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1.
Comput Intell Neurosci ; 2021: 6503029, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34853585

RESUMO

Electric shovels are widely used in the mining industry to dig ore, and the teeth in shovels' bucket can be lost due to the tremendous pressure exerted by ore materials during operation. When the teeth fall off and enter the crusher with other ore materials, serious damages to crusher gears and other equipment happen, which causes millions of economic loss, because it is made of high-manganese steel. Thus, it is urgent to develop an efficient and automatic algorithm for detecting broken teeth. However, existing methods for detecting broken teeth have little effect and most research studies depended on sensor skills, which will be disturbed by closed cavity in shovel and not stable in practice. In this paper, we present an intelligent computer vision system for monitoring teeth condition and detecting missing teeth. Since the pixel-level algorithm is carried out, the amount of calculation should be reduced to improve the superiority of the algorithm. To release computational pressure of subsequent work, salient detection based on deep learning is proposed for extracting the key frame images from video flow taken by the camera installed on the shovel including the teeth we intend to analyze. Additionally, in order to more efficiently monitor teeth condition and detect missing teeth, semantic segmentation based on deep learning is processed to get the relative position of the teeth in the image. Once semantic segmentation is done, floating images containing the shape of teeth are obtained. Then, to detect missing teeth effectively, image registration is proposed. Finally, the result of image registration shows whether teeth are missing or not, and the system will immediately alert staff to check the shovel when teeth fall off. Through sufficient experiments, statistical result had demonstrated superiority of our presented model that serves more promising prospect in mining industry.

2.
Free Radic Biol Med ; 2021 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-34774698

RESUMO

Hepatocyte necroptosis is a core pathogenetic event during alcoholic liver disease. This study was aimed to explore the potential of tetramethylpyrazine (TMP), an active hepatoprotective ingredient extracted from Ligusticum Wallichii Franch, in limiting alcohol-triggered hepatocyte necroptosis and further specify the molecular mechanism. Results revealed that TMP reduced activation of receptor-interacting protein kinase 1 (RIPK1)/RIPK3 necrosome in ethanol-exposed hepatocytes and phosphorylation of mixed-lineage kinase domain-like protein (MLKL), which thereby diminished necroptosis and leakage of damage-associated molecular patterns. Suppression on mitochondrial translocation of p-MLKL by TMP contributed to recovery of mitochondrial function in ethanol-damaged hepatocytes. TMP also disrupted necroptotic signal loop by interrupting mitochondrial reactive oxygen species (ROS)-dependent positive feedback between p-MLKL and RIPK1/RIPK3 necrosome. Further, TMP promoted clearance of impaired mitochondria in ethanol-incubated hepatocytes via restoring PINK1/parkin-mediated mitophagy. Ubiquinol-cytochrome c reductase core protein 2 (UQCRC2) was downregulated in ethanol-exposed hepatocytes, which was restored after TMP treatment. In vitro UQCRC2 knockdown lowered the capacities of TMP in reducing mitochondrial ROS accumulation, relieving mitochondria damage, and enhancing PINK1/parkin-mediated mitophagy in ethanol-exposed hepatocytes. Analogously, systematic UQCRC2 knockdown interrupted the actions of TMP to trigger autophagic signal, repress necroptotic signal, and protect against alcoholic liver injury, inflammation, and ROS overproduction. In conclusion, this work concluded that TMP rescued UQCRC2 expression in ethanol-challenged hepatocytes, which contributed to necroptosis inhibition by facilitating PINK1/parkin-mediated mitophagy. These findings uncovered a potential molecular pharmacological mechanism underlying the hepatoprotective action of TMP and suggested TMP as a promising therapeutic candidate for alcoholic liver disease.

