1), leading to accumulation of the endogenous metabolite itaconate. However, the precise mechanisms by which elevated itaconate levels alter macrophage function are not clear. Our hypothesis is itaconate affects macrophage function through some uncertain mechanism. Based on this, we established a transcriptional and proteomic signature of macrophages stimulated by itaconate and identified the pathways of IL-1ß secretion and altered iron metabolism. Consistently, the effect of IRG1 deficiency on IL-1ß secretion and iron metabolism was confirmed in IRG1 knockout THP-1 cell lines. Several common inhibitors and other compounds were used to examine the molecular mechanisms involved. Only cysteine and antioxidants (catechin hydrate) could inhibit caspase-1 activation and IL-1ß secretion in itaconate-stimulated macrophages. We further found that aconitase activity was decreased by itaconate stimulation. Our results demonstrate the counteracting effects of overexpression of mitochondrial aconitase (ACO2, a tricarboxylic acid cycle enzyme) or cytosolic aconitase (ACO1, an iron regulatory protein) on IL-1ß secretion and altered iron metabolism. Both enzyme activities were inhibited by itaconate because of iron-sulfur (Fe-S) cluster destruction. Our findings indicate that the immunoregulatory functions of IRG1 and itaconate in macrophages are stressful Fe-S cluster of aconitases disrupting and iron metabolism rebalancing.


Assuntos
Ferro/metabolismo , Macrófagos/metabolismo , Succinatos/metabolismo , Enxofre/metabolismo , Aconitato Hidratase/metabolismo , Carboxiliases/metabolismo , Linhagem Celular , Cisteína/metabolismo , Citocinas/metabolismo , Humanos , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteoma/metabolismo , Proteômica
8.
Malar J ; 20(1): 374, 2021 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-34538247

RESUMO

BACKGROUND: Plasmodium falciparum erythrocyte binding antigen-175 (PfEBA-175) is a candidate antigen for a blood-stage malaria vaccine, while various polymorphisms and dimorphism have prevented to development of effective vaccines based on this gene. This study aimed to investigate the dimorphism of PfEBA-175 on both the Bioko Island and continent of Equatorial Guinea, as well as the genetic polymorphism and natural selection of global PfEBA-175. METHODS: The allelic dimorphism of PfEBA-175 region II of 297 bloods samples from Equatorial Guinea in 2018 and 2019 were investigated by nested polymerase chain reaction and sequencing. Polymorphic characteristics and the effect of natural selection were analyzed using MEGA 7.0, DnaSP 6.0 and PopART programs. Protein function prediction of new amino acid mutation sites was performed using PolyPhen-2 and Foldx program. RESULTS: Both Bioko Island and Bata district populations, the frequency of the F-fragment was higher than that of the C-fragment of PfEBA-175 gene. The PfEBA-175 of Bioko Island and Bata district isolates showed a high degree of genetic variability and heterogeneity, with π values of 0.00407 & 0.00411 and Hd values of 0.958 & 0.976 for nucleotide diversity, respectively. The values of Tajima's D of PfEBA-175 on Bata district and Bioko Island were 0.56395 and - 0.27018, respectively. Globally, PfEBA-175 isolates from Asia were more diverse than those from Africa and South America, and genetic differentiation quantified by the fixation index between Asian and South American countries populations was significant (FST > 0.15, P < 0.05). A total of 310 global isolates clustered in 92 haplotypes, and only one cluster contained isolates from three continents. The mutations A34T, K109E, D278Y, K301N, L305V and D329N were predicted as probably damaging. CONCLUSIONS: This study demonstrated that the dimorphism of F-fragment PfEBA-175 was remarkably predominant in the study area. The distribution patterns and genetic diversity of PfEBA-175 in Equatorial Guinea isolates were similar another region isolates. And the levels of recombination events suggested that natural selection and intragenic recombination might be the main drivers of genetic diversity in global PfEBA-175. These results have important reference value for the development of blood-stage malaria vaccine based on this antigen.


