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1.
Cell ; 178(1): 176-189.e15, 2019 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-31155231

RESUMO

RLR-mediated type I IFN production plays a pivotal role in elevating host immunity for viral clearance and cancer immune surveillance. Here, we report that glycolysis, which is inactivated during RLR activation, serves as a barrier to impede type I IFN production upon RLR activation. RLR-triggered MAVS-RIG-I recognition hijacks hexokinase binding to MAVS, leading to the impairment of hexokinase mitochondria localization and activation. Lactate serves as a key metabolite responsible for glycolysis-mediated RLR signaling inhibition by directly binding to MAVS transmembrane (TM) domain and preventing MAVS aggregation. Notably, lactate restoration reverses increased IFN production caused by lactate deficiency. Using pharmacological and genetic approaches, we show that lactate reduction by lactate dehydrogenase A (LDHA) inactivation heightens type I IFN production to protect mice from viral infection. Our study establishes a critical role of glycolysis-derived lactate in limiting RLR signaling and identifies MAVS as a direct sensor of lactate, which functions to connect energy metabolism and innate immunity.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteína DEAD-box 58/antagonistas & inibidores , Proteína DEAD-box 58/metabolismo , Ácido Láctico/farmacologia , Receptores de Superfície Celular/antagonistas & inibidores , Receptores de Superfície Celular/metabolismo , Animais , Feminino , Glicólise , Células HEK293 , Humanos , Interferon beta/metabolismo , L-Lactato Desidrogenase/genética , L-Lactato Desidrogenase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células RAW 264.7 , Receptores Imunológicos , Transdução de Sinais/efeitos dos fármacos , Transfecção
2.
Mol Cell ; 81(18): 3803-3819.e7, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34547240

RESUMO

Mitochondrial dynamics regulated by mitochondrial fusion and fission maintain mitochondrial functions, whose alterations underline various human diseases. Here, we show that inositol is a critical metabolite directly restricting AMPK-dependent mitochondrial fission independently of its classical mode as a precursor for phosphoinositide generation. Inositol decline by IMPA1/2 deficiency elicits AMPK activation and mitochondrial fission without affecting ATP level, whereas inositol accumulation prevents AMPK-dependent mitochondrial fission. Metabolic stress or mitochondrial damage causes inositol decline in cells and mice to elicit AMPK-dependent mitochondrial fission. Inositol directly binds to AMPKγ and competes with AMP for AMPKγ binding, leading to restriction of AMPK activation and mitochondrial fission. Our study suggests that the AMP/inositol ratio is a critical determinant for AMPK activation and establishes a model in which AMPK activation requires inositol decline to release AMPKγ for AMP binding. Hence, AMPK is an inositol sensor, whose inactivation by inositol serves as a mechanism to restrict mitochondrial fission.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Inositol/metabolismo , Dinâmica Mitocondrial/fisiologia , Proteínas Quinases Ativadas por AMP/fisiologia , Animais , Linhagem Celular , Humanos , Inositol/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Células PC-3 , Monoéster Fosfórico Hidrolases/metabolismo , Fosforilação , Estresse Fisiológico/fisiologia
3.
Nature ; 611(7936): 496-500, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36385539

RESUMO

Theory1 and numerical modelling2 suggest that tropical cyclones (TCs) will strengthen with rising ocean temperatures. Even though models have reached broad agreement on projected TC intensification3-5, observed trends in TC intensity remain inconclusive and under active debate6-10 in all ocean basins except the North Atlantic, where aircraft reconnaissance data greatly reduce uncertainties11. The conventional satellite-based estimates are not accurate enough to ascertain the trend in TC intensity6,11, suffering from contamination by heavy rain, clouds, breaking waves and spray12. Here we show that weak TCs (that is, tropical storms to category-1 TCs based on the Saffir-Simpson scale) have intensified in all ocean basins during the period 1991-2020, based on huge amounts of highly accurate ocean current data derived from surface drifters. These drifters have submerged 'holy sock' drogues at 15 m depth to reduce biases induced by processes at the air-sea interface and thereby accurately measure near-surface currents, even under the most destructive TCs. The ocean current speeds show a robust upward trend of ~4.0 cm s-1 per decade globally, corresponding to a positive trend of 1.8 m s-1 per decade in the TC intensity. Our analysis further indicates that globally TCs have strengthened across the entirety of the intensity distribution. These results serve as a historical baseline that is crucial for assessing model physics, simulations and projections given the failure of state-of-the-art climate models in fully replicating these trends13.

