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Alcoholic liver injury (ALI) stands as a prevalent affliction within the spectrum of complex liver diseases. Prolonged and excessive alcohol consumption can pave the way for liver fibrosis, cirrhosis, and even hepatocellular carcinoma. Recent findings have unveiled the protective role of proline serine-threonine phosphatase interacting protein 2 (PSTPIP2) in combating liver ailments. However, the role of PSTPIP2 in ALI remains mostly unknown. This study aimed to determine the expression profile of PSTPIP2 in ALI and to uncover the mechanism through which PSTPIP2 affects the survival and apoptosis of hepatocytes in ALI, using both ethyl alcohol (EtOH)-fed mice and an EtOH-induced AML-12 cell model. We observed a consistent decrease in PSTPIP2 expression both in vivo and in vitro. Functionally, we assessed the impact of PSTPIP2 overexpression on ALI by administering adeno-associated virus 9 (AAV9)-PSTPIP2 into mice. The results demonstrated that augmenting PSTPIP2 expression significantly shielded against liver parenchymal distortion and curbed caspase-dependent hepatocyte apoptosis in EtOH-induced ALI mice. Furthermore, enforcing PSTPIP2 expression reduced hepatocyte apoptosis in a stable PSTPIP2-overexpressing AML-12 cell line established through lentivirus-PSTPIP2 transfection in vitro. Mechanistically, this study also identified signal transducer and activator of transcription 3 (STAT3) as a direct signaling pathway regulated by PSTPIP2 in ALI. In conclusion, our findings provide compelling evidence that PSTPIP2 has a regulatory role in hepatocyte apoptosis via the STAT3 pathway in ALI, suggesting PSTPIP2 as a promising therapeutic target for ALI.
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Apoptose , Fator de Transcrição STAT3 , Animais , Masculino , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Apoptose/efeitos dos fármacos , Linhagem Celular , Etanol/toxicidade , Etanol/administração & dosagem , Hepatócitos/metabolismo , Hepatócitos/patologia , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/patologia , Hepatopatias Alcoólicas/prevenção & controle , Camundongos Endogâmicos C57BL , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genéticaRESUMO
A Gram-stain positive, aerobic, alkalitolerant and halotolerant bacterium, designated HH7-29 T, was isolated from the confluence of the Fenhe River and the Yellow River in Shanxi Province, PR China. Growth occurred at pH 6.0-12.0 (optimum, pH 8.0-8.5) and 15-40â (optimum, 32â) with 0.5-24% NaCl (optimum, 2-9%). The predominant fatty acids (> 10.0%) were iso-C15:0 and anteiso-C15:0. The major menaquinones were MK-7 and MK-8. The polar lipids were phosphatidylglycerol, diphosphatidylglycerol and two unidentified phospholipids. Phylogenetic analyses based on the 16S rRNA gene sequence revealed that strain HH7-29 T was a member of the genus Jeotgalibacillus, exhibiting high sequence similarity to the 16S rRNA gene sequences of Jeotgalibacillus alkaliphilus JC303T (98.4%), Jeotgalibacillus salarius ASL-1 T (98.1%) and Jeotgalibacillus alimentarius YKJ-13 T (98.1%). The genomic DNA G + C content was 43.0%. Gene annotation showed that strain HH7-29 T had lower protein isoelectric points (pIs) and possessed genes related to ion transport and organic osmoprotectant uptake, implying its potential tolerance to salt and alkali. The average nucleotide identity, digital DNA-DNA hybridization values, amino acid identity values, and percentage of conserved proteins values between strain HH7-29 T and its related species were 71.1-83.8%, 19.5-27.4%, 66.5-88.4% and 59.8-76.6%, respectively. Based on the analyses of phenotypic, chemotaxonomic, phylogenetic and genomic features, strain HH7-29 T represents a novel species of the genus Jeotgalibacillus, for which the name Jeotgalibacillus haloalkalitolerans sp. nov. is proposed. The type strain is HH7-29 T (= KCTC 43417 T = MCCC 1K07541T).
