RESUMO
BACKGROUND: Daptomycin is widely used in critically ill patients for Gram-positive bacterial infections. Extracorporeal membrane oxygenation (ECMO) is increasingly used in this population and can potentially alter the pharmacokinetic (PK) behaviour of antibiotics. However, the effect of ECMO has not been evaluated in daptomycin. Our study aims to explore the effect of ECMO on daptomycin in critically ill patients through population pharmacokinetic (PopPK) analysis and to determine optimal dosage regimens based on both efficacy and safety considerations. METHODS: A prospective, open-label PK study was carried out in critically ill patients with or without ECMO. The total concentration of daptomycin was determined by UPLC-MS/MS. NONMEM was used for PopPK analysis and Monte Carlo simulations. RESULTS: Two hundred and ninety-three plasma samples were collected from 36 critically ill patients, 24 of whom received ECMO support. A two-compartment model with first-order elimination can best describe the PK of daptomycin. Creatinine clearance (CLCR) significantly affects the clearance of daptomycin while ECMO has no significant effect on the PK parameters. Monte Carlo simulations showed that, when the MICs for bacteria are â≥1â mg/L, the currently recommended dosage regimen is insufficient for critically ill patients with CLCRâ>â30â mL/min. Our simulations suggest 10â mg/kg for patients with CLCR between 30 and 90â mL/min, and 12â mg/kg for patients with CLCR higher than 90â mL/min. CONCLUSIONS: This is the first PopPK model of daptomycin in ECMO patients. Optimal dosage regimens considering efficacy, safety, and pathogens were provided for critical patients based on pharmacokinetic-pharmacodynamic analysis.
Assuntos
Antibacterianos , Estado Terminal , Daptomicina , Oxigenação por Membrana Extracorpórea , Método de Monte Carlo , Humanos , Daptomicina/farmacocinética , Daptomicina/administração & dosagem , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto , Idoso , Testes de Sensibilidade Microbiana , Espectrometria de Massas em Tandem , Infecções por Bactérias Gram-Positivas/tratamento farmacológicoRESUMO
Pancreatic cancer (PaCa) is one of the most fatal malignancies of the digestive system, and most patients are diagnosed at advanced stages due to the lack of specific and effective tumor-related biomarkers for the early detection of PaCa. miR-492 has been found to be upregulated in PaCa tumor tissue and may serve as a potential therapeutic target. However, the molecular mechanisms by which miR-492 promotes PaCa tumor growth and progression are unclear. In this study, we first found that miR-492 in enhancer loci activated neighboring genes (NR2C1/NDUFA12/TMCC3) and promoted PaCa cell proliferation, migration, and invasion in vitro. We also observed that miR-492-activating genes significantly enriched the TGF-ß/Smad3 signaling pathway in PaCa to promote epithelial-mesenchymal transition (EMT) during tumorigenesis and development. Using CRISPR-Cas9 and ChIP assays, we further observed that miR-492 acted as an enhancer trigger, and that antagomiR-492 repressed PaCa tumorigenesis in vivo, decreased the expression levels of serum TGF-ß, and suppressed the EMT process by downregulating the expression of NR2C1. Our results demonstrate that miR-492, as an enhancer trigger, facilitates PaCa progression via the NR2C1-TGF-ß/Smad3 pathway.
Assuntos
MicroRNAs , Neoplasias Pancreáticas , Humanos , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , MicroRNAs/genética , Transição Epitelial-Mesenquimal/genética , Linhagem Celular Tumoral , Neoplasias Pancreáticas/genética , Carcinogênese/genética , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica , Proliferação de Células/genética , Proteína Smad3/genética , Proteína Smad3/metabolismo , NADPH Desidrogenase/genética , NADPH Desidrogenase/metabolismo , Neoplasias PancreáticasRESUMO
Peroxidase (POD) Nanozyme-based hydrogen peroxide (H2 O2 ) detection is popular, but hardly adapt to high concentration of H2 O2 owing to narrow linear range (LR) and low LR maximum. Here, a solution of combining POD and catalase (CAT) is raised to expand the LR of H2 O2 assay via decomposing part of H2 O2 . As a proof of concept, a cascade enzyme system (rGRC) is constructed by integrating ruthenium nanoparticles (RuNPs), CAT and graphene together. The rGRC-based sensor does perform an expanded LR and higher LR maximum for H2 O2 detection. Meanwhile, it is confirmed that LR expansion is closely associated with apparent Km of rGRC, which is determined by the relative enzyme activity between CAT and POD both in theory and in experiment. At last, rGRC is successfully used to detect high concentration of H2 O2 (up to 10 mm) in contact lens care solution, which performs higher assay accuracy (close to 100% recovery at 10 mm of H2 O2 ) than traditional POD nanozymes. This study brings up a kind of POD/CAT cascade enzyme system and provides a new concept for accurate and facile H2 O2 detection. Additionally, it replenishes a new enzyme-substrate model of achieving the same pattern with competitive inhibition in enzyme reactions.