4.
Mol Cell ; 80(2): 263-278.e7, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33022274

RESUMO

Cancer metastasis accounts for the major cause of cancer-related deaths. How disseminated cancer cells cope with hostile microenvironments in secondary site for full-blown metastasis is largely unknown. Here, we show that AMPK (AMP-activated protein kinase), activated in mouse metastasis models, drives pyruvate dehydrogenase complex (PDHc) activation to maintain TCA cycle (tricarboxylic acid cycle) and promotes cancer metastasis by adapting cancer cells to metabolic and oxidative stresses. This AMPK-PDHc axis is activated in advanced breast cancer and predicts poor metastasis-free survival. Mechanistically, AMPK localizes in the mitochondrial matrix and phosphorylates the catalytic alpha subunit of PDHc (PDHA) on two residues S295 and S314, which activates the enzymatic activity of PDHc and alleviates an inhibitory phosphorylation by PDHKs, respectively. Importantly, these phosphorylation events mediate PDHc function in cancer metastasis. Our study reveals that AMPK-mediated PDHA phosphorylation drives PDHc activation and TCA cycle to empower cancer cells adaptation to metastatic microenvironments for metastasis.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Ciclo do Ácido Cítrico , Complexo Piruvato Desidrogenase/metabolismo , Animais , Domínio Catalítico , Linhagem Celular Tumoral , Sobrevivência Celular , Ativação Enzimática , Feminino , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica , Fosforilação , Fosfosserina/metabolismo , Transdução de Sinais , Estresse Fisiológico , Análise de Sobrevida
5.
Proc Natl Acad Sci U S A ; 120(52): e2305684120, 2023 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-38113258

RESUMO

Metastasis is a major cause of cancer therapy failure and mortality. However, targeting metastatic seeding and colonization remains a significant challenge. In this study, we identified NSD2, a histone methyltransferase responsible for dimethylating histone 3 at lysine 36, as being overexpressed in metastatic tumors. Our findings suggest that NSD2 overexpression enhances tumor metastasis both in vitro and in vivo. Further analysis revealed that NSD2 promotes tumor metastasis by activating Rac1 signaling. Mechanistically, NSD2 combines with and activates Tiam1 (T lymphoma invasion and metastasis 1) and promotes Rac1 signaling by methylating Tiam1 at K724. In vivo and in vitro studies revealed that Tiam1 K724 methylation could be a predictive factor for cancer prognosis and a potential target for metastasis inhibition. Furthermore, we have developed inhibitory peptide which was proved to inhibit tumor metastasis through blocking the interaction between NSD2 and Tiam1. Our results demonstrate that NSD2-methylated Tiam1 promotes Rac1 signaling and cancer metastasis. These results provide insights into the inhibition of tumor metastasis.


Assuntos
Neoplasias do Colo , Fatores de Troca do Nucleotídeo Guanina , Humanos , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Transdução de Sinais/fisiologia , Invasividade Neoplásica/patologia , Metilação , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismo
6.
Proc Natl Acad Sci U S A ; 119(31): e2205469119, 2022 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-35895684

RESUMO

T regulatory (Treg) cells are essential for self-tolerance whereas they are detrimental for dampening the host anti-tumor immunity. How Treg cells adapt to environmental signals to orchestrate their homeostasis and functions remains poorly understood. Here, we identified that transcription factor EB (TFEB) is induced by host nutrition deprivation or interleukin (IL)-2 in CD4+ T cells. The loss of TFEB in Treg cells leads to reduced Treg accumulation and impaired Treg function in mouse models of cancer and autoimmune disease. TFEB intrinsically regulates genes involved in Treg cell differentiation and mitochondria function while it suppresses expression of proinflammatory cytokines independently of its established roles in autophagy. This coordinated action is required for mitochondria integrity and appropriate lipid metabolism in Treg cells. These findings identify TFEB as a critical regulator for orchestrating Treg generation and function, which may contribute to the adaptive responses of T cells to local environmental cues.


Assuntos
Adaptação Fisiológica , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Mitocôndrias , Neoplasias , Linfócitos T Reguladores , Adaptação Fisiológica/genética , Adaptação Fisiológica/fisiologia , Animais , Doenças Autoimunes/imunologia , Autofagia/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/fisiologia , Modelos Animais de Doenças , Interleucina-2/metabolismo , Camundongos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Neoplasias/imunologia , Linfócitos T Reguladores/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Acta Pharmacol Sin ; 45(2): 366-377, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37770579