3.
Front Biosci (Landmark Ed) ; 26(10): 740-751, 2021 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-34719202

RESUMO

Objectives: To quantify the integrated levels of ACE2 and TMPRSS2, the two well-recognized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry-related genes, and to further identify key factors contributing to SARS-CoV-2 susceptibility in head and neck squamous cell carcinoma (HNSC). Methods: We developed a metric of the potential for tissue infected with SARS-CoV-2 ("TPSI") based on ACE2 and TMPRSS2 transcript levels and compared TPSI levels between tumor and matched normal tissues across 11 tumor types. For further analysis of HNSC, weighted gene co-expression network analysis (WGCNA), functional analysis, and single sample gene set enrichment analysis (ssGSEA) were conducted to investigate TPSI-relevant biological processes and their relationship with the immune landscape. TPSI-related factors were identified from clinical and mutational domains, followed by lasso regression to determine their relative effects on TPSI levels. Results: TPSI levels in tumors were generally lower than in the normal tissues. In HNSC, the genes highly associated with TPSI were enriched in viral entry-related processes, and TPSI levels were positively correlated with both eosinophils and T helper 17 (Th17) cell infiltration. Furthermore, the site of onset, human papillomaviruses (HPV) status, and nuclear receptor binding SET domain protein 1 (NSD1) mutations were identified as the most important factors shaping TPSI levels. Conclusions: This study identified the infection risk of SARS-CoV-2 between tumor and normal tissues, and provided evidence for the risk stratification of HNSC.


Assuntos
Enzima de Conversão de Angiotensina 2/genética , COVID-19/genética , Carcinoma de Células Escamosas/genética , Neoplasias de Cabeça e Pescoço/genética , Serina Endopeptidases/genética , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/metabolismo , COVID-19/virologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/virologia , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiologia , Serina Endopeptidases/metabolismo , Internalização do Vírus
4.
Opt Express ; 29(19): 30123-30139, 2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34614742

RESUMO

Linear Computed Laminography (LCL) is used to yield slice images of plate-like objects (PLO) for the advantage of short exposure time, high control precision and low cost. Shift and Add (SAA) is a widely used reconstruction algorithm for LCL. One limitation of SAA is that the reconstructed image of the in-focus layer (IFL) contains information from off-focus layers (OFL), resulting in inter-slice aliasing and blurring. In this paper, an Iterative Difference Deblurring (IDD) algorithm based on LCL is proposed to reduce the blur in reconstructed images. The core idea of the IDD algorithm is: contributions from OFL are subtracted from the projection data to remove the blur from the IFL. The corrected projections are then reconstructed using the SAA to remove the superimposed contributions of OFL from the IFL. An iterative approach is utilized to adjust a weighting factor applied during the subtraction stage. The results demonstrate that IDD algorithm can achieve PLO reconstruction in the LCL system under extremely sparse sampling conditions, and can effectively reduce the inter-slice aliasing and blurring.

5.
Toxicology ; 461: 152923, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34474091

RESUMO

Receptor-interacting protein kinase (RIPK) 3-dependent necroptosis plays a critical role in alcoholic liver disease. RIPK3 also facilitates steatosis, oxidative stress, and inflammation. Pterostilbene (PTS) has favorable hepatoprotective activities. The present study was aimed to reveal the therapeutic effects of PTS on ethanol-induced hepatocyte necroptosis and further illustrate possible molecular mechanisms. Human hepatocytes LO2 were incubated with 100 mM ethanol for 24 h to mimic alcoholic hepatocyte injury. Results showed that PTS at 20 µM reduced damage-associated molecular patterns (DAMPs) release, including IL-1α and high-mobility group box 1 (HMGB1), and blocked necroptotic signaling, evidenced by decreased RIPK1 and RIPK3 expression. Trypan blue staining visually showed that PTS reduced nonviable hepatocytes after ethanol exposure, which was counteracted by adenovirus-mediated ectopic overexpression of RIPK3 but not RIPK1. Besides, PTS inhibited ethanol-induced hepatocyte steatosis via restricting lipogenesis and enhancing lipolysis, decreased oxidative stress via rescuing mitochondrial membrane potential, reducing oxidative system, and enhancing antioxidant system, and relieved inflammation evidenced by decreased expression of proinflammatory factors. Notably, RIPK3 overexpression diminished these protective effects of PTS. Subsequent work indicated that PTS suppressed the expression and nuclear translocation of nuclear factor of activated T-cells 4 (NFATc4), an acetylated protein, in ethanol-exposed hepatocytes, while NFATc4 overexpression impaired the negative regulation of PTS on RIPK3 and DAMPs release. Further, PTS rescued sirtuin 2 (SIRT2) expression, and SIRT2 knockdown abrogated the inhibitory effects of PTS on nuclear translocation and acetylation status of NFATc4 in ethanol-incubated hepatocytes. In conclusion, PTS attenuated RIPK3-dependent hepatocyte necroptosis after ethanol exposure via SIRT2-mediated NFATc4 deacetylation.