Assuntos
Peroxidase , Peroxidases , Catalase , Peróxido de HidrogênioRESUMO
Aquatic ecosystems are being more contaminated with polyhalogenated carbazoles (PHCZs), which raising concerns about their impact on aquatic organisms. Lycopene (LYC) exhibits several beneficial properties for fish via enhance antioxidant defenses and improve immunity. In this study, we attempted to investigate the hepatotoxic effects of typical PHCZs 3, 6-dichlorocarbazole (3,6-DCCZ) and the protective mechanisms of LYC. In this study, we found that yellow catfish (Pelteobagrus fulvidraco) exposure to 3,6-DCCZ (1.2 mg/L) resulted in hepatic inflammatory infiltration and disordered hepatocyte arrangement. Besides, we observed that 3,6-DCCZ exposure resulted in hepatic reactive oxygen species (ROS) overproduction and excessive autophagosome accumulation, accompanied with inhibition of phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) pathway. Subsequently, we confirmed that 3,6-DCCZ exposure triggered hepatic uncontrolled inflammatory response via activation of nuclear factor-κB (NF-κB) pathway, along with decreased plasma complement C3 (C3) and complement C4 (C4) levels. Meanwhile, yellow catfish exposed to 3,6-DCCZ exhibit an increased hepatic apoptosis phenomenon, as evidenced by the elevated number of positive TUNEL cells and upregulated expression of caspase3 and cytochrome C (CytC). In contrast, LYC treatment could alleviate the 3,6-DCCZ-induced pathological changes, hepatic ROS accumulation, autophagy, inflammatory response and apoptosis. To sum up, this study provided the demonstration that LYC exerts hepatoprotective effects to alleviate 3,6-DCCZ-induced liver damage by inihibiting ROS/PI3K-AKT/NF-κB signaling in yellow catfish.
Assuntos
Peixes-Gato , NF-kappa B , Animais , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Licopeno/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Peixes-Gato/metabolismo , Carbazóis/metabolismo , Carbazóis/farmacologia , Ecossistema , Fígado/metabolismoRESUMO
Epidemiological evidence has shown that fine particulate matter (PM2.5)-triggered inflammatory cascades are pivotal causes of chronic obstructive pulmonary disease (COPD). However, the specific molecular mechanism involved in PM2.5-induced COPD has not been clarified. Herein, we found that PM2.5 significantly downregulated miR-149-5p and activated the mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways and generated the inflammatory response in COPD mice and in human bronchial epithelial (BEAS-2B) cells. We determined that increased expression of interleukin-1ß (IL-1ß), IL-6, IL-8, and tumor necrosis factor-α (TNF-α) induced by PM2.5 was associated with decreased expression of miR-149-5p. The loss- and gain-of-function approach further confirmed that miR-149-5p could inhibit PM2.5-induced cell inflammation in BEAS-2B cells. The double luciferase reporter assay showed that miR-149-5p directly targeted TGF-beta-activated kinase 1 binding protein 2 (TAB2), which regulates the MAPK and NF-κB signaling pathways. We showed that miR-149-5p mediated the inflammatory response by targeting the 3'-UTR sequence of TAB2 and that it subsequently weakened the TAB2 promotor effect via the MAPK and NF-κB signaling pathways in BEAS-2B cells exposed to PM2.5. Thus, miR-149-5p may be a key factor in PM2.5-induced COPD. This study improves our understanding of the molecular mechanism of COPD.