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Composição de Bases , DNA Bacteriano , Ácidos Graxos , Filogenia , RNA Ribossômico 16S , Rios , RNA Ribossômico 16S/genética , China , Rios/microbiologia , DNA Bacteriano/genética , Ácidos Graxos/análise , Cloreto de Sódio/metabolismo , Técnicas de Tipagem Bacteriana , Fosfolipídeos/análise , Análise de Sequência de DNA , Hibridização de Ácido NucleicoRESUMO
BACKGROUND: Models for predicting hepatitis B e antigen (HBeAg) seroconversion in patients with HBeAg-positive chronic hepatitis B (CHB) after nucleos(t)ide analog treatment are rare. AIM: To establish a simple scoring model based on a response-guided therapy (RGT) strategy for predicting HBeAg seroconversion and hepatitis B surface antigen (HBsAg) clearance. METHODS: In this study, 75 previously treated patients with HBeAg-positive CHB underwent a 52-week peginterferon-alfa (PEG-IFNα) treatment and a 24-wk follow-up. Logistic regression analysis was used to assess parameters at baseline, week 12, and week 24 to predict HBeAg seroconversion at 24 wk post-treatment. The two best predictors at each time point were used to establish a prediction model for PEG-IFNα therapy efficacy. Parameters at each time point that met the corresponding optimal cutoff thresholds were scored as 1 or 0. RESULTS: The two most meaningful predictors were HBsAg ≤ 1000 IU/mL and HBeAg ≤ 3 S/CO at baseline, HBsAg ≤ 600 IU/mL and HBeAg ≤ 3 S/CO at week 12, and HBsAg ≤ 300 IU/mL and HBeAg ≤ 2 S/CO at week 24. With a total score of 0 vs 2 at baseline, week 12, and week 24, the response rates were 23.8%, 15.2%, and 11.1% vs 81.8%, 80.0%, and 82.4%, respectively, and the HBsAg clearance rates were 2.4%, 3.0%, and 0.0%, vs 54.5%, 40.0%, and 41.2%, respectively. CONCLUSION: We successfully established a predictive model and diagnosis-treatment process using the RGT strategy to predict HBeAg and HBsAg seroconversion in patients with HBeAg-positive CHB undergoing PEG-IFNα therapy.
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A Gram-stain-negative, aerobic, rod-shaped and halotolerant bacterium, designated as strain ASW11-75T, was isolated from intertidal sediments in Qingdao, PR China, and identified using a polyphasic taxonomic approach. Growth of strain ASW11-75T occurred at 10-45â°C (optimum, 37â°C), pH 6.5-9.0 (optimum, pH 8.0) and 0.5-18.0â% NaCl concentrations (optimum, 2.5â%). Phylogenetic analyses based on 16S rRNA gene sequences and 1179 single-copy orthologous clusters indicated that strain ASW11-75T is affiliated with the genus Marinobacter. Strain ASW11-75T showed highest 16S rRNA gene sequence similarity to 'Marinobacter arenosus' CAU 1620T (98.5â%). The digital DNA-DNA hybridization and average nucleotide identity values between strain ASW11-75T and its closely related strains (Marinobacter salarius R9SW1T, Marinobacter similis A3d10T, 'Marinobacter arenosus' CAU 1620T, Marinobacter sediminum R65T, Marinobacter salinus Hb8T, Marinobacter alexandrii LZ-8T and Marinobacter nauticus ATCC 49840T) were 19.8-24.5â% and 76.6-80.7â%, respectively. The predominant cellular fatty acids were C16â:â0, C18â:â1 ω9c and C16â:â0 N alcohol. The polar lipids were phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, one unidentified aminophospholipid and two unidentified lipids. The major isoprenoid quinone was ubiquinone-9. The genomic DNA G+C content was 62.2âmol%. Based on genomic and gene function analysis, strain ASW11-75T had lower protein isoelectric points with higher ratios of acidic residues to basic residues and possessed genes related to ion transport and organic osmoprotectant uptake, implying its potential tolerance to salt. The results of polyphasic characterization indicated strain ASW11-75T represents a novel Marinobacter species, for which the name Marinobacter qingdaonensis sp. nov. with the type strain ASW11-75T is proposed. The type strain is ASW11-75T (=KCTC 82497T=MCCC 1K05587T).
