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1.
Cell Mol Life Sci ; 81(1): 325, 2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-39079969

RESUMO

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. The inflammatory cytokine storm causes systemic organ damage, especially acute lung injury in sepsis. In this study, we found that the expression of S-phase kinase-associated protein 2 (Skp2) was significantly decreased in sepsis-induced acute lung injury (ALI). Sepsis activated the MEK/ERK pathway and inhibited Skp2 expression in the pulmonary epithelium, resulting in a reduction of K48 ubiquitination of solute carrier family 3 member 2 (SLC3A2), thereby impairing its membrane localization and cystine/glutamate exchange function. Consequently, the dysregulated intracellular redox reactions induced ferroptosis in pulmonary epithelial cells, leading to lung injury. Finally, we demonstrated that intravenous administration of Skp2 mRNA-encapsulating lipid nanoparticles (LNPs) inhibited ferroptosis in the pulmonary epithelium and alleviated lung injury in septic mice. Taken together, these data provide an innovative understanding of the underlying mechanisms of sepsis-induced ALI and a promising therapeutic strategy for sepsis.


Assuntos
Lesão Pulmonar Aguda , Ferroptose , Camundongos Endogâmicos C57BL , Proteínas Quinases Associadas a Fase S , Sepse , Ubiquitinação , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/etiologia , Sepse/metabolismo , Sepse/complicações , Sepse/patologia , Animais , Camundongos , Humanos , Masculino , Proteínas Quinases Associadas a Fase S/metabolismo , Proteínas Quinases Associadas a Fase S/genética , Pulmão/patologia , Pulmão/metabolismo , Sistema y+ de Transporte de Aminoácidos/metabolismo , Sistema y+ de Transporte de Aminoácidos/genética
2.
J Immunol ; 208(3): 618-632, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35022270

RESUMO

Sepsis is an acute life-threatening disorder associated with multiorgan dysfunction that remains the leading cause of death in intensive care units. As sepsis progresses, it causes prolonged immunosuppression, which results in sustained mortality, morbidity, and susceptibility to secondary infections. Using a mouse model of sepsis, we found that the long noncoding RNA HOTAIRM1 (HOXA transcript antisense RNA myeloid-specific 1) was highly expressed in mice during the late phase of sepsis. The upregulation of HOTAIRM1 was induced by Notch/Hes1 activation and, moreover, was critical for the formation of an immunosuppressive microenvironment. HOTAIRM1 induced T cell exhaustion by increasing the percentage of PD-1+ T cells and regulatory T cells, accompanied by elevated PD-L1. Blockade of either Notch/Hes1 signaling or HOTAIRM1 inhibited T cell exhaustion in late sepsis, having alleviated lung injury and improved survival of mice. Further mechanistic studies identified HOXA1 as a key transcription factor targeted by HOTAIRM1 to regulate PD-L1 expression in lung alveolar epithelial cells. These results implicated that the Notch/Hes1/HOTAIRM1/HOXA1/PD-L1 axis was critical for sepsis-induced immunosuppression and could be a potential target for sepsis therapies.


Assuntos
Tolerância Imunológica/imunologia , MicroRNAs/genética , Sepse/imunologia , Linfócitos T Reguladores/imunologia , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Sepse/microbiologia , Fatores de Transcrição HES-1/metabolismo , Fatores de Transcrição/metabolismo
3.
Dig Dis Sci ; 69(4): 1214-1227, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38376789

