RESUMO
Zelkova schneideriana is a fast-growing tree species endemic to China. Recent surveys and reports have highlighted a continued decline in its natural populations; therefore, it is included in the Red List of Threatened Species by The International Union for Conservation of Nature. A new variety "HenTianGao" (H) has been developed with smaller plant height, slow growth, and lower branching points. In this study, we attempted to understand the differences in plant height of Z. schneideriana (J) and its dwarf variety H. We determined the endogenous hormone content in the annual grafted branches of both J and H. J exhibited higher gibberellic acid (GA)-19 and trans-Zeatin (tZ) levels, whereas H had higher levels of indole-3-acetic acid (IAA) catabolite 2-oxindole-3-acetic acid (OxIAA), IAA-Glu conjugate, and jasmonic acid (JA) (and its conjugate JA-Ile). The transcriptome comparison showed differential regulation of 20,944 genes enriched in growth and development, signaling, and metabolism-related pathways. The results show that the differential phytohormone level (IAA, JA, tZ, and GA) was consistent with the expression of the genes associated with their biosynthesis. The differences in relative OxIAA, IAA-Glu, GA19, trans-Zeatin, JA, and JA-Ile levels were linked to changes in respective signaling-related genes. We also observed significant differences in the expression of cell size, number, proliferation, cell wall biosynthesis, and remodeling-related genes in J and H. The differences in relative endogenous hormone levels, expression of biosynthesis, and signaling genes provide a theoretical basis for understanding the plant height differences in Z. schneideriana.
Assuntos
Reguladores de Crescimento de Plantas , Zeatina , Reguladores de Crescimento de Plantas/metabolismo , Transcriptoma , Ácidos Indolacéticos/metabolismo , Hormônios , Ulmaceae/metabolismo , Regulação da Expressão Gênica de PlantasRESUMO
Fusobacterium nucleatum is a lesion-associated obligate anaerobic pathogen of destructive periodontal disease; it is also implicated in the progression and severity of colorectal cancer. Four genes (FN0625, FN1055, FN1220, and FN1419) of F. nucleatum are involved in producing hydrogen sulfide (H2S), which plays an essential role against oxidative stress. The molecular functions of Fn1419 are known, but their mechanisms remain unclear. We determined the crystal structure of Fn1419 at 2.5 Å, showing the unique conformation of the PLP-binding site when compared with L-methionine γ-lyase (MGL) proteins. Inhibitor screening for Fn1419 with L-cysteine showed that two natural compounds, gallic acid and dihydromyricetin, selectively inhibit the H2S production of Fn1419. The chemicals of gallic acid, dihydromyricetin, and its analogs containing trihydroxybenzene, were potentially responsible for the enzyme-inhibiting activity on Fn1419. Molecular docking and mutational analyses suggested that Gly112, Pro159, Val337, and Arg373 are involved in gallic acid binding and positioned close to the substrate and pyridoxal-5'-phosphate-binding site. Gallic acid has little effect on the other H2S-producing enzymes (Fn1220 and Fn1055). Overall, we proposed a molecular mechanism underlying the action of Fn1419 from F. nucleatum and found a new lead compound for inhibitor development.
Assuntos
Fusobacterium nucleatum , Sulfeto de Hidrogênio , Fusobacterium nucleatum/metabolismo , Simulação de Acoplamento Molecular , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/metabolismo , Liases de Carbono-Enxofre/genética , Liases de Carbono-Enxofre/metabolismoRESUMO
Butanol dehydrogenase (BDH) plays a significant role in the biosynthesis of butanol in bacteria by catalyzing butanal conversion to butanol at the expense of the NAD(P)H cofactor. BDH is an attractive enzyme for industrial application in butanol production; however, its molecular function remains largely uncharacterized. In this study, we found that Fusobacterium nucleatum YqdH (FnYqdH) converts aldehyde into alcohol by utilizing NAD(P)H, with broad substrate specificity toward aldehydes but not alcohols. An in vitro metal ion substitution experiment showed that FnYqdH has higher enzyme activity in the presence of Co2+. Crystal structures of FnYqdH, in its apo and complexed forms (with NAD and Co2+), were determined at 1.98 and 2.72 Å resolution, respectively. The crystal structure of apo- and cofactor-binding states of FnYqdH showed an open conformation between the nucleotide binding and catalytic domain. Key residues involved in the catalytic and cofactor-binding sites of FnYqdH were identified by mutagenesis and microscale thermophoresis assays. The structural conformation and preferred optimal metal ion of FnYqdH differed from that of TmBDH (homolog protein of FnYqdH). Overall, we proposed an alternative model for putative proton relay in FnYqdH, thereby providing better insight into the molecular function of BDH.
