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To understand the bud banks response to grazing exclusion, we conducted a demographic experiment in long-term grazing exclusion (20 year and 30 year) typical steppe. Results showed that grass functional group constituted the vast majority of the aboveground vegetation and belowground bud bank in all treatments. Long-term grazing exclusion significantly increased total aboveground biomass (2.5 and 2.6 times in 20y and 30y grazing exclusion grasslands, respectively), and decreased total stem density (31% and 37% in 20y and 30y grazing exclusion grasslands, respectively). Grazing exclusion for 20 and 30 years increased grass aboveground biomass respectively by 6.0 and 8.0 times, and decreased grass stem density by 38% and 33%. Grazing exclusion had different effects on belowground bud density of grass and forb functional group. Long-term grazing exclusion significantly increased plant buds and bud bank size (25% and 37% in 20y and 30y grazing exclusion grasslands, respectively), especially for grass functional group (49% and 95% in 20y and 30y grazing exclusion grasslands, respectively), but had no significant effects on forb bud density. Changes of aboveground community were significantly related to changes of belowground bud bank under both grazing and grazing exclusion grasslands. The bud bank density of grass functional group was significantly positive with total (R2â¯=â¯0.33, Pâ¯<â¯0.05) and grass aboveground biomass (R2â¯=â¯0.36, Pâ¯<â¯0.01), while negative related with total (R2â¯=â¯-0.27, Pâ¯<â¯0.05) and grass stem density (R2â¯=â¯-0.22, Pâ¯<â¯0.05). Grazed grasslands, 20y and 30y grazing exclusion grasslands all were not meristem limited and had large reserve bud banks, which would completely replace the aboveground stem population during the growing season. These findings indicate that grazing exclusion could not only improve a large bud bank for grassland restoration but also improve the dominance of grass functional group by increasing grass belowground bud banks in typical steppe community. We propose that the belowground bud bank might be a good approach to indicating potential succession direction of aboveground community.
Assuntos
Pradaria , Poaceae , Biomassa , Plantas , Estações do AnoRESUMO
Cellular repressor of E1A-stimulated genes (CREG), a novel cellular glycoprotein, has been identified as a suppressor of various cardiovascular diseases because of its capacity to reduce hyperplasia, maintain vascular homeostasis, and promote endothelial restoration. However, the effects and mechanism of CREG in metabolic disorder and hepatic steatosis remain unknown. Here, we report that hepatocyte-specific CREG deletion dramatically exacerbates high-fat diet and leptin deficiency-induced (ob/ob) adverse effects such as obesity, hepatic steatosis, and metabolic disorders, whereas a beneficial effect is conferred by CREG overexpression. Additional experiments demonstrated that c-Jun N-terminal kinase 1 (JNK1) but not JNK2 is largely responsible for the protective effect of CREG on the aforementioned pathologies. Notably, JNK1 inhibition strongly prevents the adverse effects of CREG deletion on steatosis and related metabolic disorders. Mechanistically, CREG interacts directly with apoptosis signal-regulating kinase 1 (ASK1) and inhibits its phosphorylation, thereby blocking the downstream MKK4/7-JNK1 signaling pathway and leading to significantly alleviated obesity, insulin resistance, and hepatic steatosis. Importantly, dramatically reduced CREG expression and hyperactivated JNK1 signaling was observed in the livers of nonalcoholic fatty liver disease (NAFLD) patients, suggesting that CREG might be a promising therapeutic target for NAFLD and related metabolic diseases. CONCLUSION: The results of our study provides evidence that CREG is a robust suppressor of hepatic steatosis and metabolic disorders through its direct interaction with ASK1 and the resultant inactivation of ASK1-JNK1 signaling. This study offers insights into NAFLD pathogenesis and its complicated pathologies, such as obesity and insulin resistance, and paves the way for disease treatment through targeting CREG. (Hepatology 2017;66:834-854).