RESUMO

Diabetic nephropathy (DN) is characterized by chronic low-grade renal inflammatory responses, which greatly contribute to disease progression. Abnormal glucose metabolism disrupts renal lipid metabolism, leading to lipid accumulation, nephrotoxicity, and subsequent aseptic renal interstitial inflammation. In this study, we investigated the mechanisms underlying the renal inflammation in diabetes, driven by glucose-lipid metabolic rearrangement with a focus on the role of acetyl-CoA synthetase 2 (ACSS2) in lipid accumulation and renal tubular injury. Diabetic models were established in mice by the injection of streptozotocin and in human renal tubular epithelial HK-2 cells cultured under a high glucose (HG, 30 mmol/L) condition. We showed that the expression levels of ACSS2 were significantly increased in renal tubular epithelial cells (RTECs) from the diabetic mice and human diabetic kidney biopsy samples, and ACSS2 was co-localized with the pro-inflammatory cytokine IL-1ß in RTECs. Diabetic ACSS2-deficient mice exhibited reduced renal tubular injury and inflammatory responses. Similarly, ACSS2 knockdown or inhibition of ACSS2 by ACSS2i (10 µmol/L) in HK-2 cells significantly ameliorated HG-induced inflammation, mitochondrial stress, and fatty acid synthesis. Molecular docking revealed that ACSS2 interacted with Sirtuin 1 (SIRT1). In HG-treated HK-2 cells, we demonstrated that ACSS2 suppressed SIRT1 expression and activated fatty acid synthesis by modulating SIRT1-carbohydrate responsive element binding protein (ChREBP) activity, leading to mitochondrial oxidative stress and inflammation. We conclude that ACSS2 promotes mitochondrial oxidative stress and renal tubular inflammation in DN by regulating the SIRT1-ChREBP pathway. This highlights the potential therapeutic value of pharmacological inhibition of ACSS2 for alleviating renal inflammation and dysregulation of fatty acid metabolic homeostasis in DN. Metabolic inflammation in the renal region, driven by lipid metabolism disorder, is a key factor in renal injury in diabetic nephropathy (DN). Acetyl-CoA synthetase 2 (ACSS2) is abundantly expressed in renal tubular epithelial cells (RTECs) and highly upregulated in diabetic kidneys. Deleting ACSS2 reduces renal fatty acid accumulation and markers of renal tubular injury in diabetic mice. We demonstrate that ACSS2 deletion inhibits ChREBP-mediated fatty acid lipogenesis, mitochondrial oxidative stress, and inflammatory response in RTECs, which play a major role in the progression of diabetic renal tubular injury in the kidney. These findings support the potential use of ACSS2 inhibitors in treating patients with DN.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Humanos , Camundongos , Animais , Sirtuína 1/metabolismo , Nefropatias Diabéticas/patologia , Acetilcoenzima A/metabolismo , Acetilcoenzima A/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Simulação de Acoplamento Molecular , Rim/patologia , Fatores de Transcrição/metabolismo , Metabolismo dos Lipídeos , Glucose/metabolismo , Ácidos Graxos/metabolismo , Inflamação/metabolismo , Ligases/metabolismo , Lipídeos
8.
Mol Genet Genomics ; 298(2): 353-360, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36574082

RESUMO

Male infertility, a global public health problem, exhibits complex pathogenic causes and genetic factors deserve further discovery and study. We identified a novel homozygous missense mutation c.224A > C (p.D75A) in ACTL7A gene in two infertile brothers with teratozoospermia by whole-exome sequencing (WES). In vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) showed fertilization failure of the two affected couples. The three-dimensional (3D) models showed that a small section of α-helix transformed into random coil in the mutant ACTL7A protein and mutant amino acid lacked a hydrogen bond with Ser170 amino acid. Immunofluorescence revealed that ACTL7A protein was degraded in sperms of patients. Transmission electron microscopy (TEM) analysis of sperms from the infertile patients showed that the irregular perinuclear theca (PT) and acrosomal ultrastructural defects. Furthermore, ACTL7A mutation caused abnormal localization and reduced the expression of PLCZ1 in sperms of the patients, which may be the key reasons for the fertilization failure after ICSI. Our findings expand the spectrum of ACTL7A mutations and provide novel theoretical basis for genetic counseling.


Assuntos
Infertilidade Masculina , Sêmen , Humanos , Masculino , Infertilidade Masculina/genética , Injeções de Esperma Intracitoplásmicas/métodos , Fertilização in vitro , Mutação
9.
J Virol ; 96(6): e0165721, 2022 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-35080427