6.
Hepatology ; 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34387904

RESUMO

BACKGROUND & AIMS: Peroxisome proliferator-activated receptor α (PPARα, NR1C1) is a ligand-activated nuclear receptor involved in the regulation of lipid catabolism and energy homeostasis. PPARα activation induces hepatomegaly and plays an important role in liver regeneration, but the underlying mechanisms remain unclear. APPROACH & RESULTS: In this study, the effect of PPARα activation on liver enlargement and regeneration was investigated in several strains of genetically-modified mice. PPARα activation by the specific agonist WY-14643 significantly induced hepatomegaly and accelerated liver regeneration after 70% partial hepatectomy (PHx) in wild-type mice and Pparafl/fl mice, while these effects were abolished in hepatocyte-specific Pparα-deficient (PparaΔHep ) mice. Moreover, PPARα activation promoted hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. Mechanistically, PPARα activation regulated expression of yes-associated protein (YAP) and its downstream targets (CTGF, CYR61 and ANKRD1) as well as proliferation-related proteins (CCNA1, CCND1 and CCNE1). Binding of YAP with the PPARα E domain was critical for the interaction between YAP and PPARα. PPARα activation further induced nuclear translocation of YAP. Disruption of the YAP-transcriptional enhancer factor domain family member (TEAD) association significantly suppressed PPARα-induced hepatomegaly, and hepatocyte enlargement and proliferation. In addition, PPARα failed to induce hepatomegaly in AAV-Yap shRNA-treated mice and liver-specific Yap-deficient (YapΔHep ) mice. Blockade of YAP signaling abolished PPARα-induced hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. CONCLUSIONS: This study revealed a novel function of PPARα in regulating liver size and liver regeneration via activation of the YAP-TEAD signaling pathway. These findings have implications for understanding the physiological functions of PPARα and suggest its potential for manipulation of liver size and liver regeneration.

7.
Cell Biol Toxicol ; 2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34405320

RESUMO

Hepatocyte senescence is a key event participating in the progression of alcoholic liver disease. Autophagy is a critical biological process that controls cell fates by affecting cell behaviors like senescence. Pterostilbene is a natural compound with hepatoprotective potential; however, its implication for alcoholic liver disease was not understood. This study was aimed to investigate the therapeutic effect of pterostilbene on alcoholic liver disease and elucidate the potential mechanism. Our results showed that pterostilbene alleviated ethanol-triggered hepatocyte damage and senescence. Intriguingly, pterostilbene decreased the protein abundance of cellular communication network factor 1 (CCN1) in ethanol-exposed hepatocytes, which was essential for pterostilbene to execute its anti-senescent function. In vivo studies verified the anti-senescent effect of pterostilbene on hepatocytes of alcohol-intoxicated mice. Pterostilbene also relieved senescence-associated secretory phenotype (SASP), redox imbalance, and steatosis by suppressing hepatic CCN1 expression. Mechanistically, pterostilbene-forced CCN1 reduction was dependent on posttranscriptional regulation via autophagy machinery but not transcriptional regulation. To be specific, pterostilbene restored autophagic flux in damaged hepatocytes and activated p62-mediated selective autophagy to recognize and lead CCN1 to autolysosomes for degradation. The protein abundance of Sestrin2 (SESN2), a core upstream modulator of autophagy pathway, was decreased in ethanol-administrated hepatocytes but rescued by co-treatment with pterostilbene. Induction of SESN2 protein by pterostilbene rescued ethanol-triggered autophagic dysfunction in hepatocytes, which then reduced senescence-associated markers, postponed hepatocyte senescence, and relieved alcohol-caused liver injury and inflammation. In conclusion, this work discovered a novel compound pterostilbene with therapeutic implications for alcoholic liver disease and uncover its underlying mechanism.