Assuntos
Dieta Hiperlipídica , Regulação da Expressão Gênica , Resistência à Insulina/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Proteínas Repressoras/genética , Animais , Biópsia por Agulha , Modelos Animais de Doenças , Humanos , Imuno-Histoquímica , Metabolismo dos Lipídeos/genética , MAP Quinase Quinase Quinase 5/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Distribuição Aleatória , Valores de Referência , Transdução de Sinais , Estatísticas não ParamétricasRESUMO
Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, impaired insulin sensitivity, and chronic low-grade inflammation. However, the pathogenic mechanism of NAFLD is poorly understood, which hinders the exploration of possible treatments. Here, we report that ubiquitin-specific protease 18 (USP18), a member of the deubiquitinating enzyme family, plays regulatory roles in NAFLD progression. Expression of USP18 was down-regulated in the livers of nonalcoholic steatohepatitis patients and high-fat diet (HFD)-induced or genetically obese mice. When challenged with HFD, hepatocyte-specific USP18 transgenic mice exhibited improved lipid metabolism and insulin sensitivity, whereas mice knocked out of USP18 expression showed adverse trends regarding hepatic steatosis and glucose metabolic disorders. Furthermore, the concomitant inflammatory response was suppressed in USP18-hepatocyte-specific transgenic mice and promoted in USP18-hepatocyte-specific knockout mice treated with HFD. Mechanistically, hepatocyte USP18 ameliorates hepatic steatosis by interacting with and deubiquitinating transforming growth factorß-activated kinase 1 (TAK1), which inhibits TAK1 activation and subsequently suppresses the downstream c-Jun N-terminal kinase and nuclear factor kappa B signaling pathways. This is further validated by alleviated steatotic phenotypes and highly activated insulin signaling in HFD-fed USP18-hepatocyte-specific knockout mice administered a TAK1 inhibitor. The therapeutic effect of USP18 on NAFLD relies on its deubiquitinating activity because HFD-fed mice injected with active-site mutant USP18 failed to inhibit hepatic steatosis. CONCLUSION: USP18 associates with and deubiquitinates TAK1 to protect against hepatic steatosis, insulin resistance, and the inflammatory response. (Hepatology 2017;66:1866-1884).
Assuntos
Endopeptidases/metabolismo , Fígado Gorduroso/enzimologia , Inflamação/enzimologia , Resistência à Insulina , Ubiquitina Tiolesterase/metabolismo , Animais , Enzimas Desubiquitinantes/metabolismo , Humanos , Fígado/enzimologia , MAP Quinase Quinase Quinases/metabolismo , Camundongos KnockoutRESUMO
Ex vivo red blood cell (RBC) production generates unsatisfactory erythroid cells. A deep exploration into terminally differentiated cells is required to understand the impairments for RBC generation and the underlying mechanisms. Here, we mapped an atlas of terminally differentiated cells from umbilical cord blood mononuclear cells (UCBMN) and pluripotent stem cells (PSC) and observed their dynamic regulation of erythropoiesis at single-cell resolution. Interestingly, we detected a few progenitor cells and non-erythroid cells from both origins. In PSC-derived erythropoiesis (PSCE), the expression of haemoglobin switch regulators (BCL11A and ZBTB7A) were significantly absent, which could be the restraint for its adult globin expression. We also found that PSCE were less active in stress erythropoiesis than in UCBMN-derived erythropoiesis (UCBE), and explored an agonist of stress erythropoiesis gene, TRIB3, could enhance the expression of adult globin in PSCE. Compared with UCBE, there was a lower expression of epigenetic-related proteins (e.g., CASPASE 3 and UBE2O) and transcription factors (e.g., FOXO3 and TAL1) in PSCE, which might restrict PSCE's enucleation. Moreover, we characterized a subpopulation with high proliferation capacity marked by CD99high in colony-forming unit-erythroid cells. Inhibition of CD99 reduced the proliferation of PSC-derived cells and facilitated erythroid maturation. Furthermore, CD99-CD99 mediated the interaction between macrophages and erythroid cells, illustrating a mechanism by which macrophages participate in erythropoiesis. This study provided a reference for improving ex vivo RBC generation.
Assuntos
Diferenciação Celular , Eritropoese , Sangue Fetal , Leucócitos Mononucleares , Células-Tronco Pluripotentes , Humanos , Células-Tronco Pluripotentes/metabolismo , Células-Tronco Pluripotentes/citologia , Sangue Fetal/citologia , Sangue Fetal/metabolismo , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/citologia , Células Cultivadas , Proliferação de CélulasRESUMO
Retinopathy is one of the main causes of blindness worldwide. Investigating its pathogenesis is essential for the early diagnosis and timely treatment of retinopathy. Unfortunately, ethical barriers hinder the collection of evidence from humans. Recently, numerous studies have shown that human pluripotent stem cells (PSCs) can be differentiated into retinal organoids (ROs) using different induction protocols, which have enormous potential in retinopathy for disease modeling, drug screening, and stem cell-based therapies. This study describes an optimized induction protocol to generate neural retina (NR) that significantly reduces the probability of vesiculation and fusion, increasing the success rate of production until day 60. Based on the ability of PSCs to self-reorganize after dissociation, combined with certain complementary factors, this new method can specifically drive NR differentiation. Furthermore, the approach is uncomplicated, cost-effective, exhibits notable repeatability and efficiency, presents encouraging prospects for personalized models of retinal diseases, and supplies a plentiful cell reservoir for applications such as cell therapy, drug screening, and gene therapy testing.