Assuntos
Antígenos de Protozoários/genética , Plasmodium falciparum/genética , Polimorfismo Genético , Proteínas de Protozoários/genética , Seleção Genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Guiné Equatorial , Humanos , Lactente , Malária Falciparum/parasitologia , Pessoa de Meia-Idade , Adulto Jovem
9.
Cancer Treat Res Commun ; 28: 100437, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34425470

RESUMO

PURPOSE: PAX5 haploinsufficiency promoting tumorigenesis is related to immune escape. But the mechanisms of PAX5 mutations inducing tumor immune escape have not been clarified. Our aim was to study how PAX5 haploinsufficiency influences effector CD8 + T cells in tumor microenvironment. METHODS: We estimated the proportions of 22 immune cell types and the expressions of immune inhibitory-related molecules based on gene expression profiles (GEPs) from children's B- acute lymphoblastic leukemia(B-ALL) with PAX5 mutations by CIBERSORT, an established algorithm. We constructed the PAX5 haplodeletion A20 cell lines, built allografted A20 tumor models and evaluated the effect of PAX5 haplodeletion on immune inhibitory-related molecules in the tumor microenvironment (TME). RESULTS: Our results indicated the percentages of T cells in bone marrow of children's B-ALL with PAX5 mutations were not statistically different from that in bone marrow of B-ALL without PAX5 mutations, except for T follicular helper (Tfh) cells. But a variety of up-regulated immune inhibitory-related molecules in bone marrow of children's B- ALL with PAX5 mutations were identified. By different approaches, we found that several immune inhibitory-related molecules of CD8+ T cells in TME of PAX5 haplodeletion clones such as TIM3, NR4A1 and BATF, were increased significantly compared with that of PAX5 wild type control. The IFN-ɤ of CD8+ T cells in TME of PAX5 haplodeletion tumors was decreased significantly compared with that of PAX5 wild type control. CONCLUSION: Our study showed that PAX5 haploinsufficiency induced CD8+ T cells dysfunction or exhaustion by high expression of TIM3, NR4A1 and BATF in the CD8+ T cells of TME.

10.
Science ; 373(6557): 912-918, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34413235

RESUMO

In human-made malleable materials, microdamage such as cracking usually limits material lifetime. Some biological composites, such as bone, have hierarchical microstructures that tolerate cracks but cannot withstand high elongation. We demonstrate a directionally solidified eutectic high-entropy alloy (EHEA) that successfully reconciles crack tolerance and high elongation. The solidified alloy has a hierarchically organized herringbone structure that enables bionic-inspired hierarchical crack buffering. This effect guides stable, persistent crystallographic nucleation and growth of multiple microcracks in abundant poor-deformability microstructures. Hierarchical buffering by adjacent dynamic strain-hardened features helps the cracks to avoid catastrophic growth and percolation. Our self-buffering herringbone material yields an ultrahigh uniform tensile elongation (~50%), three times that of conventional nonbuffering EHEAs, without sacrificing strength.

11.
Front Pediatr ; 9: 691146, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34422719

RESUMO

Left posterior fascicular ventricular tachycardia (LPFVT) is extremely rare in neonates. We described a 17-day-old girl with LPFVT who was initially misdiagnosed as supraventricular tachycardia (SVT). Eventually, she was successfully treated by amiodarone infusion followed by oral amiodarone with propranolol for 9 months, and LPFVT spontaneously resolved after a 1-year follow-up. This case report illustrated the basic principles and caveats in differential diagnosis of LPFVT in the neonatal age group. With proper diagnosis and therapy, neonatal LPFVT might regress in the first year of life.