8.
Acta Pharmacol Sin ; 2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34253877

RESUMO

Vacuolar protein sorting 33B (VPS33B) is important for intracellular vesicular trafficking process and protein interactions, which is closely associated with the arthrogryposis, renal dysfunction, and cholestasis syndrome. Our previous study has shown a crucial role of Vps33b in regulating metabolisms of bile acids and lipids in hepatic Vps33b deficiency mice with normal chow, but it remains unknown whether VPS33B could contribute to cholestatic liver injury. In this study we investigated the effects of hepatic Vps33b deficiency on bile acid metabolism and liver function in intrahepatic cholestatic mice. Cholestasis was induced in Vps33b hepatic knockout and wild-type male mice by feeding 1% CA chow diet for 5 consecutive days. We showed that compared with the wild-type mice, hepatic Vps33b deficiency greatly exacerbated CA-induced cholestatic liver injury as shown in markedly increased serum ALT, AST, and ALP activities, serum levels of total bilirubin, and total bile acid, as well as severe hepatocytes necrosis and inflammatory infiltration. Target metabolomics analysis revealed that hepatic Vps33b deficiency caused abnormal profiles of bile acids in cholestasis mice, evidenced by the upregulation of conjugated bile acids in serum, liver, and bile. We further demonstrated that the metabolomics alternation was accompanied by gene expression changes in bile acid metabolizing enzymes and transporters including Cyp3a11, Ugt1a1, Ntcp, Oatp1b1, Bsep, and Mrp2. Overall, these results suggest a crucial role of hepatic Vps33b deficiency in exacerbating cholestasis and liver injury, which is associated with the altered metabolism of bile acids.

9.
J Hazard Mater ; 419: 126205, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34216964

RESUMO

The control of degrader populations and the stochasticity and certainty of the microbial community in contaminated groundwater are not well-understood. In this study, a long-term contaminated groundwater ecosystem was selected to investigate the impact of BTEX on microbial communities and how microbial communities respond to BTEX pollution. 16S rRNA gene sequencing and metagenomic sequencing provided insights on microbial community assemblage patterns and their role in BTEX cleaning. The operational taxonomy units (OTUs) in the contaminated groundwater ecosystem were clustered distinguishably between the Plume and the Deeper Zone (lower contaminated zone). ßNTI analysis revealed that the assembly strategies of abundant and rare OTU subcommunities preferred deterministic processes. Redundancy Analysis (RDA) and mantel testing indicated that benzene, toluene, ethylbenzene, and xylenes (BTEX) strongly drove the abundant OTU subcommunity, while the rare OTU subcommunity was only weakly affected. Deltaproteobacteria, the most dominant degrading microorganism, contains the complete degradation genes in the plume layer. In summary, our finding revealed that BTEX was the major factor in shaping the microbial community structure, and functional bacteria contribute greatly to water cleaning. Investigating the pattern of microbial community assembly will provide insights into the ecological controls of contaminant degradation in groundwater.


Assuntos
Água Subterrânea , Poluentes Químicos da Água , Bactérias/genética , Benzeno , Derivados de Benzeno , Biodegradação Ambiental , Ecossistema , RNA Ribossômico 16S/genética , Tolueno , Xilenos
10.
Appl Opt ; 60(16): 4778-4786, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34143042

RESUMO

An inelastic hyperspectral Scheimpflug lidar system was developed for microalgae classification and quantification. The correction for the refraction at the air-glass-water interface was established, making our system suitable for aquatic environments. The fluorescence spectrum of microalgae was extracted by principal component analysis, and seven species of microalgae from different phyla have been classified. It was verified that when the cell density of Phaeocystis globosa was in the range of ${{1}}{{{0}}^4}\sim{{1}}{{{0}}^6}\;{\rm{cell}}\;{\rm{m}}{{\rm{L}}^{- 1}}$, the cell density had a linear relationship with the fluorescence intensity. The experimental results show our system can identify and quantify microalgae, with application prospects for microalgae monitoring in the field environment and early warning of red tides or algal blooms.