Assuntos
Células-Tronco Pluripotentes , Doenças Retinianas , Humanos , Retina , Doenças Retinianas/terapia , Cegueira , Diferenciação CelularRESUMO
In the current study, we assessed the effects of antibacterial peptide-producing Bacillus subtilis (BS), gallic acid (GA) and cellulase (CL) on the fermentation quality and bacterial community of various varieties of whole-plant corn silage. Three different varieties of whole-plant corn (Yuqing386, Enxiai298, and Nonghe35) were treated with 0.02% BS (fresh material basis), 0.2% GA (fresh material basis) and 0.02% CL (fresh material basis), after which 45 days of anaerobic fermentation were conducted. With the exception of its low dry matter content, the results showed that Yuqing386's crude protein, water-soluble carbohydrate, and lactic acid contents were significantly higher than those of the other two corn varieties. However, its acid detergent fiber and cellulose contents were significantly lower than those of the other two corn varieties. Among the three corn variety silages, Yuqing386 had the highest relative abundance of Lactobacillus at the genus level and the biggest relative abundance of Firmicutes at the phylum level. In addition, the three additives markedly enhanced the quantity of dry matter and crude protein as compared to the control group. The application of GA considerably decreased the level of neutral detergent fiber while significantly increasing the content of lactic acid and water-soluble carbohydrates. Even though all additives enhanced the structure of the bacterial community following silage, the GA group experienced the greatest enhancement. On a phylum and genus level, the GA group contains the highest relative abundance of Firmicutes and Lactobacillus, respectively. Overall, of the three corn varieties, Yuqing386 provides the best silage qualities. GA has the biggest impact among the additions employed in this experiment to enhance the nutritional preservation and fermentation quality of whole-plant corn silage.
RESUMO
Nonalcoholic steatohepatitis (NASH) is a progressive liver disease and has become a leading indication for liver transplantation in the United States. The development of effective therapies for NASH is a major unmet need. Here, we identified a small molecule, IMA-1, that can treat NASH by interrupting the arachidonate 12-lipoxygenase (ALOX12)acetyl-CoA carboxylase 1 (ACC1) interaction. IMA-1 markedly blocked diet-induced NASH progression in both male mice and Cynomolgus macaque therapeutic models. The anti-NASH efficacy of IMA-1 was comparable to ACC inhibitor in both species. Protein docking simulations and following functional experiments suggested that the anti-NASH effects of IMA-1 were largely dependent on its direct binding to a pocket in ALOX12 proximal to its ACC1-interacting surface instead of inhibiting ALOX12 lipoxygenase activity. IMA-1 treatment did not elicit hyperlipidemia, a known side effect of direct inhibition of ACC enzymatic activity, in both mice and macaques. These findings provide proof of concept across multiple species for the use of small moleculebased therapies for NASH.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Acetil-CoA Carboxilase , Animais , Fígado/metabolismo , Macaca/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismoRESUMO
The prognostic power of circulating cardiac biomarkers, their utility, and pattern of release in coronavirus disease 2019 (COVID-19) patients have not been clearly defined. In this multicentered retrospective study, we enrolled 3219 patients with diagnosed COVID-19 admitted to 9 hospitals from December 31, 2019 to March 4, 2020, to estimate the associations and prognostic power of circulating cardiac injury markers with the poor outcomes of COVID-19. In the mixed-effects Cox model, after adjusting for age, sex, and comorbidities, the adjusted hazard ratio of 28-day mortality for hs-cTnI (high-sensitivity cardiac troponin I) was 7.12 ([95% CI, 4.60-11.03] P<0.001), (NT-pro)BNP (N-terminal pro-B-type natriuretic peptide or brain natriuretic peptide) was 5.11 ([95% CI, 3.50-7.47] P<0.001), CK (creatine phosphokinase)-MB was 4.86 ([95% CI, 3.33-7.09] P<0.001), MYO (myoglobin) was 4.50 ([95% CI, 3.18-6.36] P<0.001), and CK was 3.56 ([95% CI, 2.53-5.02] P<0.001). The cutoffs of those cardiac biomarkers for effective prognosis of 28-day mortality of COVID-19 were found to be much lower than for regular heart disease at about 19%-50% of the currently recommended thresholds. Patients with elevated cardiac injury markers above the newly established cutoffs were associated with significantly increased risk of COVID-19 death. In conclusion, cardiac biomarker elevations are significantly associated with 28-day death in patients with COVID-19. The prognostic cutoff values of these biomarkers might be much lower than the current reference standards. These findings can assist in better management of COVID-19 patients to improve outcomes. Importantly, the newly established cutoff levels of COVID-19-associated cardiac biomarkers may serve as useful criteria for the future prospective studies and clinical trials.