Assuntos
Ácidos Graxos , Marinobacter , Ácidos Graxos/química , Fosfolipídeos/química , Água do Mar/microbiologia , Filogenia , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Composição de Bases , DNA Bacteriano/genética , Técnicas de Tipagem BacterianaRESUMO
A novel Gram-stain-negative, strictly aerobic and bioflocculant-producing bacterium, designated as ASW11-36T, was isolated from an intertidal sand collected from coastal areas of Qingdao, PR China. Growth occurred at 15-40 °C (optimum, 30 °C), pH 7.0-9.0 (optimum, pH 7.5) and with 1.5-7.0% (w/v) NaCl (optimum, 2.5-3.0%). In the whole-cell fatty acid pattern prevailed C16:0 and summed feature 3 (C16:1 ω7c and/or C16:1 ω6c). The major isoprenoid quinone was determined to be Q-8 and the major polar lipids were phosphatidylethanolamine (PE) and phosphatidylglycerol (PG), one unidentified aminolipid (AL), one unidentified glycolipid (GL), and two lipids (L1, L2). Based on the phylogenetic analyses of 16S rRNA gene sequences and 618 single-copy orthologous clusters, strain ASW11-36T could represent a novel member of the genus Alteromonas and was closely related to Alteromonas flava P0211T (98.4%) and Alteromonas facilis P0213T (98.3%). The pairwise average nucleotide identity and digital DNA-DNA hybridization values of the ASW11-36T genome assembly against the closely related species genomes were 71.8% and 21.7%, respectively, that clearly lower than the proposed thresholds for species. Based on phenotypic, phylogenetic, and chemotaxonomic analyses, strain ASW11-36T is considered to represent a novel species of the genus Alteromonas, for which the name Alteromonas arenosi sp. nov. is proposed. The type strain is ASW11-36T (= KCTC 82496T = MCCC 1K05585T). In addition, the strain yielded 65% of flocculating efficiency in kaolin suspension with CaCl2 addition. The draft genome of ASW11-36T shared abundant putative CAZy family related genes, especially involved in the biosynthesis of exopolysaccharides, implying its potential environmental and biological applications.
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Alteromonas , Areia , Filogenia , RNA Ribossômico 16S/genética , Técnicas de Tipagem Bacteriana , Ácidos Graxos , Ubiquinona , DNA , Análise de Sequência de DNA , DNA Bacteriano/genética , FosfolipídeosRESUMO
BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is chronic, with its progression leading to liver fibrosis and end-stage cirrhosis. Although NAFLD is increasingly common, no treatment guideline has been established. Many mechanistic studies and drug trials have been conducted for new drug development to treat NAFLD. An up-to-date overview on the knowledge structure of NAFLD through bibliometrics, focusing on research hotspots, is necessary to reveal the rational and timely directions of development in this field. AIM: To research the latest literature and determine the current trends in treatment for NAFLD. METHODS: Publications related to treatment for NAFLD were searched on the Web of Science Core Collection database, from 2010 to 2023. VOSviewers, CiteSpace, and R package "bibliometrix" were used to conduct this bibliometric analysis. The key information was extracted, and the results of the cluster analysis were based on network data for generating and investigating maps for country, institution, journal, and author. Historiography analysis, bursts and cluster analysis, co-occurrence analysis, and trend topic revealed the knowledge structure and research hotspots in this field. GraphPad Prism 9.5.1.733 and Microsoft Office Excel 2019 were used for data analysis and visualization. RESULTS: In total, 10829 articles from 120 countries (led by China and the United States) and 8785 institutions were included. The number of publications related to treatment for NAFLD increased annually. While China produced the most publications, the United States was the most cited country, and the United Kingdom collaborated the most from an international standpoint. The University of California-San Diego, Shanghai Jiao Tong University, and Shanghai University of Traditional Chinese Medicine produced the most publications of all the research institutions. The International Journal of Molecular Sciences was the most frequent journal out of the 1523 total journals, and Hepatology was the most cited and co-cited journal. Sanyal AJ was the most cited author, the most co-cited author was Younossi ZM, and the most influential author was Loomba R. The most studied topics included the epidemiology and mechanism of NAFLD, the development of accurate diagnosis, the precise management of patients with NAFLD, and the associated metabolic comorbidities. The major cluster topics were "emerging drug," "glucagon-like peptide-1 receptor agonist," "metabolic dysfunction-associated fatty liver disease," "gut microbiota," and "glucose metabolism." CONCLUSION: The bibliometric study identified recent research frontiers and hot directions, which can provide a valuable reference for scholars researching treatments for NAFLD.