12.
Autophagy ; : 1-17, 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34382907

RESUMO

Lipid accumulation often leads to lipotoxic injuries to hepatocytes, which can cause nonalcoholic steatohepatitis. The association of inflammation with lipid accumulation in liver tissue has been studied for decades; however, key mechanisms have been identified only recently. In particular, it is still unknown how hepatic inflammation regulates lipid metabolism in hepatocytes. Herein, we found that PA treatment or direct stimulation of STING1 promoted, whereas STING1 deficiency impaired, MTORC1 activation, suggesting that STING1 is involved in PA-induced MTORC1 activation. Mechanistic studies revealed that STING1 interacted with several components of the MTORC1 complex and played an important role in the complex formation of MTORC1 under PA treatment. The involvement of STING1 in MTORC1 activation was dependent on SQSTM1, a key regulator of the MTORC1 pathway. In SQSTM1-deficient cells, the interaction of STING1 with the components of MTORC1 was weak. Furthermore, the impaired activity of MTORC1 via rapamycin treatment or STING1 deficiency decreased the numbers of LDs in cells. PA treatment inhibited lipophagy, which was not observed in STING1-deficient cells or rapamycin-treated cells. Restoration of MTORC1 activity via treatment with amino acids blocked lipophagy and LDs degradation. Finally, increased MTORC1 activation concomitant with STING1 activation was observed in liver tissues of nonalcoholic fatty liver disease patients, which provided clinical evidence for the involvement of STING1 in MTORC1 activation. In summary, we identified a novel regulatory loop of STING1-MTORC1 and explain how hepatic inflammation regulates lipid accumulation. Our findings may facilitate the development of new strategies for clinical treatment of hepatic steatosis.Abbreviations: AA: amino acid; ACTB: actin beta; cGAMP: cyclic GMP-AMP; CGAS: cyclic GMP-AMP synthase; DEPTOR: DEP domain containing MTOR interacting protein; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; FFAs: free fatty acids; GFP: green fluorescent protein; HFD: high-fat diet; HT-DNA: herring testis DNA; IL1B: interleukin 1 beta; LAMP1: lysosomal associated membrane protein 1; LDs: lipid droplets; MAP1LC3: microtubule associated protein 1 light chain 3; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MEFs: mouse embryonic fibroblasts; MLST8: MTOR associated protein, LST8 homolog; MT-ND1: mitochondrially encoded NADH: ubiquinone oxidoreductase core subunit 1; mtDNA: mitochondrial DNA; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; NAFL: nonalcoholic fatty liver; NAFLD: nonalcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis; NPCs: non-parenchymal cells; PA: palmitic acid; PLIN2: perilipin 2; RD: regular diet; RELA: RELA proto-oncogene, NF-kB subunit; RPS6: ribosomal protein S6; RPS6KB1: ribosomal protein S6 kinase B1; RPTOR: regulatory associated protein of MTOR complex 1; RRAGA: Ras related GTP binding A; RRAGC: Ras related GTP binding C; SQSTM1: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TGs: triglycerides; TREX1: three prime repair exonuclease 1.

13.
Ann Palliat Med ; 10(7): 7706-7720, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34353059

RESUMO

BACKGROUND: Osteoarthritis (OA) is a chronic joint disease characterized by cartilage destruction and periarticular osteophyte formation. One therapeutic option for this condition, the Wutou Decoction (WTD) Chinese medicine formula, is satisfactory in its efficacy. Here, we used bioinformatic and molecular docking techniques to investigate the mechanism of action of WTD in the treatment of OA. METHODS: The active compounds (and their target proteins) of 5 Chinese herbs in WTD were obtained by searching the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. The action targets of WTD for OA were obtained by searching the Therapeutic Target Database and by mining the microarray data in the Gene Expression Omnibus. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed to identify key targets for OA treatment with the help of Database for Annotation, Visualization, and Integrated Discovery. Based on the Cytoscape software version 3.6.1, the visual networks of the "TCM drugs-Active Compounds-Targets-Diseases" and protein-protein interaction of the key targets of WTD for the treatment of OA were constructed. The core active compounds and the key targets obtained were molecularly docked and validated. RESULTS: Analyses revealed 140 active compounds in WTD, 123 of which had a total of 163 corresponding targets. In addition, 331 differentially expressed genes and 227 OA-related targets were obtained. The interaction networks among 32 key targets were identified. The biological processes of WTD in treating OA mainly involved regulation of inflammatory factors, transcription of genetic materials, cell cycle, angiogenesis, and endocrine regulation. The signaling pathways involved mainly included TNF signaling pathway, rheumatoid arthritis signaling pathway, cancer-related signals, vascular endothelial growth factor signaling pathway, and osteoclast differentiation signaling pathways. Molecular docking showed that 7 core compounds including quercetin and kaempferol had strong affinities with key target proteins for the WTD treatment of OA. CONCLUSIONS: WTD with multi-component can treats OA through multi-pathway. Its active compounds, including quercetin and kaempferol, can exert their therapeutic effects on OA by acting on TNF, PTGS2, MMP2, IL-6, IL-1ß, and other key targets to regulate inflammation, immunity, autophagy, and endocrine-related signaling pathways.