Assuntos
Fusobacterium nucleatum , NAD , Fusobacterium nucleatum/metabolismo , NAD/metabolismo , Oxirredutases do Álcool/metabolismo , Álcoois , Butanóis , 1-Butanol , Especificidade por Substrato , Cristalografia por Raios X , Álcool Desidrogenase/metabolismoRESUMO
OBJECTIVE: Most hepatocellular carcinoma (HCC) patients in China have some degree of liver cirrhosis. The effect of cirrhosis on the long-term prognosis of HCC patients after hepatectomy is still unclear. This study aimed to investigate the effect of liver cirrhosis on the prognosis of HCC patients after hepatectomy. METHODS: Data from patients who underwent hepatectomy and had pathologically confirmed HCC were retrospectively collected. The patients' clinical pathological data were recorded. Propensity score matching (PSM) was used to eliminate the influence of potential confounding factors. The Kaplan-Meier method was used to calculate the recurrence-free survival (RFS) and overall survival (OS) rates, and Cox regression analysis was used to screen for independent risk factors affecting OS and RFS. RESULTS: A total of 1381 HCC patients who were initially treated with hepatectomy were included, including 797 patients with liver cirrhosis. The RFS and OS rates in the group with cirrhosis were significantly lower than those in the group without cirrhosis (after PSM, RFS: P < 0.001; OS: P = 0.001). Subgroup analysis showed that among patients with Barcelona Clinic Liver Cancer (BCLC) stage 0-B disease, RFS and OS were significantly lower in those with cirrhosis than in those without cirrhosis (both P < 0.05); while in patients with stage C disease, there was no significant difference between those with and without cirrhosis. In the group with cirrhosis, alpha-fetoprotein (AFP) > 400, intraoperative blood loss, tumor diameter > 5 cm, satellite lesions, and large vessel invasion were independent risk factors for RFS, while albumin-bilirubin (ALBI) grade, neutrophil-to-lymphocyte ratio (NLR), tumor diameter > 5 cm, satellite lesions, microvascular invasion, and macrovascular invasion were independent risk factors for OS. CONCLUSION: HCC with liver cirrhosis has specific characteristics. Compared with patients without cirrhosis, patients with cirrhosis have worse long-term survival after surgery. In addition, the independent risk factors for RFS and OS are different between patients with cirrhosis and without cirrhosis; liver cirrhosis is an independent risk factor for the long-term prognosis of HCC patients, especially patients with BCLC stage 0-B disease after hepatectomy.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/cirurgia , Humanos , Cirrose Hepática/complicações , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/cirurgia , Pontuação de Propensão , Estudos Retrospectivos , Análise de SobrevidaRESUMO
We describe a mild and broadly applicable protocol for the preparation of a diverse array of multisubstituted α-selenoenals and -enones from readily accessible propargylic alcohols and diselenides. The transformation proceeds via the Selectfluor-promoted selenirenium pathway, which enables selenenylation/rearrangement of a variety of propargylic alcohols. Gram-scale experiments showed the potential of this synergistic protocol for practical application.