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Hepatopatia Gordurosa não Alcoólica , Humanos , Bibliometria , China , Análise por Conglomerados , Análise de Dados , Cirrose Hepática , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/terapiaRESUMO
BACKGROUND: Hydrogen sulfide (H2S) is a recently discovered gaseous neurotransmitter in the nervous and gastrointestinal systems. It exerts its effects through multiple signaling pathways, impacting various physiological activities. The nucleus tractus solitarius (NTS), a vital nucleus involved in visceral sensation, was investigated in this study to understand the role of H2S in regulating gastric function in rats. AIM: To examine whether H2S affects the nuclear factor kappa-B (NF-κB) and transient receptor potential vanilloid 1 pathways and the neurokinin 1 (NK1) receptor in the NTS. METHODS: Immunohistochemical and fluorescent double-labeling techniques were employed to identify cystathionine beta-synthase (CBS) and c-Fos co-expressed positive neurons in the NTS during rat stress. Gastric motility curves were recorded by inserting a pressure-sensing balloon into the pylorus through the stomach fundus. Changes in gastric motility were observed before and after injecting different doses of NaHS (4 nmol and 8 nmol), physiological saline, Capsazepine (4 nmol) + NaHS (4 nmol), pyrrolidine dithiocarbamate (PDTC, 4 nmol) + NaHS (4 nmol), and L703606 (4 nmol) + NaHS (4 nmol). RESULTS: We identified a significant increase in the co-expression of c-Fos and CBS positive neurons in the NTS after 1 h and 3 h of restraint water-immersion stress compared to the expressions observed in the control group. Intra-NTS injection of NaHS at different doses significantly inhibited gastric motility in rats (P < 0.01). However, injection of saline, first injection NF-κB inhibitor PDTC or transient receptor potential vanilloid 1 (TRPV1) antagonist Capsazepine or NK1 receptor blockers L703606 and then injection NaHS did not produce significant changes (P > 0.05). CONCLUSION: NTS contains neurons co-expressing CBS and c-Fos, and the injection of NaHS into the NTS can suppress gastric motility in rats. This effect may be mediated by activating TRPV1 and NK1 receptors via the NF-κB channel.
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Sulfeto de Hidrogênio , Animais , Ratos , Sulfeto de Hidrogênio/farmacologia , NF-kappa B , Núcleo Solitário , DesidrataçãoRESUMO
There are numerous prescription drugs and non-prescription drugs that cause drug-induced liver injury (DILI), which is the main cause of liver disease in humans around the globe. Its mechanism becomes clearer as the disease is studied further. For an instance, when acetaminophen (APAP) is taken in excess, it produces N-acetyl-p-benzoquinone imine (NAPQI) that binds to biomacromolecules in the liver causing liver injury. Treatment of DILI with traditional Chinese medicine (TCM) has shown to be effective. For example, activation of the Nrf2 signaling pathway as well as regulation of glutathione (GSH) synthesis, coupling, and excretion are the mechanisms by which ginsenoside Rg1 (Rg1) treats APAP-induced acute liver injury. Nevertheless, reducing the toxicity of TCM in treating DILI is still a problem to be overcome at present and in the future. Accumulated evidences show that hydrogel-based nanocomposite may be an excellent carrier for TCM. Therefore, we reviewed TCM with potential anti-DILI, focusing on the signaling pathway of these drugs' anti-DILI effect, as well as the possibility and prospect of treating DILI by TCM based on hydrogel materials in the future. In conclusion, this review provides new insights to further explore TCM in the treatment of DILI.