Assuntos
MicroRNAs , Doença Pulmonar Obstrutiva Crônica , Humanos , Camundongos , Animais , NF-kappa B/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Transdução de Sinais , Material Particulado/toxicidade , Inflamação/genética , Inflamação/patologia , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismoRESUMO
PURPOSE: There is a lack of studies that systematically evaluate the clinical factors of PICC-RVT such as treatment, tumor stage, metastasis, and chemotherapy drugs in cancer patients. This study, therefore, aims to evaluate the clinical factors of catheter-related venous thrombosis in cancer patients with indwelling PICC to provide a basis for the clinical prevention and reduction of thrombosis. METHODS: Relevant studies were retrieved from major databases (PubMed, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), WanFang Data, and China Biology Medicine disc (CMB)) and searched from their earliest available dates until July 2022. If two or more studies had the same outcome, a meta-analysis using RevMan 5.4.1 was performed. This systematic review was registered at PROSPERO (number CRD42022358426). RESULTS: A total of 19 articles involving 19,824 patients were included for quantitative analysis. Meta-analysis of these studies indicated that a history of chemotherapy, tumor type, tumor stage, presence or absence of metastasis, and use of fluorouracil, etoposide, platinum drugs, and taxane were all risk factors for PICC catheter thrombosis in cancer patients. CONCLUSION: In clinical PICC catheter thrombosis prevention, patients with the above characteristics should be watched more closely than other patients, as they have a higher risk for PICC catheter thrombosis. Based on the present evidence at hand, radiotherapy cannot be considered to be related to the formation of PICC-RVT in cancer patients.
Assuntos
Catéteres , Neoplasias , Humanos , China , Bases de Dados Factuais , Etoposídeo , Neoplasias/tratamento farmacológicoRESUMO
Imidacloprid (IMI) is among the common neonicotinoid insecticides used in agriculture worldwide, posing a potential toxic threat to non-target animals and humans. Numerous studies have shown that ferroptosis is involved in the pathophysiological progression of renal diseases. However, it remains unclear whether ferroptosis is involved in IMI-induced nephrotoxicity. In the present study, we investigated the potential pathogenic role of ferroptosis in IMI-induced kidney damage in vivo. Transmission electron microscopy (TEM) showed that the mitochondrial crest of kidney cells significantly decreased following IMI exposure. Moreover, IMI exposure triggered ferroptosis and lipid peroxidation in the kidney. We confirmed that nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant capability was negatively correlated with the ferroptosis induced by IMI exposure. Importantly, we verified that NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3)-driven inflammation occurred in the kidneys following IMI exposure, but pretreatment with the ferroptosis inhibitor ferrostatin (Fer-1) blocked this phenomenon. Additionally, IMI exposure induced F4/80+ macrophages to accumulated in the proximal tubules of the kidneys, and also increased the protein expression of high-mobility group box 1 (HMGB1), receptor for advanced glycation end products (RAGE), receptor for advanced glycation end products (TLR4), and nuclear factor kappa-B (NF-κB). In contrast, inhibition of ferroptosis by Fer-1 blocked IMI-induced NLRP3 inflammasome activation, F4/80 positive macrophages, and the HMGB1-RAGE/TLR4 signaling pathway. To the best of our knowledge, this is the first study to reveal that IMI stress can induce Nrf2 inactivation, thereby triggering ferroptosis, causing an initial wave of death, and activating HMGB1-RAGE/TLR4 signaling, which promotes pyroptosis that perpetuates kidney dysfunction.