RESUMO

BACKGROUND: HSK3486 (ciprofol), a new candidate drug similar to propofol, exerts sedative and hypnotic effects through gamma-aminobutyric acid type A receptors; however, its potential role in colorectal cancer is currently unknown. AIMS: This study aimed to evaluate the effects of HSK3486 on colorectal cancer cell proliferation. METHODS: Imaging was performed to detect reactive oxygen species and mitochondrial membrane potential. Western blotting was used to determine the expression of target signals. The HSK3486 molecular mechanism was investigated through ATPase inhibitory factor 1 knockdown and xenograft model experiments to assess mitochondrial function in colorectal cancer cells. RESULTS: Cell Counting Kit-8 and Annexin V/propidium iodide double staining assays showed that HSK3486 inhibited colorectal cancer cell proliferation in a concentration-dependent manner. In addition, HSK3486 treatment increased the expression of B-cell lymphoma-2-associated X, cleaved caspase 3, and cleaved poly (ADP-ribose) polymerase, whereas myeloid cell leukemia-1 and B-cell lymphoma 2 expression decreased. HSK3486 promoted mitochondrial dysfunction by inducing ATPase inhibitor factor 1 expression. Furthermore, HSK3486 promoted oxidative stress, as shown by the increase in reactive oxygen species and lactate dehydrogenase levels, along with a decrease in mitochondrial membrane potential and ATP levels. ATPase inhibitor factor 1 small interfering RNA pretreatment dramatically increased the mitochondrial membrane potential and tumor size in a xenograft model following exposure to HSK3486. CONCLUSION: Collectively, our findings revealed that HSK3486 induces oxidative stress, resulting in colorectal cancer cell apoptosis, making it a potential candidate therapeutic strategy for colorectal cancer.


Assuntos
Apoptose , Neoplasias Colorretais , Humanos , Adenosina Trifosfatases/metabolismo , Adenosina Trifosfatases/farmacologia , Adenosina Trifosfatases/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Potencial da Membrana Mitocondrial , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Proteína Inibidora de ATPase/efeitos dos fármacos
4.
Curr Oncol Rep ; 24(11): 1501-1511, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35763189

RESUMO

PURPOSE OF REVIEW: The stress response to surgery is essential for maintaining homeostasis and exhibits anti-tumor effects; however, an ongoing and exaggerated stress response may have adverse clinical consequences and even promote cancer progression. This review will discuss the complex relationship between surgical stress and cancer progression. RECENT FINDINGS: Surgical stress exhibits both anti-tumor and cancer-promoting effects by causing changes in the neuroendocrine, circulatory, and immune systems. Many studies have found that many mechanisms are involved in the process, and the corresponding targets could be applied for cancer therapy. Although surgical stress may have anti-tumor effects, it is necessary to inhibit an excessive stress response, mostly showing cancer-promoting effects.


Assuntos
Neoplasias , Humanos , Neoplasias/patologia , Sistema Imunitário
5.
Br J Anaesth ; 129(2): 244-253, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35697547

RESUMO

BACKGROUND: Intravenous lidocaine has been postulated to improve long-term survival after surgery for pancreatic cancer through anti-inflammatory effects, anti-tumour effects, or both. We investigated whether intraoperative lidocaine improves survival after pancreatectomy for pancreatic cancer and whether lidocaine modified the formation of neutrophil extracellular traps (NETs), high levels of which are associated with poor prognosis. METHODS: Patients undergoing pancreatectomy were randomly assigned to i.v. lidocaine (continuous intraoperative infusion of 2 mg kg-1 h-1, after 1.5 mg kg-1 bolus at induction of anaesthesia) or saline placebo. The co-primary outcomes were survival/disease-free survival 3 yr after surgery. Secondary outcomes (masked to treatment allocation) included intraoperative opioid (sufentanil) dose, postoperative complications, and circulating and tumour-associated NETs (immunofluorescence assay, enzyme-linked immune assay, or both). RESULTS: A total of 563 participants (34.6% female; median age, 64 yr) completed 3 yr of clinical follow-up. Overall, 283 participants were randomised to lidocaine infusion, and 280 participants were randomised to placebo. Infusion of lidocaine did not alter overall (hazard ratio [HR]=0.98; 95% confidence interval [CI], 0.81-1.17; P=0.79) or disease-free survival (HR=0.91; 95% CI, 0.71-1.17; P=0.44). Mean intraoperative sufentanil dose was reduced by lidocaine infusion (47.6 µg [4.6]) compared with placebo (68.4 µg [4.8]; P<0.001), but postoperative complications and length of hospital stay were similar between groups. Circulating NETs were lower after lidocaine infusion up to 3 days after surgery, but tumour-associated NETs were not altered by intraoperative treatment. CONCLUSION: In patients undergoing pancreatectomy for pancreatic cancer, intraoperative infusion of lidocaine did not improve overall or disease-free survival. Reduced formation of circulating NETs was absent in pancreatic tumour tissue. CLINICAL TRIAL REGISTRATION: NCT03245346; updated in Chi-CTR-2000035469.