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Produtos Biológicos , Doença Hepática Induzida por Substâncias e Drogas , Medicamentos de Ervas Chinesas , Acetaminofen , Produtos Biológicos/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Hidrogéis , Medicina Tradicional ChinesaRESUMO
Liver fibrosis is a reversible wound healing reaction characterized by abnormal accumulation of extracellular matrix (ECM) in response to liver injury. Recent studies have shown that it can be epigenetically regulated, especially by microRNAs (miRNAs). It has been acknowledged that activation of hepatic stellate cells (HSCs) is a pivotal step in the initiation and progression of liver fibrosis. Notably, our results showed that miR-195-3p was increased in HSCs isolated from CCl4-treated mice and that the increase was more pronounced as the degree of liver fibrosis increased. Moreover, treatment of LX-2 cells, a human immortalized hepatic stellate cell line, with TGF-ß1 resulted remarkable upregulation of miR-195-3p. Gain-of-function and loss-of-function experiments have suggested that the increased levels of miR-195-3p inhibit the expression of phosphatase and tension homolog deleted on chromosome 10 (PTEN), a negative regulator of the PI3K/Akt/mTOR signaling pathway in liver fibrosis, thereby contributing to HSC activation and proliferation and promoting the expression of profibrotic genes, such as α-SMA and collagen I, in LX-2 cells, which accelerates the accumulation of fibrous extracellular matrix deposition in the liver, while knockdown of miR-195-3p induced the opposite effect. Taken together, these results provide evidence for the harmful role of miR-195-3p in CCl4-treated mouse liver fibrosis.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Células Estreladas do Fígado/metabolismo , Cirrose Hepática/induzido quimicamente , MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Regiões 3' não Traduzidas , Animais , Intoxicação por Tetracloreto de Carbono/patologia , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Regulação para CimaRESUMO
Slow development has been shown to be a general mechanism to restore the fertility of thermo-sensitive and photoperiod-sensitive genic male sterile (TGMS and PGMS) lines in Arabidopsis. rpg1 is a TGMS line defective in primexine, which is essential for pollen wall pattern formation. Here, we showed that RPG1-GFP was highly expressed in microsporocytes, microspores, and pollen grains but not in the tapetum in the complemented transgenic line, suggesting that microsporocytes are the main sporophytic cells for primexine formation. Further cytological observations showed that primexine formation in rpg1 was partially restored under slow growth conditions, leading to its fertility restoration. RPG2 is the homolog of RPG1 in Arabidopsis. We revealed that the fertility recovery of rpg1 rpg2 was significantly reduced compared with that of rpg1 under low temperature. The RPG2-GFP protein was also expressed in microsporocytes in the RPG2-GFP (WT) transgenic line. These results suggest that RPG2 plays a redundant role in rpg1 fertility restoration. rpg1 plants were male sterile at the early growth stage, while their fertility was partially restored at the late developmental stage. The fertility of the rpg1 lateral branches was also partially restored. Further growth analysis showed that slow growth at the late reproductive stage or on the lateral branches led to fertility restoration. This work reveals the importance of gene redundancy in fertility restoration for TGMS lines and provides further insight into pollen wall pattern formation.
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Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Fertilidade/genética , Infertilidade das Plantas/genética , Pólen/metabolismoRESUMO
Alcohol metabolism causes hepatocytes to release damage-associated molecular patterns (DAMPs). This includes mitochondrial DNA (mtDNA), which is generated and released from damaged hepatocytes and contributes to liver injury by producing proinflammatory cytokines. STING is a pattern recognition receptor of DAMPs known to control the induction of innate immunity in various pathological processes. However, the expression profile and functions of STING in the Gao binge ethanol model remain poorly understood. We demonstrated that STING is upregulated in the Gao binge ethanol model. STING functions as an mtDNA sensor in the Kupffer cells of the liver and induces STING-signaling pathway-dependent inflammation and further aggravates hepatocyte apoptosis in the Gao binge ethanol model. This study provides novel insights into predicting disease progression and developing targeted therapies for alcoholic liver injury.