RESUMO

Avian leukosis virus subgroup J (ALV-J) induces myelocytomas, which can metastasize to multiple organs in diseased chickens. Although metastasis is the primary cause of death in such cases, the mechanism for it remains unclear. Here, we found that interaction between ALV-J surface protein (SU) and doublecortin-like kinase 1 (DCLK1) promotes epithelial-mesenchymal transition (EMT) and cell proliferation. We found that ALV-J can activate EMT in infected cells. Subsequently, proteomics analysis revealed that DCLK1, a well-established putative tumor stem cell marker, which is highly expressed in ALV-J-infected DF-1 cells and chickens, might be a potential factor mediating EMT. Furthermore, using immunofluorescence and immunoprecipitation, we verified that SU interacts with DCLK1. Functional studies suggested that overexpression of DCLK1 increased viral replication and promoted cell proliferation by accelerating the progression of cells from the G0/G1 phase to the S phase of cell cycle, whereas RNA interference of DCLK1 reduced viral replication and arrested cell proliferation by retarding cell cycle progression from the late G1 phase into the S phase in ALV-J-infected cells. Moreover, we demonstrate that the increased accumulation of DCLK1 promotes EMT by increasing the expression of N-cadherin, vimentin, MMP2, and transcription factor Snail1 and decreasing the expression of epithelial marker E-cadherin. These results suggest that ALV-J SU interacts with DCLK1, and accelerates cell proliferation, leading to increased viral replication and ultimately activating EMT, which paves the way for tumor metastasis. IMPORTANCE Tumor metastasis is a major challenge in cancer research, because of its systemic nature and the resistance of disseminated tumor cells to existing therapeutic agents. It is estimated that >90% of mortality from cancer is attributable to metastases. We found that ALV-J can activate EMT, which plays a critical role in cancer metastasis. Subsequently, we identified a tumor stem cell marker, DCLK1, in ALV-J infected cells, which interacts with surface protein (SU) of ALV-J to promote virus replication, activate EMT, and accelerate cell proliferation enabling ALV-J to obtain metastatic ability. Understanding the process of participation of ALV-J in EMT and the route of metastasis will help elucidate the mechanism of virus-induced tumor metastasis and help identify promising molecular targets and key obstacles for ALV-J control and clinical technology development.


Assuntos
Vírus da Leucose Aviária , Leucose Aviária , Quinases Semelhantes a Duplacortina , Transição Epitelial-Mesenquimal , Proteínas de Membrana , Animais , Leucose Aviária/fisiopatologia , Vírus da Leucose Aviária/genética , Proliferação de Células , Galinhas , Quinases Semelhantes a Duplacortina/metabolismo , Proteínas de Membrana/metabolismo
10.
BMC Cancer ; 23(1): 1013, 2023 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-37864137

RESUMO

BACKGROUND: Recent studies have shown that deficient mismatch repair (dMMR) rectal cancer may be related to treatment resistance, resulting in a worse prognosis than proficient MMR (pMMR) rectal cancer. The purpose of this study was to explore whether surgery plus other treatments (radiotherapy and chemotherapy) can bring more benefits to these patients than surgery alone. METHODS: A retrospective study of 168 patients with rectal adenocarcinoma who underwent total mesorectal excision was conducted using immunohistochemical methods to determine MMR status and a propensity score matching model to minimize potential confounding factors between subgroups of patients with different treatment regimens. Kaplan-Meier analysis, log-rank tests, and Cox regression models were used to assess overall survival (OS) and disease-free survival (DFS) in patient subgroups. RESULTS: Only 6.9% (n = 168) of patients in the total cohort had dMMR rectal adenocarcinoma, and the most common cause of dMMR was a PMS2 deletion (103, 61.3%). The median DFS of the surgery alone group was 45.7 months (IQR, 40.9 to 77.8), and the median DFS of the surgery plus other treatment group was 43.9 months (IQR, 14.2 to 80.1). The surgery alone group was superior to the surgery plus other treatment group (HR, 0.16; 95% CI, 0.07 to 0.38; p = 0.005). There was no significant difference in OS (45.8 (IQR, 41.0 to 79.8) vs. 45.9 (IQR, 38.5 to 80.3)) between the two groups (HR, 0.57; 95% CI, 0.23 to 1.40; p = 0.263). CONCLUSIONS: For patients with locally advanced dMMR rectal adenocarcinoma, compared with surgery alone, surgery plus other treatment options (radiotherapy and chemotherapy) do not grant long-term survival benefits but rather shorten DFS.


Assuntos
Adenocarcinoma , Neoplasias Retais , Humanos , Estadiamento de Neoplasias , Reparo de Erro de Pareamento de DNA , Estudos Retrospectivos , Prognóstico , Neoplasias Retais/genética , Neoplasias Retais/cirurgia , Adenocarcinoma/genética , Adenocarcinoma/cirurgia
11.
Pharmacol Res ; 187: 106569, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36427798