RESUMO
INTRODUCTION: Loss of hepatic epidermal growth factor receptor (EGFR) expression is a cause for the increased perioperative risk for complications and death in patients with obesity and fatty liver undergoing liver resection. Herein, we set out to identify agents that might increase EGFR expression and improve recovery for patients with fatty liver undergoing resection. Using the diet-induced obese (DIO) mouse model of fatty liver, we examined resveratrol as a therapy to induce EGFR expression and improve outcomes following 80% partial hepatectomy (PH) in a murine model. METHODS: DIO mice were fed resveratrol or carrier control by gavage. EGFR expression and the response to major (80%) PH were examined. RESULTS: Based on an Illumina analysis, resveratrol was identified as increasing EGFR gene expression in A549 cells. Resveratrol was observed to also increase EGFR protein expression in A549 cells. DIO mice fed resveratrol by gavage (75 mg/kg) demonstrated an increased EGFR expression without the identified hepatic toxicity. Resveratrol and control mice subjected to 80% PH, a model of high mortality hepatectomy in DIO mice, demonstrated macroscopically decreased fatty liver and fewer liver hemorrhagic petechiae. Resveratrol pretreatment ameliorated liver injury and accelerated regeneration of the hepatic remnant after 80% PH including decreasing serum ALT and bilirubin, while increasing hepatic PCNA expression. Resveratrol increased induction of p-STAT3 and p-AKT after 80% hepatectomy. Resveratrol pretreatment significantly improved survival rates in DIO mice undergoing extended 80% PH. CONCLUSIONS: Oral resveratrol restores EGFR expression in fatty liver. Resveratrol may be a promising protective agent in instances where extensive hepatic resection of fatty liver is required.
Assuntos
Dieta Hiperlipídica , Hepatectomia , Regeneração Hepática/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/cirurgia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/cirurgia , Obesidade/etiologia , Resveratrol/farmacologia , Células A549 , Animais , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Receptores ErbB/metabolismo , Humanos , Fígado/metabolismo , Fígado/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Obesidade/metabolismo , Obesidade/fisiopatologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Recuperação de Função Fisiológica , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para CimaRESUMO
BACKGROUND: The rapid development of genetic and genomic technologies, such as next-generation sequencing and genome editing, has made disease treatment much more precise and effective. The technologies' value can only be realized by the aggregation and analysis of people's genomic and health data. However, the collection and sharing of genomic data has many obstacles, including low data quality, information islands, tampering distortions, missing records, leaking of private data, and gray data transactions. OBJECTIVE: This study aimed to prove that emerging blockchain technology provides a solution for the protection and management of sensitive personal genomic data because of its decentralization, traceability, encryption algorithms, and antitampering features. METHODS: This paper describes the case of a blockchain-based genomic big data platform, LifeCODE.ai, to illustrate the means by which blockchain enables the storage and management of genomic data from the perspectives of data ownership, data sharing, and data security. RESULTS: Blockchain opens up new avenues for dealing with data ownership, data sharing, and data security issues in genomic big data platforms and realizes the psychological empowerment of individuals in the platform. CONCLUSIONS: The blockchain platform provides new possibilities for the management and security of genetic data and can help realize the psychological empowerment of individuals in the process, and consequently, the effects of data self-governance, incentive-sharing, and security improvement can be achieved. However, there are still some problems in the blockchain that have not been solved, and which require continuous in-depth research and innovation in the future.