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Etanol , Hepatócitos , Animais , DNA Mitocondrial/genética , Hepatócitos/metabolismo , Inflamação/patologia , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Recently, circular RNAs (circRNAs) have been frequently reported to be involved in hepatocellular carcinoma (HCC) development and progression. However, the role of circRNAs in hepatic fibrosis (HF) is still unclear. Our previous high-throughput screen revealed changes in many circRNAs in mice with carbon tetrachloride (CCl4)-induced HF. For instance, the expression of circPSD3, a circRNA derived from the Pleckstrin and Sec7 domain-containing 3 (PSD3) gene, was considerably downregulated in primary hepatic stellate cells (HSCs) and liver tissues of mice with CCl4-induced HF compared to those in the vehicle group. In vivo overexpression of circPSD3 using AAV8-circPSD3 arrested the deterioration of CCl4-induced HF as indicated by reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) content, liver hydroxyproline level, collagen deposition, and pro-fibrogenic gene and pro-inflammatory cytokine levels. Moreover, in vitro loss-of-function and gain-of-function analyses suggested that circPSD3 inhibited the activation and proliferation of HSCs. Mechanistically, circPSD3 served as a sponge for miR-92b-3p, subsequently promoting the expression of Smad7. In conclusion, our present findings reveal a novel mechanism by which circPSD3 alleviates hepatic fibrogenesis by targeting the miR-92b-3p/Smad7 axis, and they also indicate that circPSD3 may serve as a potential biomarker for HF.
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OBJECTIVE: To assess the dose-related effects of radial extracorporeal shock wave therapy on pain alleviation in knee osteoarthritis. METHODS: With the use of a 2?×?2 factorial randomized controlled design, 89 patients diagnosed with knee osteoarthritis were assigned to 1 of 4 treatment groups, which varied in terms of shock intensity (0.12 mJ/mm2, lower density, or 0.24 mJ/mm2, higher density) and shock number (2,000 impulses or 4,000 impulses), or to a placebo control. Each group received 4 sessions of radial extracorporeal shock wave therapy, one week apart. The primary outcome was pain intensity measured on a visual analogue scale, and the secondary outcome was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score. Assessments were performed at baseline, after each session, and at 4-week follow-up. RESULTS: Two-way repeated-measures analysis of variance revealed a significant effect on the Pain score for intensity (p<0.001), with no effect for number (p=0.467) or the intensity?number interaction (p=0.536). Similar results were obtained for the WOMAC scores, except for an association between number and WOMAC score (p=0.036). At the 4-week follow-up, all treatment groups showed greater reductions in the Pain and WOMAC scores than the control group. In addition, scores decreased more at higher densities of shock intensity than at lower densities, while there was no significant difference between the 2,000- and 4,000-shock conditions. CONCLUSION: Moderate-intensity radial extracorporeal shock wave therapy was effective, and a higher density might be more efficacious in alleviating pain in knee osteoarthritis.