Assuntos
Ferroptose , Proteína HMGB1 , Animais , Humanos , NF-kappa B/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Receptor 4 Toll-Like/metabolismo , Piroptose , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína HMGB1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais , Neonicotinoides/toxicidadeRESUMO
Root knot nematodes are the most devastating root pathogens, causing severe damage and serious economic losses to agriculture worldwide. Octanoic acid has been reported as one of the nematicides, and its mode of action is not fully understood. The main objective of this study was to elucidate the effect of octanoic acid on Meloidogyne incognita by transcriptomic analysis combined with physiological and biochemical assays. In the toxicity assays with octanoic acid, the threshold concentration with nematicidal activity and the maximum concentration to which nematodes could respond were 0.03 µL/mL and 0.08 µL/mL respectively. Microscopic observation combined with protein and carbohydrates assays confirmed that the structure of the second-stage juveniles (J2s) was severely disrupted after 72 h of immersion in octanoic acid. Transcriptome analysis has shown that octanoic acid can interfere with the nematode energy metabolism, lifespan and signaling. Although the effects are multifaceted, the findings strongly point to the cuticle, lysosomes, and extracellular regions and spaces as the primary targets for octanoic acid. In addition, nematodes can withstand the negative effects of low concentration of octanoic acid to some extent by up-regulating the defense enzyme system and heterologous metabolic pathways. These findings will help us to explore the nematicidal mechanism of octanoic acid and provide important target genes for the development of new nematicides in the future.
Assuntos
Tylenchoidea , Animais , Transcriptoma , Antinematódeos/farmacologia , Perfilação da Expressão GênicaRESUMO
Approximately 20% of concentrate will be produced from coal gasification wastewater after reverse osmosis treatment. The organic matter contained in the concentrate affects its evaporation crystallisation; therefore, the refractory organics must be removed. In this study, Cu-Co-Mn/AC catalytic ozonation was used to treat reverse osmosis concentrate (ROC). With the addition of the Cu-Co-Mn/AC catalyst, the production of ·OH increased by 82 µmol/L, thereby enhancing the ozonation performance. The pH, ozone dosage, and catalyst dosage all affected the catalytic ozonation performance. By constructing a response surface model, it was found that the catalyst dosage had the most significant effect on the catalytic ozonation performance. The predicted optimal reaction conditions were pH = 9.02, ozone dosage = 1.08 g/L, and catalyst dosage = 1.33 g/L, under which the chemical oxygen demand (COD) removal reached a maximum of 81.49%.
Assuntos
Ozônio , Poluentes Químicos da Água , Purificação da Água , Carvão Mineral , Catálise , OsmoseRESUMO
Recently, with increasing awareness of health issues, non-alcoholic fatty liver disease (NAFLD) has become an epidemic attracting global attention. As a serious chronic disease, NAFLD is clinically managed with pharmacological interventions that are usually associated with poor long-term efficacy and adverse effects. In this scenario, traditional Chinese medicine (TCM) characterized by "multiple ingredients-multiple targets-multiple pathways" shows promise as a potential option to treat NAFLD. Zexie decoction (ZXD) is a classical TCM formula that possesses favorable lipid-lowering and anti-inflammatory activities. Accumulating evidence indicates that ZXD displays robust efficacy in treating NAFLD. The effectiveness of ZXD against NAFLD has been evaluated in our previous studies. This study further examines its probable mechanism of action in an in-depth manner using multi-omic analysis based on the gut-liver axis and sheds light on the potential relationship among genes, hepatic lipid metabolites, and gut microbiotas. Totally, 71 differentially expressed genes (34 upregulated and 37 downregulated genes), 31 differential lipid molecules (8 upregulated and 23 downregulated), and 56 differential gut microbiotas (37 upregulated and 19 downregulated) were identified in the ZXD-treated group rats compared with the negative control group rats. Of these, owing to their key role in the association analysis, g_Blautia, g_Romboutsia, and g_Lactobacillus were hypothesized to be crucial gut microbiotas in the ZXD-mediated treatment of NAFLD. These microbiotas were found to synergize with key genes, such as AKR1B8, CCN1, and TNKS2, and hepatic lipid metabolites, such as glycerophospholipid and sphingomyelin, which might play a therapeutic role by regulating fatty acid synthesis, correcting lipid metabolism disorder, or reducing the inflammatory response. Overall, the present study provides fresh insights into the ZXD-mediated treatment of NAFLD, which, in turn, is expected to give a push to the modernization of TCM.