RESUMO

Phenolipids are characteristic phytochemicals of Syzygium genus. However, the antidiabetic potential and underlying molecular mechanism of these components are not fully elucidated. Herein, we studied the anti-diabetic effects of jambone E (JE), a phenolipid from S. cumini, with in vitro and in vivo models. Data from current study showed that JE enhanced glucose consumption and uptake, promoted glycogen synthesis, and suppressed gluconeogenesis in insulin resistant (IR)-HepG2 cells and primary mouse hepatocytes. JE also attenuated streptozotocin-induced hyperglycemia and hyperlipidemia in type 1 diabetic (T1D) mice. Eleven metabolites (e.g. trimethylamine n-oxide, 4-pyridoxic acid, phosphatidylinositol 39:4, phenaceturic acid, and hippuric acid) were identified as potential serum biomarkers for JE's antidiabetic effects by an untargeted metabolomics approach. The further molecular mechanistic study revealed that JE up-regulated phosphorylation levels of protein kinase B (AKT), glycogen synthase kinase 3 beta, and forkhead box O1 (FoxO1), promoted nuclear exclusion of FoxO1 whilst decreased gene expression levels of peroxisome proliferator-activated receptor gamma coactivator-1 alpha, phosphoenolpyruvate carboxykinase and glucose 6-phosphatase in IR-HepG2 cells and T1D mice. Our data suggested that JE might be a potent activator for AKT-mediated insulin signaling pathway, which was confirmed by the usage of AKT inhibitor and AKT-target siRNA interference, as well as the cellular thermal shift assay. Findings from the current study shed light on the anti-diabetic effects of phenolipids in the Syzygium species, which supports the use of medicinal plants in the Syzygium genus for potential pharmaceutical applications.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Hipoglicemiantes , Resistência à Insulina , Compostos Fitoquímicos , Syzygium , Animais , Camundongos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Gluconeogênese , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/química , Insulina/metabolismo , Fígado , Metaboloma , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Estreptozocina , Syzygium/química , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico
12.
Cell Mol Biol (Noisy-le-grand) ; 69(6): 67-74, 2023 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-37605587

RESUMO

This study aimed to dig new molecular mechanisms and medications for age-related hearing loss (ARHL or presbycusis) by extracting common results of publicly available datasets. Based on five datasets (GSE153882, GSE121856, GSE98070, GSE45026, and GSE98071) in studies of cochlear hair cells, we explored the interrelationships among presbycusis-related genes, including gene interactions, enrichment analysis, miRNA-mRNA matching pairs, and potential new drugs. Together, there were 25 common increased mRNAs. A total of 183 drugs can simultaneously target 11 of these mRNAs. In the interaction network, hub genes included: Cbln1, Prl, Mpp6 and Gh. Meanwhile, there were 74 common decreased mRNAs. The hub genes include Cdkn1a, Egr1, and Ctgf. After de-duplication, the 25 common increased mRNAs had 946 matched miRNAs, with 34 decreased ones; and the 74 decreased mRNAs had 1164 matched miRNAs, with 26 increased ones. Between the inhibitors of increased mRNAs and enhancers of decreased mRNAs, there were 26 common drugs. Besides, we discovered six key genes that may play a crucial role in the onset of presbycusis. In conclusion, by jointly analyzing multiple datasets, we found 25 common increased mRNAs (e.g., Cbln1, Prl, Mpp6 and Gh) and 74 common decreased mRNAs (Cdkn1a, Egr1, and Ctgf), as well as 34 potential therapeutic miRNAs and 26 pathogenic miRNAs, and three candidate drugs (calcitriol, diclofenac, and diethylstilbestrol). They may provide new targets and strategies for mechanistic and therapeutic studies in ARHL.


Assuntos
MicroRNAs , Presbiacusia , Animais , Camundongos , Presbiacusia/genética , Perfilação da Expressão Gênica , Células Ciliadas Auditivas , Calcitriol , Fator de Crescimento do Tecido Conjuntivo , MicroRNAs/genética , RNA Mensageiro/genética
13.
Ecotoxicol Environ Saf ; 266: 115593, 2023 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-37856985

RESUMO

Vermicompost is a promising amendment for immobilization of cadmium (Cd) in soils; however, its effectiveness can be influenced by rhizosphere environment conditions, such as pH and the presence of low-molecular-weight organic acids (LMWOAs). In this study, a batch experiment was conducted to examine the characteristics of Cd adsorption by vermicompost at different pH (pH = 3, 5, and 7) and after the addition of different LMWOAs (oxalic acid; citric acid; malic acid). Furthermore, a series of morphology and structural analyses were conducted to elucidate the mechanisms of observed effects. The results showed that the adsorption capacity of vermicompost for Cd increased as pH increased, and chemisorption dominated the adsorption process. Changes in pH altered adsorption performance by affecting the -OH groups of alcohol/phenol and the -CH2 groups of aliphatics. Further, the addition of oxalic acid promoted Cd adsorption, and the effect was concentration dependent. Modifying the verimicompost surface with more adsorption sites might be the main reason. Conversely, citric acid and malic acid showed the ability to inhibit Cd adsorption by vermicompost. Citric acid caused a blocking effect by covering flocculent substances on the vermicompost surface while reducing surface adsorption sites by dissolving mineral components such as iron oxides. However, the action of malic acid did not appear to be related to changes in morphology or the structure of vermicompost. Overall, the results of this study partially explain the limited effectiveness of Cd immobilization within the rhizosphere by vermicompost, and provide theoretical support for regulating rhizosphere environments to improve the effectiveness of vermicompost immobilization of Cd.