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Tratamento por Ondas de Choque Extracorpóreas/efeitos adversos , Osteoartrite do Joelho/terapia , Método Duplo-Cego , Tratamento por Ondas de Choque Extracorpóreas/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Alcoholic liver fibrosis (ALF) is commonly associated with long-term alcohol consumption and the activation of hepatic stellate cells (HSCs). Inhibiting the activation and proliferation of HSCs is a critical step to alleviate liver fibrosis. Increasing evidence indicates that ecto-5'-nucleotidase (CD73) plays a vital role in liver disease as a critical component of extracellular adenosine pathway. However, the regulatory role of CD73 in ALF has not been elucidated. In this study, both ethanol plus CCl4-induced liver fibrosis mice model and acetaldehyde-activated HSC-T6 cell model were employed and the expression of CD73 was consistently elevated in vivo and in vitro. C57BL/6 J mice were intraperitoneally injected with CD73 inhibitor Adenosine 5'-(α, ß-methylene) diphosphate sodium salt (APCP) from 5th week to the 8th week in the development of ALF. The results showed APCP could inhibit the activation of HSCs, reduce fibrogenesis marker expression and thus alleviate ALF. Silencing of CD73 inhibited the activation of HSC-T6 cells and promoted apoptosis of activated HSC-T6 cells. What's more, the proliferation of HSC-T6 cells was inhibited, which was characterized by decreased cell viability and cycle arrest. Mechanistically, Wnt/ß-catenin pathway was activated in acetaldehyde-activated HSC-T6 cells and CD73 silencing or overexpression could regulate Wnt/ß-catenin signaling pathway. Collectively, our study unveils the role of CD73 in HSCs activation, and Wnt/ß-catenin signaling pathway might be involved in this progression.
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5'-Nucleotidase/biossíntese , Proliferação de Células/fisiologia , Células Estreladas do Fígado/metabolismo , Via de Sinalização Wnt/fisiologia , 5'-Nucleotidase/antagonistas & inibidores , 5'-Nucleotidase/deficiência , Difosfato de Adenosina/análogos & derivados , Difosfato de Adenosina/farmacologia , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Células Estreladas do Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Via de Sinalização Wnt/efeitos dos fármacosRESUMO
Alcohol-induced liver injury is characterized by abnormal liver dysfunction and excessive inflammation response. Recent years a wealth of data have been yielded indicating that EtOH (ethyl alcohol)-induced macrophage activation along with liver inflammation plays a dominating role in the progression of alcohol-induced liver injury. Here we found high expression of NLRP12 (Nucleotide-binding oligomerization domain protein 12, which is generally considered to be a negative regulator of inflammatory response) in EtOH-fed mouse liver tissue, primary Kupffer cells and EtOH-induced RAW264.7 cells. Additionally, overexpression of NLRP12 following Ad (adenovirus)-NLRP12-EGFP contributed to the attenuation of steatosis and inflammation in EtOH-fed mice model and EtOH-primed RAW264.7 cells. In parallel, Knockdown of NLRP12 aggravated the inflammatory response in RAW264.7 cells triggered by EtOH. Meanwhile, after administration of overexpression or inhibition of NLRP12 expression in vitro, the expression of phosphorylated protein of NF-kB signaling pathway was significantly affected. After increasing or decreasing the expression of NLRP12 in RAW264.7 cells, AML-12 cells were cultured with the supernatant of RAW264.7 cells stimulated by EtOH, and the percent of apoptosis ratio of AML-12 cells was remarkably altered. The study suggested that reduced inflammatory response induced by NLRP12-mediated inhibition of NF-kB pathway participated in the decrease of hepatocyte apoptosis in alcohol-induced liver injury. Collectively, these findings suggested the significance of NLRP12-mediated macrophage activation in alcohol-induced liver injury.