Assuntos
Medicamentos de Ervas Chinesas , Osteoartrite , Biologia Computacional , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Simulação de Acoplamento Molecular , Osteoartrite/tratamento farmacológico , Osteoartrite/genética , Fator A de Crescimento do Endotélio Vascular
14.
Neurol Sci ; 2021 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-34455500

RESUMO

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease. Evidence has shown that lipocalin-2 (LCN2) is involved in the pathological process of PD. We aimed to explore whether serum levels of LCN2 could be a biomarker of PD. METHODS: We recruited consecutive PD patients and healthy controls (HC) in our hospital from June 2020 to July 2020. Serum LCN2 levels were detected using the LCN2 enzyme-linked immunosorbent assay (ELISA) kit. The motor section of the Unified Parkinson's Disease Rating Scale (UPDRS III) and the Hoehn and Yahr Staging Scale (H&Y) were assessed on admission to evaluate disease severity in patients with PD. Cognitive status was measured by the Montreal Cognitive Assessment (MoCA). RESULTS: We finally recruited 75 patients, including 40 PD patients and 35 HC. Serum LCN2 levels were not significantly increased in PD patients compared with HC (4.9 [- 0.7 to 18.6] vs 1.9 [- 1.5 to 16.9] ng/mL, P = 0.33). Besides, there was no significant difference in LCN2 levels between patients at early and advanced stage of PD (P = 0.75), as well as between cognitively impaired PD patients, PD patients with normal cognition, and HC (P = 0.30). Moreover, LCN2 had no correlation with disease duration (r = - 0.1, P = 0.37), UPDRS III score (r = 0.07, P = 0.65), and MoCA score (r = 0.221, P = 0.17). CONCLUSIONS: Overall, our study suggests that serum LCN2 levels may not be a biomarker for PD.

15.
Gen Physiol Biophys ; 40(4): 289-305, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34350834

RESUMO

Atrial fibrillation (AF) is a common cardiac arrhythmia that induces serious complications. However, pharmacological treatments of AF remain challenging. This study aimed to screen crucial long non-coding RNAs (lncRNAs), microRNAs (miRNAs) and messenger RNA (mRNAs) for AF using the microarray datasets (lncRNAs and mRNAs: GSE79768, GSE115574; miRNAs: GSE68475) collected from the Gene Expression Omnibus database. Weighted correlation network analysis of GSE79768 and GSE115574 datasets identified five modules were highly related to AF status. Among 118 module-related differentially expressed mRNAs, FBXW7, EGFR, CXCR2, ROCK1 and UBE2D1 were considered as hub genes according to the gene significance, module membership and the topological characteristics for the nodes in the protein-protein interaction network. lncRNA MIR100HG and LINC01105 may function by co-expressing with (MIR100HG-ROCK1/FBXW7/UBE2D1, LINC01105-EGFR) mRNAs or sponging miRNAs to regulate mRNAs (LINC01105-miR-125a-3p-EGFR, MIR100HG-miR-200b-3p- FBXW7, MIR100HG-miR-561-3p-CXCR2, MIR100HG-miR-548z-UBE2D1). Connectivity Map and Comparative Toxicogenomics Database searches predicted dexamethasone may treat AF by reversing the expression of MIR100HG; artemisinin may reverse the expression of hub DEGs. In conclusion, our results may provide novel molecular mechanisms and potential therapeutic targets and drugs for AF.


Assuntos
Fibrilação Atrial , MicroRNAs , RNA Longo não Codificante , Fibrilação Atrial/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , MicroRNAs/genética , RNA Longo não Codificante/genética , Quinases Associadas a rho
16.
Nucleic Acids Res ; 49(14): 8277-8293, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34244781