Assuntos
Blockchain , Segurança Computacional , Genômica/métodos , Disseminação de Informação , Algoritmos , Big Data , China , Humanos , Aplicativos Móveis , Propriedade , Privacidade , SoftwareRESUMO
Organochlorine pesticides have been banned for many years, but the residual trace amount of organochlorine in water may still pose ecotoxicological risk. Meanwhile, the potential risk of organochlorine pesticides released from sediments, especially into drinking water sources, is receiving increasing attention. The present study assessed the pollution and potential risk of drinking water sources along the midstream and downstream Yangtze River. Residues of organochlorine pesticides (OCPs) in water, suspended particle matter (SPM), and sediment were evaluated with isotope dilution HRGC/HRMS. The results indicated that OCPs in water, SPM, and sediment ranged in 0.52-92.97â¯ng/L, 0.10-4.10â¯ng/L, and 0.038-11.36â¯ng/g, respectively. The predominant OCPs in water, SPM, and sediment were ß-HCH, p,p'-DDE and PeCB. At site Y1, 8, 13, 18, ß-HCH has a higher proportion in sediment samples, while, α-HCH has a higher proportion in SPM samples. The industrial use of HCHs in the history was the main HCHs source for most water and sediment samples, which indicated an absence of fresh inputs of industrial HCHs. Meanwhile, the abundance of p,p'-DDE in water, sediment and SPM samples could be attributed to long-term aerobic degradation of DDTs. The values of ffsw of HCHs, DDTs and PeCB indicate the transfer from water to sediment. Risk assessment showed that HCHs and DDTs posed low ecotoxicological risk to the Yangtze River.
Assuntos
Diclorodifenil Dicloroetileno/análise , Água Potável/química , Monitoramento Ambiental/métodos , Hexaclorocicloexano/análise , Resíduos de Praguicidas/análise , Rios/química , China , Sedimentos Geológicos/química , Medição de Risco , Poluentes Químicos da Água/análiseRESUMO
Organochlorine pesticides (OCPs) are ubiquitous environmental contaminants, while their correlations with δ15N values and fatty acids (FAs) in fish tissues remain largely unexplored. In the present study, six species of fish for daily consumption were collected from Dongting Lake, and they were dissected to tissue samples to analyze the δ15N values, FAs and OCPs. The results showed that the δ15N values of fish were ranked in the same order in different fish tissues. The polyunsaturated fatty acids (PUFAs) had a different distribution pattern in fish tissues, while the saturated fatty acid (SFAs) and monounsaturated fatty acids (MUFAs) were not. The composition of HCHs in fish tissues exhibited a tissue-specific and species-specific manner, while such pattern was not detected for DDTs. The correlation analysis indicated that the ratio of DHA/EPA was increased with the increase of δ15N value in the muscle, liver, gill, skin and intestine, indicating the substance flow in freshwater ecosystem. In addition, there were significant positive correlations between the concentrations of some PUFAs and OCPs in the muscle, suggesting that people should pay attention to co-intake of OCPs when they supplemented the PUFAs needed by the human body through fish.
Assuntos
Ácidos Graxos/metabolismo , Hidrocarbonetos Clorados/metabolismo , Praguicidas/metabolismo , Poluentes Químicos da Água/metabolismo , Animais , China , Correlação de Dados , Monitoramento Ambiental , Peixes , Humanos , Hidrocarbonetos Clorados/análise , Hidrocarbonetos Clorados/toxicidade , Lagos , Isótopos de Nitrogênio , Praguicidas/análise , Praguicidas/toxicidade , Alimentos Marinhos/análise , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidadeRESUMO
The contamination of perfluoroalkyl substances (PFASs) in the Baiyangdian Lake has exacerbated readily since 2008. This study analyzed the perfluoroalkyl carboxylic acids (PFCAs) and perfluoroalkane sulfonic acids (PFSAs) in the surface water, sediment, and fish of the Baiyangdian Lake. In the surface water, the total concentration of PFASs ranged in 1193-3462â¯ngâ¯L-1 (mean 1734â¯ngâ¯L-1) in the rainy season and 469-1724â¯ngâ¯L-1 (mean 876â¯ngâ¯L-1) in the dry season. The total concentration of PFASs in the sediment ranged in 1.97-13.3â¯ngâ¯g-1 (mean 6.53â¯ngâ¯g-1). It was found that PFCAs and PFSAs with longer chains were more easily adsorbed in the sediment. Among the collected fish samples, the enrichment of PFASs in the tissues fell in the order of liverâ¯>â¯cheekâ¯>â¯muscle. For the muscle, stomach, and liver tissues of the fish samples, significant correlations existed between the δ15N values and the concentration of perfluorooctane sulfonic acid (PFOS). The contents of PFOS and perfluorooctanoic acid (PFOA) in the fish were not at a level high enough to significantly risk human health.