Assuntos
Infecções por Coronavirus , Creatina Quinase Forma MB/sangue , Cardiopatias , Peptídeo Natriurético Encefálico/sangue , Pandemias , Fragmentos de Peptídeos/sangue , Pneumonia Viral , Troponina I/sangue , Betacoronavirus/isolamento & purificação , Biomarcadores/sangue , COVID-19 , China/epidemiologia , Infecções por Coronavirus/sangue , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/terapia , Feminino , Cardiopatias/sangue , Cardiopatias/mortalidade , Cardiopatias/virologia , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade , Avaliação de Resultados em Cuidados de Saúde , Pneumonia Viral/sangue , Pneumonia Viral/mortalidade , Pneumonia Viral/terapia , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , SARS-CoV-2RESUMO
Activation of apoptosis signal-regulating kinase 1 (ASK1) in hepatocytes is a key process in the progression of nonalcoholic steatohepatitis (NASH) and a promising target for treatment of the condition. However, the mechanism underlying ASK1 activation is still unclear, and thus the endogenous regulators of this kinase remain open to be exploited as potential therapeutic targets. In screening for proteins that interact with ASK1 in the context of NASH, we identified the deubiquitinase tumor necrosis factor alpha-induced protein 3 (TNFAIP3) as a key endogenous suppressor of ASK1 activation, and we found that TNFAIP3 directly interacts with and deubiquitinates ASK1 in hepatocytes. Hepatocyte-specific ablation of Tnfaip3 exacerbated nonalcoholic fatty liver disease- and NASH-related phenotypes in mice, including glucose metabolism disorders, lipid accumulation and enhanced inflammation, in an ASK1-dependent manner. In contrast, transgenic or adeno-associated virus-mediated TNFAIP3 gene delivery in the liver in both mouse and nonhuman primate models of NASH substantially blocked the onset and progression of the disease. These results implicate TNFAIP3 as a functionally important endogenous suppressor of ASK1 hyperactivation in the pathogenesis of NASH and identify it as a potential new molecular target for NASH therapy.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Fígado/enzimologia , MAP Quinase Quinase Quinase 5/antagonistas & inibidores , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Animais , Apoptose , Dieta Hiperlipídica , Fibrose/prevenção & controle , Humanos , Inflamação/prevenção & controle , Resistência à Insulina , Camundongos , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Transdução de Sinais , Ubiquitinação , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Nonalcoholic steatohepatitis (NASH) is a common clinical condition that can lead to advanced liver diseases. Lack of effective pharmacotherapies for NASH is largely attributable to an incomplete understanding of its pathogenesis. The deubiquitinase cylindromatosis (CYLD) plays key roles in inflammation and cancer. Here we identified CYLD as a suppressor of NASH in mice and in monkeys. CYLD is progressively degraded upon interaction with the E3 ligase TRIM47 in proportion to NASH severity. We observed that overexpression of Cyld in hepatocytes concomitantly inhibits lipid accumulation, insulin resistance, inflammation and fibrosis in mice with NASH induced in an experimental setting. Mechanistically, CYLD interacts directly with the kinase TAK1 and removes its K63-linked polyubiquitin chain, which blocks downstream activation of the JNK-p38 cascades. Notably, reconstitution of hepatic CYLD expression effectively reverses disease progression in mice with dietary or genetically induced NASH and in high-fat diet-fed monkeys predisposed to metabolic syndrome. Collectively, our findings demonstrate that CYLD mitigates NASH severity and identify the CYLD-TAK1 axis as a promising therapeutic target for management of the disease.