11.
Toxicol Lett ; 350: 10-21, 2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34192554

RESUMO

BACKGROUND: Hepatocyte senescence is a core event that mediates the occurrence and development of alcoholic liver disease. Nuclear factor of activated T-cells 4 (NFATc4) is a key driver of nonalcoholic steatohepatitis. However, little was known about the implication of NFATc4 for alcoholic liver disease. This study was aimed to investigate the role of NFATc4 in hepatocyte senescence and further elucidate the underlying mechanism. METHODS: Real-time PCR, Western blot, immunofluorescence staining, and enzyme-linked immunosorbent assay were performed to explore the role of NFATc4 in hepatocyte senescence. RESULTS: NFATc4 was induced in ethanol-incubated hepatocytes. NFATc4 knockdown recovered cell viability and reduced the release of aspartate transaminase, alanine transaminase, and lactic dehydrogenase from ethanol-incubated hepatocytes. NFATc4 knockdown protected mice from alcoholic liver injury and inflammation. NFATc4 knockdown counteracted ethanol-induced hepatocyte senescence, evidenced by decreased senescence-associated ß-galactosidase positivity and reduced p16, p21, HMGA1, and γH2AX, which was validated in in vivo studies. Peroxisome proliferator-activated receptor (PPAR)γ was inhibited by NFATc4 in ethanol-treated hepatocytes. PPARγ deficiency abrogated the inhibitory effects of NFATc4 knockdown on hepatocyte senescence, oxidative stress, and hepatic steatosis in mice with alcoholic liver disease. CONCLUSIONS: This work discovered that ethanol enhanced NFATc4 expression, which further triggered hepatocyte senescence via repression of PPARγ.


Assuntos
Senescência Celular/efeitos dos fármacos , Etanol/efeitos adversos , Etanol/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatopatias Alcoólicas/tratamento farmacológico , Hepatopatias Alcoólicas/fisiopatologia , Fatores de Transcrição NFATC/metabolismo , Fatores de Transcrição NFATC/farmacologia , Animais , Células Cultivadas/efeitos dos fármacos , Humanos , Hepatopatias Alcoólicas/metabolismo , Camundongos , Modelos Animais
12.
Sci Total Environ ; 781: 146506, 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-33794455

RESUMO

Microbial community assembly mechanisms are pivotal for understanding the ecological functions of microorganisms in biogeochemical cycling in Earth's ecosystems, yet rarely investigated in the context of deep terrestrial ecology. Here, the microbial communities in the production waters collected from water injection wells and oil production wells across eight oil reservoirs throughout northern China were determined and analyzed by proportional distribution analysis and null model analysis. A 'core' microbiota consisting of three bacterial genera, including Arcobacter, Pseudomonas and Acinetobacter, and eight archaeal genera, including Archaeoglobus, Methanobacterium, Methanothermobacter, unclassified Methanobacteriaceae, Methanomethylovorans, Methanoculleus, Methanosaeta and Methanolinea, was found to be present in all production water samples. Canonical correlation analysis reflected that the core archaea were significantly influenced by temperature and reservoir depth, while the core bacteria were affected by the combined impact of the core archaea and environmental factors. Thermodynamic calculations indicate that bioenergetic constraints are the driving force that governs the enrichment of two core archaeal guilds, aceticlastic methanogens versus hydrogenotrophic methanogens, in low- and high-temperature oil reservoirs, respectively. Collectively, our study indicates that microbial community structures in wells of oil reservoirs are structured by the thermodynamic window of opportunity, through which the core archaeal communities are accommodated directly followed by the deterministic recruiting of core bacterial genera, and then the stochastic selection of some other microbial members from local environments. Our study enhances the understanding of the microbial assembly mechanism in deep terrestrial habitats. Meanwhile, our findings will support the development of functional microbiota used for bioremediation and bioaugmentation in microbial enhanced oil recovery.