Assuntos
Ácidos Alcanossulfônicos/análise , Caprilatos/análise , Monitoramento Ambiental/métodos , Fluorocarbonos/análise , Lagos/química , Poluentes Químicos da Água/análise , Animais , China , Peixes/metabolismo , Sedimentos Geológicos/química , Medição de RiscoRESUMO
Drug resistance and relapse is common in cancer treatments with chemotherapeutics, and while drug combinations with naturally occurring, differentiation-inducing retinoic acid (RA) provide remission-free cures for one type of liquid tumor, solid tumors present major problems for delivery. Here, inspired by filoviruses that can be microns in length, flexible filomicelles that self-assemble from an amphiphilic block copolymer (PEG-PCL) are shown to effectively deliver RA and paclitaxel (TAX) to several solid tumor models, particularly in the liver. These hydrophobic compounds synergistically load into the cores of the elongated micelles, and the coloaded micelles prove most effective at causing cell death, ploidy, and durable regression of tumors compared to free drugs or to separately loaded drugs. RA-TAX filomicelles also reduce mortality of human lung or liver derived cancers engrafted at liver, intraperitoneal, and subcutaneous sites in immunodeficient mice. In vitro studies show that the dual drug micelles effectively suppress proliferation while upregulating a generic differentiation marker. The results highlight the potency of dual-loaded filomicelles in killing cancer cells or else driving their differentiation away from growth.
Assuntos
Antineoplásicos/administração & dosagem , Portadores de Fármacos/química , Neoplasias Hepáticas/tratamento farmacológico , Paclitaxel/administração & dosagem , Poliésteres/química , Polietilenoglicóis/química , Tretinoína/administração & dosagem , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Micelas , Paclitaxel/uso terapêutico , Tretinoína/uso terapêuticoRESUMO
BACKGROUND: Intra-abdominal adhesions are a major cause of morbidity after abdominal or gynecologic surgery. However, knowledge about the pathogenic mechanism(s) is limited, and there are no effective treatments. Here, we investigated a mouse model of bowel adhesion formation and the effect(s) of an Federal Drug Administration-approved drug (trametinib) in preventing adhesion formation. MATERIALS AND METHODS: C57BL/6 mice were used to develop a consistent model of intra-abdominal adhesion formation by gentle cecal abrasion with mortality rates of <10%. Adhesion formation was analyzed histologically and immunochemically to characterize the expression of pro-fibrotic marker proteins seen in pathologic scaring and included alpha smooth muscle actin (αSMA) and fibronectin EDA (FNEDA) which arises from alternative splicing of the fibronectin messenger RNA resulting in different protein isoforms. Trichrome staining assessed collagen deposition. Quantitative polymerase chain reaction analysis of RNA isolated from adhesions by laser capture microscopy was carried out to assess pro-fibrotic gene expression. To block adhesion formation, trametinib was administered via a subcutaneous osmotic pump. RESULTS: Adhesions were seen as early as post-operative day 1 with extensive adhesions being formed and vascularized by day 5. The expression of the FNEDA isoform occurred first with subsequent expression of αSMA and collagen. The drug trametinib was chosen for in vivo studies because it effectively blocked the mesothelial to mesenchymal transition of rat mesothelium. Trametinib, at the highest dose used (3 mg/kg/d), prevented adhesion formation while at lower doses, adhesions were usually limited, as evidenced by the presence of FNEDA isoform but not αSMA. CONCLUSIONS: Cecal abrasion in mice is a reliable model to study abdominal adhesions, which can be ameliorated using the MEK1/2 inhibitor trametinib. While blocking adhesion formation at the cell and molecular levels, trametinib, at the therapeutic doses utilized, did not impair the wound healing at the laparotomy site.