RESUMO

Phosphorothioate (PS) modified antisense oligonucleotide (ASO) drugs can trigger RNase H1 cleavage of cellular target RNAs to modulate gene expression. Internalized PS-ASOs must be released from membraned endosomal organelles, a rate limiting step that is not well understood. Recently we found that M6PR transport between Golgi and late endosomes facilitates productive release of PS-ASOs, raising the possibility that Golgi-mediated transport may play important roles in PS-ASO activity. Here we further evaluated the involvement of Golgi in PS-ASO activity by examining additional Golgi proteins. Reduction of certain Golgi proteins, including Golgi-58K, GCC1 and TGN46, decreased PS-ASO activity, without substantial effects on Golgi integrity. Upon PS-ASO cellular uptake, Golgi-58K was recruited to late endosomes where it colocalized with PS-ASOs. Reduction of Golgi-58K caused slower PS-ASO release from late endosomes, decreased GCC2 late endosome relocalization, and led to slower retrograde transport of M6PR from late endosomes to trans-Golgi. Late endosome relocalization of Golgi-58K requires Hsc70, and is most likely mediated by PS-ASO-protein interactions. Together, these results suggest a novel function of Golgi-58K in mediating Golgi-endosome transport and indicate that the Golgi apparatus plays an important role in endosomal release of PS-ASO, ensuring antisense activity.


Assuntos
Complexo de Golgi/genética , Proteínas da Matriz do Complexo de Golgi/genética , Glicoproteínas de Membrana/genética , Receptor IGF Tipo 2/genética , Transporte Biológico/genética , Endocitose/genética , Endossomos/genética , Complexo de Golgi/efeitos dos fármacos , Células HeLa , Humanos , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Fosforotioatos/genética , Ribonuclease H/genética
17.
Front Microbiol ; 12: 691008, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220783

RESUMO

Dengue virus (DENV) infection can lead to a complex spectrum of clinical outcomes, ranging from asymptomatic infection to life-threatening severe dengue. The reasons for thus drastically varying manifestations of the disease remain an enigma. Herein, we reported an original discovery of the synergistic effect between preexisting Epstein-Barr virus (EBV) infection and DENV superinfection in vitro and of a strong correlation of these two viruses in the clinical samples from dengue patients. We showed that (I) DENV-2 infection of an EBV-positive cell line (EBV + Akata cell) reactivated EBV, and it could be blocked by wortmannin treatment. (II) Examination of human peripheral blood mononuclear cell (PBMC) samples from dengue patients revealed significantly elevated cell-associated EBV DNA copy number at the time of hospitalization vs. at the time of disease recovery in most individuals. (III) EBV infection promoted DENV propagation in both EBV-hosting B cells and indirectly in THP-1 cells, supported by the following evidence: (A) EBV + Akata cells were more permissive to DENV-2 infection compared with Akata cells harboring no EBV virus (EBV- Akata cells). (B) Low-molecular weight fraction secreted from EBV + Akata cells could enhance DENV-2 propagation in monocytic THP-1 cells. (C) While reactivation of EBV in EBV + Akata cells further increased DENV-2 yield from this cell line, pharmacological inhibition of EBV replication by acyclovir had the opposite effect. To our knowledge, this is the first investigation demonstrating a positive correlation between EBV and DENV in vitro and in human biospecimens.