Assuntos
Archaea , Campos de Petróleo e Gás , Archaea/genética , Bactérias/genética , China , Filogenia , RNA Ribossômico 16S/genética
13.
Acta Pharm Sin B ; 11(3): 727-737, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33777678

RESUMO

The constitutive androstane receptor (CAR, NR3I1) belongs to nuclear receptor superfamily. It was reported that CAR agonist TCPOBOP induces hepatomegaly but the underlying mechanism remains largely unknown. Yes-associated protein (YAP) is a potent regulator of organ size. The aim of this study is to explore the role of YAP in CAR activation-induced hepatomegaly and liver regeneration. TCPOBOP-induced CAR activation on hepatomegaly and liver regeneration was evaluated in wild-type (WT) mice, liver-specific YAP-deficient mice, and partial hepatectomy (PHx) mice. The results demonstrate that TCPOBOP can increase the liver-to-body weight ratio in wild-type mice and PHx mice. Hepatocytes enlargement around central vein (CV) area was observed, meanwhile hepatocytes proliferation was promoted as evidenced by the increased number of KI67+ cells around portal vein (PV) area. The protein levels of YAP and its downstream targets were upregulated in TCPOBOP-treated mice and YAP translocation can be induced by CAR activation. Co-immunoprecipitation results suggested a potential protein-protein interaction of CAR and YAP. However, CAR activation-induced hepatomegaly can still be observed in liver-specific YAP-deficient (Yap -/-) mice. In summary, CAR activation promotes hepatomegaly and liver regeneration partially by inducing YAP translocation and interaction with YAP signaling pathway, which provides new insights to further understand the physiological functions of CAR.

14.
Acta Pharmacol Sin ; 2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33782543

RESUMO

Mifepristone (Mif), an effective synthetic steroidal antiprogesterone drug, is widely used for medical abortion and pregnancy prevention. Due to its anti-glucocorticoid effect, high-dose Mif is also used to treat Cushing's syndrome. Mif was reported to active pregnane X receptor (PXR) in vitro and PXR can induce hepatomegaly via activation and interaction with yes-associated protein (YAP) pathway. High-dose Mif was reported to induce hepatomegaly in rats and mice, but the underlying mechanism remains unclear. Here, the role of PXR was studied in Mif-induced hepatomegaly in C57BL/6 mice and Pxr-knockout mice. The results demonstrated that high-dose Mif (100 mg · kg-1 · d-1, i.p.) treatment for 5 days significantly induced hepatomegaly with enlarged hepatocytes and promoted proliferation, but low dose of Mif (5 mg · kg-1 · d-1, i.p.) cannot induce hepatomegaly. The dual-luciferase reporter gene assays showed that Mif can activate human PXR in a concentration-dependent manner. In addition, Mif could promote nuclear translocation of PXR and YAP, and significantly induced the expression of PXR, YAP, and their target proteins such as CYP3A11, CYP2B10, UGT1A1, ANKRD, and CTGF. However, Mif (100 mg · kg-1 · d-1, i.p.) failed to induce hepatomegaly in Pxr-knockout mice, as well as hepatocyte enlargement and proliferation, further indicating that Mif-induced hepatomegaly is PXR-dependent. In summary, this study demonstrated that PXR-mediated Mif-induced hepatomegaly in mice probably via activation of YAP pathway. This study provides new insights in Mif-induced hepatomegaly, and provides novel evidence on the crucial function of PXR in liver enlargement and regeneration.

15.
Phytomedicine ; 84: 153520, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33662920

RESUMO

BACKGROUND: Schisandrol B (SolB) is one of the bioactive components from a traditional Chinese medicine Schisandra chinensis or Schisandra sphenanthera. It has been demonstrated that SolB exerts hepatoprotective effects against drug-induced liver injury and promotes liver regeneration. It was found that SolB can induce hepatomegaly but the involved mechanisms remain unknown. PURPOSE: This study aimed to explore the mechanisms involved in SolB-induced hepatomegaly. METHODS: Male C57BL/6 mice were injected intraperitoneally with SolB (100 mg/kg) for 5 days. Serum and liver samples were collected for biochemical and histological analyses. The mechanisms of SolB were investigated by qRT-PCR and western blot analyses, luciferase reporter gene assays and immunofluorescence. RESULTS: SolB significantly increased hepatocyte size and proliferation, and then promoted liver enlargement without liver injury and inflammation. SolB transactivated human PXR, activated PXR in mice and upregulated hepatic expression of its downstream proteins, such as CYP3A11, CYP2B10 and UGT1A1. SolB also significantly enhanced nuclear translocation of PXR and YAP in human cell lines. YAP signal pathway was activated by SolB in mice. CONCLUSION: These findings demonstrated that SolB can significantly induce liver enlargement, which is associated with the activation of PXR and YAP pathways.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Ciclo-Octanos/toxicidade , Dioxóis/toxicidade , Hepatomegalia/induzido quimicamente , Lignanas/toxicidade , Receptor de Pregnano X/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proliferação de Células/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Medicamentos de Ervas Chinesas/efeitos adversos , Medicamentos de Ervas Chinesas/química , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Hepatomegalia/metabolismo , Hepatomegalia/patologia , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Receptor de Pregnano X/genética , Schisandra/química , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/genética
16.
mSystems ; 6(1)2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33594004