Assuntos
Ceco/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Complicações Pós-Operatórias/prevenção & controle , Inibidores de Proteínas Quinases/farmacologia , Piridonas/farmacologia , Pirimidinonas/farmacologia , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Parede Abdominal/cirurgia , Animais , Ceco/efeitos dos fármacos , Ceco/cirurgia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peritônio/efeitos dos fármacos , Peritônio/patologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Aderências Teciduais/etiologia , Aderências Teciduais/patologia , Aderências Teciduais/prevenção & controle , Cicatrização/efeitos dos fármacosRESUMO
The exact mechanism of delayed death of Toxoplasma gondii is not known. FAS II synthesis in the apicoplast of T. gondii is essential for the survival of Toxoplasma gondii, while ß-hydroxyacylacyl carrier protein dehydratase (FabZ) is indispensable for fatty acid synthesis. The present study investigated the relationship between the delayed death of T. gondii by inducing metabolic disorders due to suppression the expression of FabZ. A tetracycline-induced knockout vector inserted with T. gondii fabZ gene was constructed, and transfected into T. gondii TATi strain by electroporation. The stable mutants with tetracycline-induced knockout were selected, expression of FabZ was suppressed by using anhydrotetracycline (ATc), and FAS II deficient tachyzoites were prepared. The Western blot and qPCR results revealed that proliferation of FAS II deficient tachyzoites was not significantly different compared to the normal tachyzoites at 24 h and 48 h; however, after 72 h, the number of T. gondii tachyzoites in the ATc treated group was significantly (p < 0.05) less than that of non-treated group, indicating the delayed death of T. gondii caused by the loss of apicoplast and decrease in the expression of FabZ, which inhibited the FAS II metabolism. The results of this study can be used for prevention of toxoplasmosis by inducing delayed death of T. gondii.
Assuntos
Doenças Metabólicas , Toxoplasma , Antibacterianos , Humanos , Reação em Cadeia da Polimerase em Tempo Real , Tetraciclina , Toxoplasma/genéticaRESUMO
OBJECTIVE: Our study was to explore the roles between serum soluble suppression of tumorigenicity 2 (sST2) and N-terminal pro-brain natriuretic peptide (NT-proBNP) while evaluating ventricular function to properly diagnose chronic heart failure (CHF). METHODS: In total, 197 CHF patients were recruited and classified into ventricular function's II, III, and IV groups, and 106 healthy people into normal control group. To detect concentrations of Sst2 and NT-proBNP, ELISA and electro-chemiluminescence immuno assay were implemented. An automatic biochemical analyzer was used to determine the levels of the following: blood urea nitrogen (BUN), creatinine (Cr), alanine aminotransferase (ALT), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and uric acid (UA). A receiver operating characteristic (ROC) curve was adopted to detect the diagnostic value sST2 and NT-ProBNP in CHF and the logistic regression analysis involving the risk factors of CHF. RESULTS: Serum sST2 and NT-proBNP concentrations were increased significantly in the ventricular function's II, III, and IV groups in a manner dependent on concentration as opposed to the manner the normal control group occupied. The area under the curve (AUC) of sST2, found NT-proBNP and sST2+NT-proBNP to be 0.942 (95% CI: 0.917-0.966), 0.920 (95% CI: 0.891-0.948), and 0.968 (95% CI: 0.953-0.984), respectively. sST2, NT-proBNP, UA, and Cr were verified as important risk factors of CHF. CONCLUSION: Serum sST2 and NT-ProBNP could act as diagnostic indicators for CHF.