Assuntos
Cisteína Endopeptidases/genética , Inflamação/genética , MAP Quinase Quinase Quinases/genética , Hepatopatia Gordurosa não Alcoólica/genética , Animais , Proteínas de Transporte/genética , Cisteína Endopeptidases/química , Cisteína Endopeptidases/metabolismo , Enzima Desubiquitinante CYLD , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Haplorrinos , Humanos , Inflamação/fisiopatologia , Fígado/metabolismo , Fígado/patologia , MAP Quinase Quinase 4/genética , MAP Quinase Quinase Quinases/química , MAP Quinase Quinase Quinases/metabolismo , Síndrome Metabólica/genética , Síndrome Metabólica/patologia , Camundongos , Proteínas de Neoplasias/genética , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Proteínas Nucleares/genética , Ligação Proteica/genética , Índice de Gravidade de Doença , Transdução de Sinais/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genéticaRESUMO
Ovarian cancer is one of the three most common gynecological malignant tumors worldwide. The prognosis of patients suffering from this malignancy remains poor because of limited therapeutic strategies. Herein, we investigated the role of a long noncoding RNA named MIR4697 host gene (MIR4697HG) in the cell growth and metastasis of ovarian cancer. Results showed that the transcriptional level of MIR4697HG in cancerous tissues increased twofold compared with that in adjacent noncancerous tissues. MIR4697HG was differentially expressed in ovarian cancer cell lines, with the highest levels in OVCAR3 and SKOV3 cells. MIR4697HG knockdown by specific shRNA significantly inhibited cell proliferation and colony formation in both OVCAR3 and SKOC3 cells. Consistently, in a xenograft model of ovarian cancer, MIR4697HG depletion also significantly restricted tumor volumes and weights. Furthermore, MIR4697HG knockdown inhibited cell migration and invasion capacities. Invasion ability was inhibited by 58% in SKOV3 cells and 40% in OVCAR3 cells, and migration ability was inhibited by 73% in SKOV3 cells and 62% in OVCAR3 cells after MIR4697HG knockdown. MIR4697HG knockdown also caused a decrease in matrix metalloprotease-9, phosphorylated ERK, and phosphorylated AKT. These data suggested that MIR4697HG promoted ovarian cancer growth and metastasis. The aggressive role of MIR4697HG in ovarian cancer may be related to the ERK and AKT signaling pathways.
Assuntos
Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , RNA Longo não Codificante/genética , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Sistema de Sinalização das MAP Quinases , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Nus , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Neoplasias Ovarianas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Transdução de Sinais , Ensaio Tumoral de Célula-Tronco , Regulação para CimaRESUMO
Nonalcoholic steatohepatitis (NASH) is a progressive disease that is often accompanied by metabolic syndrome and poses a high risk of severe liver damage. However, no effective pharmacological treatment is currently available for NASH. Here we report that CASP8 and FADD-like apoptosis regulator (CFLAR) is a key suppressor of steatohepatitis and its metabolic disorders. We provide mechanistic evidence that CFLAR directly targets the kinase MAP3K5 (also known as ASK1) and interrupts its N-terminus-mediated dimerization, thereby blocking signaling involving ASK1 and the kinase MAPK8 (also known as JNK1). Furthermore, we identified a small peptide segment in CFLAR that effectively attenuates the progression of steatohepatitis and metabolic disorders in both mice and monkeys by disrupting the N-terminus-mediated dimerization of ASK1 when the peptide is expressed from an injected adenovirus-associated virus 8-based vector. Taken together, these findings establish CFLAR as a key suppressor of steatohepatitis and indicate that the development of CFLAR-peptide-mimicking drugs and the screening of small-molecular inhibitors that specifically block ASK1 dimerization are new and feasible approaches for NASH treatment.
Assuntos
Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/genética , Fígado/metabolismo , MAP Quinase Quinase Quinase 5/metabolismo , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Adolescente , Adulto , Animais , Biópsia , Glicemia/metabolismo , Dependovirus , Dimerização , Feminino , Técnicas de Introdução de Genes , Vetores Genéticos , Hepatócitos/metabolismo , Humanos , Imuno-Histoquímica , Imunoprecipitação , Resistência à Insulina/genética , Interleucina-6/metabolismo , Fígado/diagnóstico por imagem , Fígado/patologia , Macaca fascicularis , Masculino , Camundongos , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Tomografia por Emissão de Pósitrons , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Ultrassonografia , Adulto JovemRESUMO
This corrects the article DOI: 10.1038/nm.4290.