Assuntos
Microbioma Gastrointestinal , Hepatopatia Gordurosa não Alcoólica , Ratos , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Esfingomielinas/metabolismo , Fígado/metabolismo , Ácidos Graxos/metabolismo , Glicerofosfolipídeos/metabolismo , Glicerofosfolipídeos/farmacologia , Glicerofosfolipídeos/uso terapêutico , Dieta Hiperlipídica/efeitos adversosRESUMO
BACKGROUND: Growing evidence shows that C-Type Lectin Domain Containing 7A (Clec7a) may be involved into neuroinflammatory injury of various neurological diseases. However, its roles in neuropathic pain remain unclear. METHODS: A chronic constriction injury (CCI) rat model was constructed, and gene expression profilings in spinal cord tissues of CCI-insulted rats were detected by both microarray and RNA-seq studies. A series of bioinformatics analyses identified C/EBPß-Clec7a to be a candidate axis involved into neuropathic pain. Then, its roles in mechanical allodynia, and pathological and molecular changes during CCI progression were determined by various gain-of-function and loss-of-function experiments in vivo and in vitro. RESULTS: Significant upregulation of Clec7a at both mRNA and protein levels were verified in spinal cord tissues of CCI-insulted rats. Clec7a knockdown markedly attenuated CCI-induced mechanical allodynia, obstructed Syk, ERK and JNK phosphorylation, inhibited NLRP3 inflammasome and caspase-1 activation, GSDMD cleavage, and consequently reduced the release of pro-inflammatory cytokines (all P < 0.05). Mechanically, the rat Clec7a promoter was predicted to bind with transcription factor C/EBPß, confirmed by Luciferase assay and ChIP-qPCR. Both in vivo and in vitro assays demonstrated that C/EBPß knockdown significantly suppressed CCI- or LPS/ATP-induced Clec7a upregulation, and subsequently reduced Syk, ERK and JNK phosphorylation, NLRP3 oligomerization, caspase-1 activation, GSDMD expression and pyroptosis, which were markedly reversed by the co-transfection of Clec7a expression vector. CONCLUSIONS: This pre-clinical investigation reveals that C/EBPß-Clec7a axis may be a potential target for relieving neuropathic pain through alleviating neuroinflammation, paving its way for clinical translation as a promising approach for neuropathic pain therapy.
Assuntos
Inflamassomos , Neuralgia , Ratos , Animais , Inflamassomos/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Ratos Sprague-Dawley , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Hiperalgesia/patologia , Caspases , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismoRESUMO
BACKGROUND: Autologous fat grafting has become a commonly used procedure for breast reconstruction after breast cancer surgical treatment. Nevertheless, oncological considerations remain concerning autologous fat grafting after breast cancer surgery. OBJECTIVE: This meta-analysis aimed to summarize the current matched cohort studies and provide high-quality evidence-based conclusions on the oncological safety of fat grafting in breast reconstruction. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines were followed. A literature search was performed on August 1, 2021, using PubMed. All relevant matched cohort studies of patients undergoing autologous fat grafting after breast cancer surgery were included. After independently screening the studies and extracting the data, pooled estimates for local and regional recurrence as well as distant metastases were conducted using Review Manager software (RevMan, version 5.3). Outcomes were expressed as odds ratios and 95% confidence intervals. RESULTS: Seventeen studies involving 7494 patients were included. The observed outcomes indicated that no significant differences existed in the risks of local and regional recurrence or distant metastases between autologous fat grafting and control groups. Also, there was no significant heterogeneity among the studies. CONCLUSION: This study provided evidence-based conclusions that support the use of autologous fat grafting in breast reconstruction. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
Assuntos
Neoplasias da Mama , Mamoplastia , Tecido Adiposo/transplante , Neoplasias da Mama/patologia , Estudos de Coortes , Feminino , Humanos , Mamoplastia/efeitos adversos , Mamoplastia/métodos , Estudos Retrospectivos , Transplante Autólogo/métodos , Resultado do TratamentoRESUMO
Mercury is a naturally occurring element and highly toxic to humans even at a low dosage. Curcumin is a polyphenol found in turmeric (Curcuma longa), widely used as a treatment strategy to improve antioxidant and anti-inflammatory properties. The purpose of this study was to investigate the potential protective mechanisms of curcumin in spleen damage induced by HgCl2. The mice were given curcumin by intragastric administration 2 h before HgCl2 injection for 24 h. At first, splenic transcriptome analysis showed that 3334 genes (2134 up and 1200 down) were differently expressed in HgCl2-induced spleen damage model. Notably, KEGG enrichment showed phosphatidylinositol 3-kinase (PI3K)-AKT might be a key signaling pathways in HgCl2-induced spleen damage. Furthermore, our data demonstrated that HgCl2 could induce autophagic cell death, evidenced by increases the protein expression of PI3K, AKT, LC3-II and p62 and the number of apoptotic cells. Furthermore, we found that curcumin significantly combated autophagic cell death, sodium overload and calcium leak induced by HgCl2. Simultaneously, further studies demonstrated that curcumin significantly activated nuclear factor (erythroid-derived-2)-like 2 (Nrf2) signaling pathway, and subsequent enhancing antioxidant defenses. Taken together, our data indicated that inorganic mercury could result in autophagic cell death, which may be related to the regulation of PI3K-AKT signaling cascades. Furthermore, Nrf2-mediated antioxidant defenses may be the target of curcumin to confers an adaptive survival response to resist spleen damage induced by HgCl2. The present study perfects the mechanism theory of HgCl2-induced spleen damage and provides a way for pharmacological intervention to prevent spleen injury.