Assuntos
Insuficiência Cardíaca , Proteína 1 Semelhante a Receptor de Interleucina-1/sangue , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Adulto , Idoso , Estudos de Casos e Controles , Doença Crônica , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/epidemiologia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Curva ROCRESUMO
Hepatic steatosis is a common histological finding in obese patients. Even mild steatosis is associated with delayed hepatic regeneration and poor outcomes following liver resection or transplantation. We sought to identify and target molecular pathways that mediate this dysfunction. Lean mice and mice made obese through feeding of a high-fat, hypercaloric diet underwent 70 or 80% hepatectomy. After 70% resection, obese mice demonstrated 100% survival but experienced increased liver injury, reduced energy stores, reduced mitoses, increased necroapoptosis, and delayed recovery of liver mass. Increasing liver resection to 80% was associated with mortality of 40% in lean and 80% in obese mice (P < 0.05). Gene expression profiling showed decreased epidermal growth factor receptor (EGFR) in fatty liver. Meta-analysis of expression studies in mice, rats, and patients also demonstrated reduction of EGFR in fatty liver. In mice, both EGFR and phosphorylated EGFR decreased with increasing percent body fat. Hydrodynamic transfection of EGFR plasmids in mice corrected fatty liver regeneration, reducing liver injury, increasing proliferation, and improving survival after 80% resection. Loss of EGFR expression is rate limiting for liver regeneration in obesity. Therapies directed at increasing EGFR in steatosis might promote liver regeneration and survival following hepatic resection or transplantation.
Assuntos
Receptores ErbB/genética , Hepatectomia , Regeneração Hepática/genética , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Obesidade/metabolismo , Animais , Apoptose/genética , Western Blotting , Dieta Hiperlipídica , Perfilação da Expressão Gênica , Fígado/patologia , Fígado/cirurgia , Camundongos , Camundongos Endogâmicos C57BL , Mitose/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Taxa de SobrevidaRESUMO
BACKGROUND: The universal stress proteins (USP) family member UspE is a tandem-type USP that consists of two Usp domains. The UspE expression levels of the Escherichia coli (E. coli) become elevated in response to oxidative stress and DNA damaging agents, including exposure to mitomycin C, cadmium, and hydrogen peroxide. It has been shown that UspA family members are survival factors during cellular growth arrest. The structures and functions of the UspA family members control the growth of E. coli in animal hosts. While several UspA family members have known structures, the structure of E. coli UspE remains to be elucidated. RESULTS: To understand the biochemical function of UspE, we have determined the crystal structure of E. coli UspE at 3.2 Å resolution. The asymmetric unit contains two protomers related by a non-crystallographic symmetry, and each protomer contains two tandem Usp domains. The crystal structure shows that UspE is folded into a fan-shaped structure similar to that of the tandem-type Usp protein PMI1202 from Proteus mirabilis, and it has a hydrophobic cavity that binds its ligand. Structural analysis revealed that E. coli UspE has two metal ion binding sites, and isothermal titration calorimetry suggested the presence of two Cd(2+) binding sites with a Kd value of 38.3-242.7 µM. Structural analysis suggested that E. coli UspE has two Cd(2+) binding sites (Site I: His117, His 119; Site II: His193, His244). CONCLUSION: The results show that the UspE structure has a hydrophobic pocket. This pocket is strongly bound to an unidentified ligand. Combined with a previous study, the ligand is probably related to an intermediate in lipid A biosynthesis. Subsequently, sequence analysis found that UspE has an ATP binding motif (Gly(269)- X2-Gly(272)-X9-Gly(282)-Asn) in its C-terminal domain, which was confirmed by in vitro ATPase activity monitored using Kinase-Glo® Luminescent Kinase Assay. However, the residues constituting this motif were disordered in the crystal structure, reflecting their intrinsic flexibility. ITC experiments revealed that the UspE probably has two Cd(2+) binding sites. The His117, His 119, His193, and His244 residues within the ß-barrel domain are necessary for Cd(2+) binding to UspE protein. As mentioned above, USPs are associated with several functions, such as cadmium binding, ATPase function, and involvement in lipid A biosynthesis by some unknown way.
Assuntos
Proteínas de Escherichia coli/química , Escherichia coli/química , Proteínas de Choque Térmico/química , Cádmio/química , Cristalografia por Raios X , Escherichia coli/fisiologia , Proteínas de Escherichia coli/fisiologia , Proteínas de Choque Térmico/fisiologia , Ligantes , Conformação ProteicaRESUMO
This paper reports a room temperature visible-light-driven protocol for the intermolecular [2+2] cycloadditions between coumarin-3-carboxylates and acrylamides analogs by an energy-transfer process. Using an iridium complex FIrPic as a photosensitizer and a 3â W blue LED as a light source, an array of cyclobutabenzocypyranones were prepared in moderate to excellent yields.