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Apoptose , Hepatócitos/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Hepatopatias Alcoólicas/imunologia , Ativação de Macrófagos , NF-kappa B/imunologia , Animais , Linhagem Celular , Citocinas/imunologia , Etanol , Fígado/imunologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de SinaisRESUMO
With advances in genome and transcriptome research technology, the function and mechanism of lncRNAs in physiological and pathological states have been gradually revealed. Nuclear Enriched Abundant Transcript 1 (NEAT1, a long non-coding RNA), a vital component of paraspeckles, plays an indispensable role in the formation and integrity of paraspeckles. Throughout the research history, NEAT1 is mostly aberrantly upregulated in various cancers, and high expression of NEAT1 often contributes to poor prognosis of patients. Notably, the role and mechanism of NEAT1 in liver diseases have been increasingly reported. NEAT1 accelerates the progression of non-alcoholic fatty liver disease (NAFLD), liver fibrosis and hepatocellular carcinoma, while exerting a protective role in the pathogenesis of acute-on-chronic liver failure by inhibiting the inflammatory response. In this review, we will elaborate on relevant studies on the different casting of NEAT1 in liver diseases, especially focusing on its regulatory mechanisms and new opportunities for alcoholic liver disease.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , RNA Longo não Codificante , Carcinoma Hepatocelular/genética , Humanos , Neoplasias Hepáticas/genética , Hepatopatia Gordurosa não Alcoólica/genética , RNA Longo não Codificante/genéticaRESUMO
Photoperiod- and thermosensitive genic male sterility (P/TGMS) lines are widely used in crop breeding. The fertility conversion of Arabidopsis (Arabidopsis thaliana) TGMS lines including cals5-2, which is defective in callose wall formation, relies on slow development under low temperatures. In this study, we discovered that cals5-2 also exhibits PGMS. Fertility of cals5-2 was restored when pollen development was slowed under short-day photoperiods or low light intensity, suggesting that slow development restores the fertility of cals5-2 under these conditions. We found that several other TGMS lines with defects in pollen wall formation also exhibited PGMS characteristics. This similarity indicates that slow development is a general mechanism of PGMS fertility restoration. Notably, slow development also underlies the fertility recovery of TGMS lines. Further analysis revealed the pollen wall features during the formation of functional pollens of these P/TGMS lines under permissive conditions. We conclude that slow development is a general mechanism for fertility restoration of P/TGMS lines and allows these plants to take different strategies to overcome pollen formation defects.
Assuntos
Arabidopsis/crescimento & desenvolvimento , Arabidopsis/genética , Fotoperíodo , Infertilidade das Plantas/genética , Infertilidade das Plantas/fisiologia , Pólen/crescimento & desenvolvimento , Pólen/genética , Temperatura Baixa , Regulação da Expressão Gênica de Plantas , Genes de Plantas , Variação Genética , GenótipoRESUMO
Two new compounds 7-hydroxy-4'-methoxy-3'-(7''-hydroxy-3'',7''-dimethyl-octa-2'',5''-dienyl)-isoflavone (1) and 7-hydroxy-4'-methoxy-3'-(6''-hydroxy-3'',7''-dimethyl-octa-2'',7''-dienyl)-isoflavone (2), together with five known compounds (3-7), were isolated from EtOAc-soluble extract of the seeds of Psoralea corylifolia. Their structures were elucidated on the basis of detailed spectroscopic and physico-chemical analyses. All the isolates were evaluated for in vitro inhibitory activity against diacylglycerol acyltransferase (DGAT). And compounds 1-7 displayed significant inhibitory activity on DGAT1 with IC50 values ranging from 51.2 ± 1.1 to 116.4 ± 1.3 µM.
Assuntos
Isoflavonas , Psoralea , Diacilglicerol O-Aciltransferase , Estrutura Molecular , SementesRESUMO
Deoxynivalenol (DON) is highly toxic to animals and humans, but pigs are most sensitive to it. The porcine mucosal injury related mechanism of DON is not yet fully clarified. Here, we investigated DON-induced injury in the intestinal tissues of piglet. Thirty weanling piglets [(Duroc × Landrace) × Yorkshire] were randomly divided into three groups according to single factor experimental design (10 piglets each group). Piglets were fed a basal diet in the control group, while low and high dose groups were fed a DON diet (1300 and 2200 µg/kg, respectively) for 60 days. Scanning electron microscopy results indicated that the ultrastructure of intestinal epithelial cells in the DON-treated group was damaged. The distribution and optical density (OD) values of zonula occludens 1 (ZO-1) protein in the intestinal tissues of DON-treated groups were decreased. At higher DON dosage, interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α mRNA levels were elevated in the intestinal tissues. The mRNA and protein levels of NF-κB p65, IκB-α, IKKα/ß, iNOS, and COX-2 in the small intestinal mucosa were abnormally altered with an increase in DON concentration. These results indicate that DON can persuade intestinal damage and inflammatory responses in piglets via the nuclear factor-κB signaling pathway.