Assuntos
Morte Celular Autofágica , Curcumina , Mercúrio , Oligoelementos , Animais , Curcumina/farmacologia , Mercúrio/toxicidade , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Fosfatidilinositol 3-Quinase , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Baço/metabolismoRESUMO
Extensive use of neonicotinoids insecticides (NNIs) rapidly garnered widespread attention in the toxicology, since they have been found in human samples, including urine, blood, breast milk and hair. However, the precise mechanism is not completely clear regarding the NNIs-induced hepatotoxicity. In this study, we exposed male mice to three neonicotinoids (dinotefuran (DIN), nitenpyram (NIT) and acetamiprid (ACET) for 30 days. Our results showed that NNIs remarkably induced morphological damage in the liver. Simultaneously, we found that three neonicotinoids could activate the store operated Ca2+ entry (SOCE) in the liver. Further results confirmed that reactive oxide species (ROS) scavenger n-acetylcysteine (NAC) attenuated DIN-induced calcium ion (Ca2+) overload and S-phase arrest via restoring protein expression of SOCE and S phase related genes in L02 hepatocytes. Moreover, we found that NAC obviously combated mitochondrial dysfunction caused by DIN via restoring mitochondrial membrane potential. Meanwhile, DIN treatment significantly increased pyruvate content, impaired the activities of tricarboxylic acid (TCA) cycle rate-limiting enzymes and inhibited adenosine triphosphate (ATP) generation, but these effects were reversed by Serca specific activator CDN1163. Collectively, perturbation of redox states can be recognized as the center of S-phase arrest and Ca2+ overload after NNIs exposure. In this regard, Ca2+ homeostasis dysregulation is a causative event of mitochondrial bioenergetic dysfunction in the liver. These data provides a new perspective for understanding NNI-induced hepatotoxicity mechanisms.
RESUMO
Environmental mercury is a concern for coastal ecosystem health, and exerts adverse effects on human health. Despite the growing body of evidence showing the hepatoprotective roles of curcumin on mercury, the knowledge between the macroscopic descriptions and the actual mechanism(s) underlying these processes is getting larger remains elusive. Herein, mice received single injection of mercuric chloride (HgCl2) (5 mg/kg body weight) and/or curcumin (50 mg/kg, body weight, p.o.). Firstly, the results showed curcumin could decline HgCl2-induced up-regulated the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Additionally, we also found that curcumin could suppress inflammatory damage, unbalance of trace elements (including sodium, magnesium, kalium, calcium overload), oxidative burst induced by HgCl2, which could be associated with cytochrome P450 (CYP450) signaling. Secondly, we found that curcumin could prevent HgCl2-induced cell death both in vivo and in vitro. Furthermore, curcumin significantly increased the nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) and consequently upregulated the expression of heme oxygenase 1 (HO-1) under HgCl2 treatment. Meanwhile, inhibition of HO-1 by zinc protoporphyria could abolish the cytoprotective effects of curcumin in HgCl2-treated L02 hepatocytes. In conclusion, our data identify that curcumin could enhance Nrf2-mediated HO-1 to upregulate antioxidant ability, which might be associate with CYP450 signaling to suppress liver damage induced by HgCl2. The present study further enriches and perfects the mechanism theory of HgCl2 toxicity and suggest that the CYP450 signaling and Nrf2/HO-1 pathway is important in shedding light on curcumin's hepatoprotective effects in HgCl2 toxicity.