Assuntos
Cádmio , Poluentes do Solo , Cádmio/análise , Adsorção , Rizosfera , Solo/química , Compostos Orgânicos , Ácido Oxálico/química , Ácido Cítrico/química , Concentração de Íons de Hidrogênio , Poluentes do Solo/análise
14.
Environ Toxicol ; 38(6): 1347-1360, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36947452

RESUMO

BACKGROUND: Accumulating evidence suggests that circular RNAs (circRNAs) play important regulatory roles in non-small cell lung cancer (NSCLC). At present, we aimed to explore the regulatory role of has_circ_0003528 (circ_0003528) in NSCLC. METHODS: Alterations of circ_0003528 expression in NSCLC samples and cell lines were detected by real-time quantitative polymerase chain reaction (RT-qPCR). Impacts of circ_0003528 on NSCLC cell malignant transformation were analyzed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, transwell invasion, and tube formation assays. Epithelial-mesenchymal transition (EMT)-related markers were detected with western blotting. Pro-inflammatory cytokines were detected by Enzyme-linked immunosorbent assay (ELISA). The regulation mechanism of circ_0003528 was verified by dual-luciferase reporter and RNA pull-down assays. The tumorigenesis role of circ_0003528 was verified by animal experiments. RESULTS: Higher levels of circ_0003528 were obtained in NSCLC samples and cell lines, and patients with high circ_0003528 expression had a worse prognosis. Silence of circ_0003528 decreased xenograft growth in mouse models and induced cell apoptosis and repressed cell viability, proliferation, invasion, EMT, angiogenesis, and immune escape in NSCLC cells in vitro. Mechanistically, circ_0003528 controlled programmed cell death ligand 1 (PDL1) expression through interaction with miR-511-3p. The inhibiting impacts of circ_0003528 knockdown on NSCLC cell malignant transformation and immune escape were weakened after miR-511-3p silencing. Moreover, PDL1 overexpression partially counteracted miR-511-3p upregulation-mediated suppression on NSCLC cell malignant transformation and immune escape. CONCLUSIONS: Circ_0003528 facilitated NSCLC cell malignant transformation and immune escape through regulation of the miR-511-3p/PDL1 axis, highlighting the oncogenic role of circ_0003528 in NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , MicroRNAs , Humanos , Animais , Camundongos , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Transformação Celular Neoplásica/genética , Oncogenes/genética , MicroRNAs/genética , Proliferação de Células/genética , Linhagem Celular Tumoral
15.
BMC Cancer ; 22(1): 1156, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36352365

RESUMO

BACKGROUND: We evaluated the prognostic role of deficient mismatch repair (dMMR) systems in stage II and stage III colon cancer patients during different postoperative periods. We also assessed whether patients aged ≥75 could benefit from chemotherapy. METHODS: This retrospective study was conducted across three medical centers in China. Kaplan-Meier survival methods and Cox proportional hazards models were used to evaluate the differences in overall survival (OS) and disease-free survival (DFS) rates. Propensity score matching was performed to reduce imbalances in the baseline characteristics of the patients. Landmark analysis was performed to evaluate the role of dMMR during different postoperative periods. RESULTS: The median follow-up time for all patients was 45.0 months (25-75 IQR: 38.0-82.5). There was no significant OS (p = 0.350) or DFS (p = 0.752) benefit associated with dMMR for stage II and III patients during the first postoperative year. However, significant OS (p < 0.001) and DFS (p < 0.001) benefits were observed from the second postoperative year until the end of follow-up. These differences remained after propensity score matching. Moreover, chemotherapy produced no OS (HR = 0.761, 95% CI: 0.43-1.34, p = 0.341) or DFS (HR = 0.98, 95% CI: 0.51-1.88, p = 0.961) benefit for patients aged ≥75 years. CONCLUSION: The benefits of dMMR in stage III patients were observed from the second postoperative year until the end of follow-up. However, the prognosis of patients with dMMR is not different from that of patients with proficient mismatch repair (pMMR) during the first postoperative year. In addition, elderly patients aged ≥75 years obtained no significant survival benefits from postoperative chemotherapy.