RESUMO
Four novel compounds were designed by "tailoring" 3,3'-dihydroxyisorenieratene (a natural carotenoid) based on an isoprene unit retention truncation strategy. Among them, the smallest molecule 1 (2,3,6,2',3',6'-hexamethyl-4,4'-dihydroxy-trans-stilbene) was concisely synthesized in a one-pot Stille-Heck tandem sequence, and surfaced as a promising lead molecule in terms of its selective antiproliferative activity mediated by blocking the NCI-H460 cell cycle in G1 phase. Additionally, theoretical calculations and cell uptake experiments indicate that the unique polymethylation pattern of compound 1 significantly induces a conformational change shift out of planarity and increases its cell uptake and metabolic stability. The observation should be helpful to rationally design resveratrol-inspired antiproliferative agents.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carotenoides/farmacologia , Proliferação de Células/efeitos dos fármacos , Estilbenos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Carotenoides/química , Carotenoides/farmacocinética , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Descoberta de Drogas , Humanos , Modelos Moleculares , Resveratrol , Estilbenos/química , Estilbenos/farmacocinéticaRESUMO
Constructed wetlands (CWs) are pivotal for wastewater treatment due to their high efficiency and numerous advantages. The impact of plant species and diversity on greenhouse gas (GHG) emissions from CWs requires a more comprehensive evaluation. Moreover, controversial perspectives persist about whether CWs function as carbon sinks or sources. In this study, horizontal subsurface flow (HSSF) CWs vegetated with Cyperus alternifolius, Typhae latifolia, Acorus calamus, and the mixture of these three species were constructed to evaluate pollutant removal efficiencies and GHG emissions, and estimate carbon budgets. Polyculture CWs can stably remove COD (86.79 %), NH4+-N (97.41 %), NO3--N (98.55 %), and TP (98.48 %). They also mitigated global warming potential (GWP) by suppressing N2O emissions compared with monoculture CWs. The highest abundance of the Pseudogulbenkiania genus, crucial for denitrification, was observed in polyculture CWs, indicating that denitrification dominated in nitrogen removal. While the highest nosZ copy numbers were observed in CWs vegetated with Cyperus alternifolius, suggesting its facilitation of denitrification-related microbes. Selecting Cyperus alternifolius to increase species diversity is proposed for simultaneously maintaining the water purification capacity and reducing GHG emissions. Carbon budget estimations revealed that all four types of HSSF CWs were carbon sinks after six months of operation, with carbon accumulation capacity of 4.90 ± 1.50 (Cyperus alternifolius), 3.31 ± 2.01 (Typhae latifola), 1.78 ± 1.30 (Acorus calamus), and 2.12 ± 0.88 (polyculture) kg C/m2/yr. This study implies that under these operation conditions, CWs function as carbon sinks rather than sources, aligning with carbon peak and neutrality objectives and presenting significant potential for carbon reduction efforts.
Assuntos
Gases de Efeito Estufa , Eliminação de Resíduos Líquidos , Áreas Alagadas , Gases de Efeito Estufa/análise , Eliminação de Resíduos Líquidos/métodos , Cyperus/metabolismo , Carbono/metabolismo , Águas Residuárias , Typhaceae/metabolismo , Acorus/metabolismoRESUMO
Thiosulfonylation and selenosulfonylation of vinyl azides with thiosulfonates and selenosulfonates were achieved using Cu(dap)2Cl as a photosensitizer under visible-light irradiation. This reaction is the application of a vinyl azide substrate in a group transfer radical addition (GTRA) reaction, through ß-difunctionalization, to obtain a variety of unsymmetric difunctionalized N-unprotected enamines.