Assuntos
Curcumina/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Substâncias Perigosas/toxicidade , Cloreto de Mercúrio/toxicidade , Substâncias Protetoras/farmacologia , Alanina Transaminase/metabolismo , Animais , Antioxidantes/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Ecossistema , Heme Oxigenase-1/genética , Hepatócitos/efeitos dos fármacos , Humanos , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
The low temperature of sewage in north China results in low performance of biological treatment at municipal wastewater treatment plants (MWTPs), especially in biological nitrogen removal. A modified two-stage A/O process with an embedded biofilm was proposed to enhance nitrogen removal. The operation performance of a pilot test was compared with an A2/O and SBR process at existing MWTPs to investigate the resistance to low temperature. The microbial communities for the three processes were compared based on the metagenomics results of 16sDNA high-throughput sequencing from activated sludge. The modified A/O resulted in a higher average removal of COD (90.12%) than A2/O (85.23%) and SBR (83.03%), especially of small-molecule organic compounds (< 500 Da) and macromolecular refractory organics (> 5 k Da); the TN removal rate of A2/O, SBR and the modified A/O was also increased from 74.47%, 70.63% and 78.46%, respectively. High-throughput sequencing revealed increased microbial diversity and an abundance of denitrifying functional bacteria was observed in the modified A/O process at low temperatures. The abundance of nitrite oxidation bacteria (NOB) including Nitrosomonas and Nitrospira, the amount was 1.76% and 2.34% in modified A/O, respectively, whereas NOB only accounted for 1.82% in A2/O and 1.35% in SBR.
Assuntos
Desnitrificação , Nitrogênio , Reatores Biológicos , Esgotos , Eliminação de Resíduos Líquidos , Águas ResiduáriasRESUMO
BACKGROUND: Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), spreads rapidly and has attracted worldwide attention. METHODS: To improve the forecast accuracy and investigate the spread of SARS-CoV-2, we constructed four mathematical models to numerically estimate the spread of SARS-CoV-2 and the efficacy of eradication strategies. RESULTS: Using the Susceptible-Exposed-Infected-Removed (SEIR) model, and including measures such as city closures and extended leave policies implemented by the Chinese government that effectively reduced the ß value, we estimated that the ß value and basic transmission number, R0, of SARS-CoV-2 was 0.476/6.66 in Wuhan, 0.359/5.03 in Korea, and 0.400/5.60 in Italy. Considering medicine and vaccines, an advanced model demonstrated that the emergence of vaccines would greatly slow the spread of the virus. Our model predicted that 100,000 people would become infected assuming that the isolation rate α in Wuhan was 0.30. If quarantine measures were taken from March 10, 2020, and the quarantine rate of α was also 0.3, then the final number of infected people was predicted to be 11,426 in South Korea and 147,142 in Italy. CONCLUSIONS: Our mathematical models indicate that SARS-CoV-2 eradication depends on systematic planning, effective hospital isolation, and SARS-CoV-2 vaccination, and some measures including city closures and leave policies should be implemented to ensure SARS-CoV-2 eradication.
Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Erradicação de Doenças , Modelos Teóricos , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Pneumonia Viral/virologia , COVID-19 , China/epidemiologia , Infecções por Coronavirus/epidemiologia , Epidemias/prevenção & controle , Governo , Humanos , Itália/epidemiologia , Pneumonia Viral/epidemiologia , Quarentena , República da Coreia/epidemiologia , SARS-CoV-2 , VacinaçãoRESUMO
Smoking is associated with an increased risk of respiratory diseases, including lung cancer and asthma. However, the mechanisms or diagnostic markers for smoking-related diseases remain largely unknown. Here we investigated the role of cigarette smoke condensate (CSC) in the regulation of human bronchial epithelial cell (BEAS-2B) behavior. We found that exposure to CSC significantly inhibited BEAS-2B cell viability, impaired cell morphology, induced cell apoptosis, triggered oxidative damage, and promoted inflammatory response, which suggests a deleterious effect of CSC on bronchial epithelial cells. In addition, CSC markedly altered the expression of apoptosis-associated protein factors, including p21, soluble tumor necrosis factor receptor 1, and Fas ligand. In sum, our study identified a panel of novel protein factors that may mediate the actions of CSC on bronchial epithelial cells and have a predictive value for the development and progression of smoking-related diseases, thus providing insights into the development of potential diagnostic and therapeutic strategies against these diseases.