RESUMO

Ammonia tolerance is a universal characteristic among the ammonia-oxidizing bacteria (AOB); in contrast, the known species of ammonia-oxidizing archaea (AOA) have been regarded as ammonia sensitive, until the identification of the genus "Candidatus Nitrosocosmicus." However, the mechanism of its ammonia tolerance has not been reported. In this study, the AOA species "Candidatus Nitrosocosmicus agrestis," obtained from agricultural soil, was determined to be able to tolerate high concentrations of NH3 (>1,500 µM). In the genome of this strain, which was recovered from metagenomic data, a full set of genes for the pathways of polysaccharide metabolism, urea hydrolysis, arginine synthesis, and polyamine synthesis was identified. Among them, the genes encoding cytoplasmic carbonic anhydrase (CA) and a potential polyamine transporter (drug/metabolite exporter [DME]) were found to be unique to the genus "Ca. Nitrosocosmicus." When "Ca. Nitrosocosmicus agrestis" was grown with high levels of ammonia, the genes that participate in CO2/HCO3 - conversion, glutamate/glutamine syntheses, arginine synthesis, polyamine synthesis, and polyamine excretion were significantly upregulated, and the polyamines, including putrescine and spermidine, had significant levels of production. Based on genome analysis, gene expression quantification, and polyamine determination, we propose that the production and excretion of polyamines is probably one of the reasons for the ammonia tolerance of "Ca. Nitrosocosmicus agrestis," and even of the genus "Ca. Nitrosocosmicus."IMPORTANCE Ammonia tolerance of AOA is usually much lower than that of the AOB, which makes the AOB rather than AOA a predominant ammonia oxidizer in agricultural soils, contributing to global N2O emission. Recently, some AOA species from the genus "Ca. Nitrosocosmicus" were also found to have high ammonia tolerance. However, the reported mechanism for the ammonia tolerance is very rare and indeterminate for AOB and for AOA species. In this study, an ammonia-tolerant AOA strain of the species "Ca. Nitrosocosmicus agrestis" was identified and its potential mechanisms for ammonia tolerance were explored. This study will be of benefit for determining more of the ecological role of AOA in agricultural soils or other environments.

17.
Acta Pharm Sin B ; 11(1): 89-99, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33532182

RESUMO

Acetaminophen (APAP) overdose is the leading cause of drug-induced liver injury, and its prognosis depends on the balance between hepatocyte death and regeneration. Sirtuin 6 (SIRT6) has been reported to protect against oxidative stress-associated DNA damage. But whether SIRT6 regulates APAP-induced hepatotoxicity remains unclear. In this study, the protein expression of nuclear and total SIRT6 was up-regulated in mice liver at 6 and 48 h following APAP treatment, respectively. Sirt6 knockdown in AML12 cells aggravated APAP-induced hepatocyte death and oxidative stress, inhibited cell viability and proliferation, and downregulated CCNA1, CCND1 and CKD4 protein levels. Sirt6 knockdown significantly prevented APAP-induced NRF2 activation, reduced the transcriptional activities of GSTµ and NQO1 and the mRNA levels of Nrf2, Ho-1, Gstα and Gstµ. Furthermore, SIRT6 showed potential protein interaction with NRF2 as evidenced by co-immunoprecipitation (Co-IP) assay. Additionally, the protective effect of P53 against APAP-induced hepatocytes injury was Sirt6-dependent. The Sirt6 mRNA was significantly down-regulated in P53 -/- mice. P53 activated the transcriptional activity of SIRT6 and exerted interaction with SIRT6. Our results demonstrate that SIRT6 protects against APAP hepatotoxicity through alleviating oxidative stress and promoting hepatocyte proliferation, and provide new insights in the function of SIRT6 as a crucial docking molecule linking P53 and NRF2.