Assuntos
Neoplasias do Colo , Neoplasias Testiculares , Idoso , Masculino , Humanos , Reparo de Erro de Pareamento de DNA , Estudos Retrospectivos , Quimioterapia Adjuvante , Fluoruracila/uso terapêutico , Estadiamento de Neoplasias , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Prognóstico , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Neoplasias do Colo/cirurgia , Neoplasias Testiculares/tratamento farmacológico , Período Pós-Operatório
16.
J Surg Oncol ; 125(4): 692-702, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34918842

RESUMO

BACKGROUND AND OBJECTIVES: Previous studies have concluded that colorectal cancer patients with deficient mismatch repair (dMMR) usually have a good prognosis. However, some studies have suggested that the prognosis of rectal cancer patients with dMMR appears to be worse. Our aim was to investigate chemoradiotherapy resistance in dMMR rectal tumors. METHODS: A retrospective study of 217 patients with locally advanced rectal adenocarcinoma treated with chemoradiotherapy and total mesorectal excision surgery was conducted using immunohistochemistry to determine MMR status and propensity score matching models to reduce potential confounders. Kaplan-Meier analysis, log-rank test, and Cox regression models were used to assess overall survival (OS) and disease-free survival (DFS) in patient subgroups. RESULTS: The 3-year DFS rates were 77.1% and 56.7% in the pMMR and dMMR groups, respectively. The pMMR group had significantly better DFS than the dMMR group (hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.10-3.91; p = 0.019). However, there was no significant difference in OS between the two groups (45.7 [interquartile range, IQR], 39.3-72.1] vs. 47.5 [IQR, 29.5-72.1]) (HR, 1.39; 95% CI, 0.70-2.77; p = 0.35). Neither OS nor DFS was significantly different between the neoadjuvant chemoradiotherapy and postoperative chemoradiotherapy groups. CONCLUSION: Locally advanced dMMR rectal adenocarcinoma exhibits greater chemoradiotherapy resistance than pMMR.


Assuntos
Adenocarcinoma/patologia , Biomarcadores Tumorais/metabolismo , Quimiorradioterapia/métodos , Enzimas Reparadoras do DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos , Tolerância a Radiação , Neoplasias Retais/patologia , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/terapia , Idoso , Biomarcadores Tumorais/genética , Reparo de Erro de Pareamento de DNA , Enzimas Reparadoras do DNA/genética , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias Retais/genética , Neoplasias Retais/metabolismo , Neoplasias Retais/terapia , Estudos Retrospectivos , Taxa de Sobrevida
17.
Nutr Neurosci ; 25(4): 737-745, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32787674

RESUMO

Objective: The influence of vaspin on vascular health had been investigated, yielding conflicting results. This study is intended to investigate the relation between vaspin and stroke severity and stroke outcome in a cohort Chinese patient with acute ischemic stroke (AIS).Methods: This was a prospective single-center observational study in Xinxiang, China. From 1 July 2017 to 30 November 2019, all patients with first-ever AIS were consecutively included. Serum levels of vaspin, stroke severity at (assessed by NIHSS score) admission and functional outcome (assessed by modified Rankin Scale (mRS)) at discharge were recorded. Multivariate analyses were assessed using logistic regression models.Results: Finally, 340 patients with AIS were included. The median age of those patients was 65 (interquartile range [IQR], 56-74) years and 61.8% were men. At admission, 88 patients (25.9%) experienced severe stroke (NIHSS>10) and serum levels of vaspin (median [IQR]: 0.72[0.48-0.90]ng/ml) in those patients were significantly lower than in those mild(0.92[0.70-1.19]ng/ml) and moderate stroke (0.93[0.63-1.21]ng/ml). At discharge, 113 patients (33.2%) experienced poor functional outcome (mRS >2) and vaspin serum levels in those patients were lower as compared with patients who experienced good outcome (0.71[0.45-0.98] vs. 0.91[0.71-1.19]ng/ml). In multivariate analyses, lower level of vaspin (< median) was associated with a 2.5-fold (odds ratio [OR] 2.46; 95% confidence interval [CI]: 1.75-4.45) increased risk for severe stroke and a 2.1-fold (2.03; 1.42-3.58) increased risk for poor outcome.Conclusion: In conclusion, reduced serum levels of vaspin at admission are significantly related to stroke severity and prognosis, which illustrates a predictive role of reduced vaspin in ischemic stroke.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Idoso , Biomarcadores , Isquemia Encefálica/complicações , Isquemia Encefálica/diagnóstico , Humanos , AVC Isquêmico/complicações , AVC Isquêmico/diagnóstico , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Índice de Gravidade de Doença
18.
BMC Vet Res ; 18(1): 253, 2022 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-35768837

RESUMO

BACKGROUND: Transmissible viral proventriculitis (TVP) causes significant economic loss to the poultry industry. However, the exact causative agents are obscure. Here we examine the virome of proventriculus from specified pathogen free (SPF) chickens that reproduced by infection of proventricular homogenate from broiler chicken with TVP using long read sequencing of the Pacific Biosciences RSII platform. The normal SPF chickens were used as control. RESULTS: Our investigation reveals a virome of proventriculitis, including three Gyrovirus genera of the Aneloviridae: Gyrovirus homsa1 (GyH1) (also known as Gyrovirus 3, GyV3) (n = 2662), chicken anemia virus (CAV) (n = 482) and Gyrovirus galga1 (GyG1) (also known as avian Gyrovirus 2, AGV2) (n = 11); a plethora of novel CRESS viral genomes (n = 26) and a novel genomovirus. The 27 novel viruses were divided into three clusters. Phylogenetic analysis showed that the GyH1 strain was more closely related to the strains from chicken (MG366592) than mammalian (human and cat), the GyG1 strain was closely related to the strains from cat in China (MK089245) and from chicken in Brazil (HM590588), and the CAV strain was more closely related to the strains from Germany (AJ297684) and United Kingdom (U66304) than that previously found in China. CONCLUSION: In this study, we revealed that Gyrovirus virome showed high abundance in chickens with TVP, suggesting their potential role in TVP, especially GyH1. This study is expected to contribute to the knowledge of the etiology of TVP.