18.
Front Pharmacol ; 12: 658362, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34194324

RESUMO

Background: Oxidative stress contributes to adverse atrial remodeling in diabetes mellitus. This remodeling can be prevented by the PPAR-γ agonist pioglitazone via its antioxidant and anti-inflammatory effects. In this study, we examined the molecular mechanisms underlying the protective effects of pioglitazone on atrial remodeling in a rabbit model of diabetes. Methods: Rabbits were randomly divided into control, diabetic, and pioglitazone-treated diabetic groups. Echocardiographic, hemodynamic, and electrophysiological parameters were measured. Serum PPAR-γ levels, serum and tissue oxidative stress and inflammatory markers, mitochondrial morphology, reactive oxygen species (ROS) production rate, respiratory function, and mitochondrial membrane potential (MMP) levels were measured. Protein expression of the pro-fibrotic marker TGF-ß1, the PPAR-γ coactivator-1α (PGC-1α), and the mitochondrial proteins (biogenesis-, fusion-, and fission-related proteins) was measured. HL-1 cells were transfected with PGC-1α small interfering RNA (siRNA) to determine the underlying mechanisms of pioglitazone improvement of mitochondrial function under oxidative stress. Results: The diabetic group demonstrated a larger left atrial diameter and fibrosis area than the controls, which were associated with a higher incidence of inducible atrial fibrillation (AF). The lower serum PPAR-γ level was associated with lower PGC-1α and higher NF-κB and TGF-ß1 expression. Lower mitochondrial biogenesis (PGC-1α, NRF1, and TFAM)-, fusion (Opa1 and Mfn1)-, and fission (Drp1)-related proteins were detected. Mitochondrial swelling, higher mitochondrial ROS, lower respiratory control rate, and lower MMP were observed. The pioglitazone group showed a reversal of structural remodeling and a lower incidence of inducible AF, which were associated with higher PPAR-γ and PGC-1α. The pioglitazone group had lower NF-κB and TGF-ß1 expression levels, whereas biogenesis-, fusion-, and fission-related protein expression was higher. Further, mitochondrial structure and function were improved. In HL-1 cells, PGC-1α siRNA transfection blunted the effect of pioglitazone on Mn-SOD protein expression and MMP collapse in H2O2-treated cells. Conclusion: Diabetes mellitus induces adverse atrial structural, electrophysiological remodeling, and mitochondrial damage and dysfunction. Pioglitazone prevented these abnormalities through the PPAR-γ/PGC-1α pathway.

19.
Aging (Albany NY) ; 13(14): 18376-18391, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34273143

RESUMO

BACKGROUND: We investigated association of a score incorporating relative grip strength (RGS) and timed up and go (TUG) test with incident type 2 diabetes mellitus (T2DM) in older Chinese. METHODS: Both RGS and TUG scores were classified into tertiles (0~2 points) and summed to yield RGS-TUG score, ranging from 0 to 4 points, with higher points indicating better physical function. Cox proportional hazards regression was used to analyze association of RGS-TUG score with incident T2DM. RESULTS: 3,892 participants without T2DM were followed up for an average of 3.6 years with 240 developing T2DM. After adjustment, those with the lowest RGS-TUG score, versus the highest, had higher fasting glucose, two-hour post-load glucose and glycosylated hemoglobin A1c, with ß (95% confidence interval (CI)) being 0.21 (0.08, 0.33), 1.06 (0.69, 1.43) and 0.16 (0.06, 0.27), respectively. In participants with BMI of ≥25 kg/m2, those with the lowest RGS-TUG score showed a higher risk of T2DM (adjusted hazard ratio 3.01, 95% CI 1.04-8.69). No association was found for BMI of 18.5~<25 kg/m2 (P for interaction < 0.05). CONCLUSIONS: This is the first study showing lower RGS-TUG score was associated with increased glycemia and incident T2DM in older people with overweight/obesity. The underlying mechanisms warrant further investigation.

20.
Diabetol Metab Syndr ; 13(1): 75, 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34238370

RESUMO

OBJECTIVES: Previous studies have analyzed the potential effect of KCNQ1 rs2237892 polymorphism on the predisposition to type 2 diabetes mellitus, but the findings are inconclusive and the subject of debate. The purpose of our study was to provide further insight into the potential association between KCNQ1 rs2237892 polymorphism and the risk of type 2 diabetes mellitus. METHODS: In total, 50 articles (60 studies) with 77,276 cases and 76,054 controls were utilized in our analysis. The pooled odds ratio (OR), 95% confidence interval (95% CI), and p value were used to evaluate the significance of our findings. Funnel plots and Beggar's regression tests were utilized to determine the presence of publication bias. RESULTS: Our meta-analysis results indicated that KCNQ1 rs2237892 polymorphism could be correlated with the risk of type 2 diabetes mellitus under the C allelic, recessive, and dominant genetic models (OR = 1.25, 95% 1.19-1.32, p < 0.001; OR = 1.50, 95% CI 1.34-1.68, p < 0.001; OR = 1.26, 95% CI 1.14-1.40, p < 0.001, respectively). Additionally, ethnicity analysis revealed that the source of control, case size, and Hardy-Weinberg Equilibrium status were correlated to the polymorphism in the three genetic models. CONCLUSIONS: Our meta-analysis demonstrated significant evidence to support the association between KCNQ1 rs2237892 polymorphism and predisposition to type 2 diabetes mellitus.

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