Assuntos
Proteínas Reguladoras de Apoptose/biossíntese , Brônquios/metabolismo , Fumar Cigarros/metabolismo , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Estresse Oxidativo , Brônquios/patologia , Linhagem Celular , Fumar Cigarros/patologia , Células Epiteliais/patologia , HumanosRESUMO
Brassica rapa L., also called NIUMA, is used empirically in Tibetan medicine for its antioxidant, anti-inflammatory and antiradiation activities. This study explored the hepatoprotective effects of B. rapa polysaccharides (BRPs) on acute liver injury induced by carbon tetrachloride (CCl4 ) in mice and the underlying mechanisms. Mice were treated with CCl4 after the oral administration of BRPs (55, 110 and 220â mg/kg) or bifendate (100â mg/kg) for 7â days. Blood and liver samples of mice were collected for analysis after 24â h. The ALP, ALT and AST levels and the biological activities of SOD, MDA and GSH-Px were measured. Histopathological changes in the liver were determined through hematoxylin and eosin staining. Moreover, TNF-α, IL-1ß and IL-6 expression levels were detected by commercial reagent kits. Finally, Western blot analysis was used to check the relative expression levels of caspase-3, p-JAK2 and p-STAT3. The BRP pre-treatment significantly decreased the enzymatic activities of ALT, ALP and AST in the serum, markedly increased the activities of SOD and GSH-Px in the liver and reduced the MDA concentration in the liver. BRPs alleviated hepatocyte injury and markedly inhibited the expression of TNF-α, IL-1ß and IL-6, also downregulating the CCl4 -induced hepatic tissue expression of caspase-3. Furthermore, BRPs inhibited the JAK2/STAT3 signaling pathway in a dose-dependent manner in the liver. This study demonstrated that BRPs exert hepatoprotective effect against the CCl4 -induced liver injury via modulating the apoptotic and inflammatory responses and downregulating the JAK2/STAT3 signaling pathway. Therefore, B. rapa could be considered a hepatoprotective medicine.
Assuntos
Apoptose/efeitos dos fármacos , Brassica rapa/química , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Citocinas/análise , Inflamação/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Polissacarídeos/farmacologia , Animais , Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citocinas/antagonistas & inibidores , Inflamação/induzido quimicamente , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos , Polissacarídeos/administração & dosagemRESUMO
The correlation between sludge reduction induced by 2,4,6-trichlorophenol (2,4,6-TCP) as an uncoupler and sludge toxicity was investigated in sequence batch reactors over a 100-d operation period. The influent concentrations of 2,4,6-TCP tested were 10 mg/L, 30 mg/L, and 50 mg/L. Sludge reduction, chemical oxygen demand (COD) removal rate, and sludge toxicity were measured. The results showed that from 30 to 80 d, when the COD removal rate was at an acceptable level, the sludge reduction levels for the 10 mg/L, 30 mg/L, and 50 mg/L groups were 9.7%, 31.6%, and 41.5%, respectively, and the average sludge toxicity values were 24.2%, 38.0%, and 53.0%, respectively. Sludge reduction was positively correlated with sludge toxicity. The two-dimensional polyacrylamide gel electrophoresis/results showed that extracellular and intracellular proteins secreted by the activated sludge during uncoupling metabolism were positively correlated with sludge toxicity. Taking the COD removal rate, sludge reduction, and sludge toxicity into consideration, the optimal influent concentration of the uncoupler 2,4,6-TCP was 30 mg/L when the initial mixed liquid suspended solids of sludge was 2,500 mg/L.