18.
J Pharm Biomed Anal ; 195: 113851, 2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33387840

RESUMO

Pregnane X receptor (PXR) is highly expressed in the liver and plays an integral role in the control of xenobiotic and endobiotic metabolism to maintain homeostasis. We previously reported that activation of PXR significantly induced liver enlargement. But the lipid profiling during PXR-induced hepatomegaly remains unclear. This study aimed to characterize the effect of PXR activation on hepatic lipid homeostasis by lipidomics analysis. Mice were intraperitoneally administered with the typical mPXR agonist, pregnenolone 16α-carbonitrile (PCN, 100 mg/kg/d), for 5 days. Liver and serum were collected for further analysis. The results confirmed that PXR activation can significantly induce liver enlargement. An obvious hepatic lipid accumulation was observed in PCN-treated mice, as determined by H&E and Oil Red O staining. Ultra-high performance liquid chromatography-Q Exactive Orbitrap high-resolution mass spectrometer (UHPLC-Q Exactive Orbitrap HRMS)-based lipidomics was performed to characterize the change in lipid species. A total of 20 potential lipid biomarkers were significantly perturbed. The most significant change was found in the triacylglycerol (TG), which constituted with the lower number of carbon atoms and double bonds. Moreover, the mRNA expression levels showed that PCN-induced PXR activation significantly regulated the expression of genes involved in the uptake, synthesis and metabolism of TG, which was consistent with increased TG levels. Collectively, these findings demonstrated that lipids such as TG were significantly accumulated during PXR-induced hepatomegaly.


Assuntos
Lipidômica , Receptores Citoplasmáticos e Nucleares , Animais , Glicosídeos , Hepatomegalia/induzido quimicamente , Hepatomegalia/genética , Fígado , Camundongos , Receptor de Pregnano X/genética , Pregnanos , Triglicerídeos
20.
J Cancer Res Clin Oncol ; 147(2): 499-505, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33225417

RESUMO

PURPOSE: There is not much progress in the treatment for lung squamous cell carcinoma LSCC in the past few years. Rapamycin Rapa, an inhibitor of mammalian target of rapamycin mTOR, has exhibited antitumor efficacy in a variety of malignant tumors. It has recently been reported that Rapamycin can induce autophagy signaling pathway in lung cancer and Glypican-3GPC3 can promote the growth of hepatocellular carcinoma by stimulating canonical Wnt signaling pathway. The aim of this study is to investigate the mechanisms of rapamycin's antitumor efficacy in relation to GPC3/Wnt/ß-catenin pathway and autophagy in LSCC. METHODS: SK-MES-1 cells, a LSCC cell line, were treated with various concentrations of rapamycin with or without Glypican-3 GPC3-targeting siRNA. SK-MES-1 cell proliferation was determined by MTT assay. Protein expression levels of GPC3, ß-catenin, Beclin-1 were checked via western blotting. We established the xenograft mice model to investigate the suppression effect of rapamycin on LSCC. In addition, we further testified the metabolism protein of autophagy process using the xenograft tumor tissue. RESULTS: Rapamycin could inhibit the SK-MES-1 cell proliferation in a concentration-dependent manner both in vitro and in vivo by decreasing the GPC3 expression and downregulating the glypican-3/Wnt/ß-catenin signaling pathway. In addition, we found that GPC3 silencing can activate the glypican-3/Wnt/ß-catenin pathway and autophagy, which contribute to the suppression of tumor growth both in vitro and in vivo. CONCLUSION: Rapamycin suppresses the growth of lung cancer through down-regulating glypican-3/Wnt/ß-catenin signaling, which mediates with activation of autophagy. This study suggests GPC3 is a new promising target for rapamycin in the treatment of lung cancer.


Assuntos
Autofagia/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Glipicanas/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Sirolimo/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo , Feminino , Glipicanas/fisiologia , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/fisiologia , Via de Sinalização Wnt/fisiologia , beta Catenina/fisiologia
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