Assuntos
Vírus da Anemia da Galinha , Gyrovirus , Doenças das Aves Domésticas , Gastropatias , Animais , Vírus da Anemia da Galinha/genética , Galinhas , Mamíferos , Filogenia , Proventrículo , Gastropatias/veterinária , Viroma
19.
BMC Pulm Med ; 22(1): 266, 2022 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-35810306

RESUMO

BACKGROUND: COPD combined with respiratory failure is very common in intensive care unit (ICU). We aimed to evaluate the current status and influencing factors of delirium in elderly COPD patients with undergoing mechanical ventilation. METHODS: Patients with COPD combined with respiratory failure and mechanically ventilated who were admitted to the ICU of our hospital were selected. The characteristics of included patients were assessed. Pearson correlation analysis was performed to evaluate the characteristics of patients and delirium. Logistic regression analysis was conducted to identify the risk factors of delirium in elderly patients with COPD combined with respiratory failure undergoing mechanical ventilation. RESULTS: A total of 237 COPD combined with respiratory failure patients were included, the incidence of delirium was 21.94%. Pearson correlation analysis indicated that age (r = 0.784), BMI (r = 0.709), hypertension (r = 0.696), APACHE II score (r = 0.801), CPOT (r = 0.513), sedation(r = 0.626) and PaO2 (r = 0.611) were all correlated with the occurrence of delirium (all p < 0.05). Logistic regression analysis indicated that age ≥ 75y (OR 3.112, 95% CI 2.144-4.602), BMI ≤ 19 kg/m2 (OR 2.742, 95% CI 1.801-3.355), hypertension(OR 1.909, 95% CI 1.415-2.421), APACHE II score ≥ 15 (OR 2.087, 95% CI 1.724-2.615), CPOT ≥ 5 (OR 1.778, 95% CI 1.206-2.641), sedation(OR 3.147, 95% CI 2.714-3.758), PaO2 ≤ 75 mmHg(OR 2.196, 95%CI 1.875-3.088) were the risk factors of delirium in elderly patients with COPD combined with respiratory failure undergoing mechanical ventilation (all p < 0.05). CONCLUSIONS: Delirium is common in patients with COPD and respiratory failure undergoing mechanical ventilation, and there are many related influencing factors. Medical staff should pay more attention to patients with risk factors and take intervention measures as soon as possible to reduce the incidence of delirium.


Assuntos
Delírio , Hipertensão , Doença Pulmonar Obstrutiva Crônica , Insuficiência Respiratória , Idoso , Delírio/epidemiologia , Humanos , Unidades de Terapia Intensiva , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Respiração Artificial , Insuficiência Respiratória/epidemiologia , Insuficiência Respiratória/terapia
20.
Molecules ; 27(17)2022 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-36080281

RESUMO

In this paper, Amomi fructus (Latin) was used to explore the mechanism of ionic liquids (ILs) in improving the extraction efficiency of essential oils. Microwave assisted ionic liquid treatment followed by a hydro-distillation (MILT-HD) process for isolating Amomi fructus essential oil was optimized by multi-objective optimization. Under optimum operating conditions, the IL-assisted extraction method not only enhances extraction efficiency but also reduces energy demands and CO2 emissions. Since the hydrogen bond structure network of cellulose in the cell wall is an important reason for hindering diffusion of essential oils, the mechanism of ILs was explored by density functional theoretical (DFT) and molecular dynamics (MD) simulations. According to DFT calculations, ILs can facilitate the cleavage of cellulose chains and have strong non-covalent interactions with cellulose. Based on the MD simulations, the degree of destruction of the cellulose hydrogen bond structure was explored. According to the DFT and MD simulations, the ILs can significantly destroy cellulose structure, thereby promoting essential oil release from the plant. These results were confirmed by scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR). This work is conducive to better understand the MILT-HD process for isolating essential oil and comprehensively understand the mechanism of ILs in the extraction process.


Assuntos
Líquidos Iônicos , Óleos Voláteis , Celulose/química , Teoria da Densidade Funcional , Líquidos Iônicos/química , Simulação de Dinâmica Molecular , Óleos Voláteis/química
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