Assuntos
Lidocaína , Neoplasias Pancreáticas , Anestésicos Locais , Método Duplo-Cego , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Dor Pós-Operatória/tratamento farmacológico , Pancreatectomia , Neoplasias Pancreáticas/cirurgia , Complicações Pós-Operatórias/induzido quimicamente , Sufentanil , Neoplasias Pancreáticas
6.
Curr Oncol Rep ; 23(10): 111, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34342720

RESUMO

PURPOSE OF REVIEW: Opioids are still the most effective and widely used treatments for acute and chronic pain in cancer patients. This review focuses on the impact of opioids and mu-opioid receptors (MOR) on tumor progression and providing new ideas for targeting the MOR in cancer treatment. RECENT FINDINGS: Studies estimated that opioids facilitate tumor progression and are related to the worse prognosis in cancer patients. As the primary receptor of opioids, MOR is involved in the regulation of malignant transformation of tumors and participating in proliferation, invasion, metastasis, and angiogenesis. MOR may be a new molecular marker of malignant tumors and thus become a new target for cancer therapy, which may be beneficial to the outcomes of cancer patients.


Assuntos
Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Receptores Opioides mu/metabolismo , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/uso terapêutico , Animais , Progressão da Doença , Humanos , Imunidade , Inflamação , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Neovascularização Patológica/metabolismo , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inibidores
7.
J Cell Biol ; 223(7)2024 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-38652117

RESUMO

Assembly of macromolecular complexes at correct cellular sites is crucial for cell function. Nuclear pore complexes (NPCs) are large cylindrical assemblies with eightfold rotational symmetry, built through hierarchical binding of nucleoporins (Nups) forming distinct subcomplexes. Here, we uncover a role of ubiquitin-associated protein 2-like (UBAP2L) in the assembly and stability of properly organized and functional NPCs at the intact nuclear envelope (NE) in human cells. UBAP2L localizes to the nuclear pores and facilitates the formation of the Y-complex, an essential scaffold component of the NPC, and its localization to the NE. UBAP2L promotes the interaction of the Y-complex with POM121 and Nup153, the critical upstream factors in a well-defined sequential order of Nups assembly onto NE during interphase. Timely localization of the cytoplasmic Nup transport factor fragile X-related protein 1 (FXR1) to the NE and its interaction with the Y-complex are likewise dependent on UBAP2L. Thus, this NPC biogenesis mechanism integrates the cytoplasmic and the nuclear NPC assembly signals and ensures efficient nuclear transport, adaptation to nutrient stress, and cellular proliferative capacity, highlighting the importance of NPC homeostasis at the intact NE.


Assuntos
Proteínas de Transporte , Membrana Nuclear , Poro Nuclear , Humanos , Transporte Ativo do Núcleo Celular , Células HeLa , Homeostase , Glicoproteínas de Membrana , Membrana Nuclear/metabolismo , Poro Nuclear/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Proteínas de Transporte/metabolismo
8.
Brain Sci ; 13(1)2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36672106

RESUMO

BACKGROUND: The neuroinflammation of the central nervous system (CNS) is a prevalent syndrome of brain dysfunction secondary to severe sepsis and is regulated by microglia. Triggering the receptor expressed on myeloid cells 2 (TREM2) is known to have protective functions that modulate the microglial polarization of M2 type to reduce inflammatory responses, thereby improving cognition. METHODS: We examined the effect of TREM2 on the polarization state of microglia during the progression of neuroinflammation. After consecutive intraperitoneal injections of lipopolysaccharide for 7 days, we evaluated the inflammation of a septic mice model by hematoxylin-eosin (H&E) and electron microscopy, and we used immunofluorescence (IF) assays and Western blotting to visualize hippocampal sections in C57BL/6 mice to assess TREM2 expression. In addition, we analyzed the state of microglia polarization with quantitative RT-PCR. RESULT: The consecutive injection of LPS for 4 days elevated systemic inflammation and caused behavioral cognitive dysfunction in the septic model. However, on Day 7, the neuroinflammation was considerably attenuated. Meanwhile, TREM2 decreased on Day 4 and increased on Day 7 in vivo. Consistently, LPS could reduce the expression of TREM2 while IFN-ß enhanced TREM2 expression in vitro. TREM2 regulated the microglial M1 phenotype's conversion to the M2 phenotype. CONCLUSION: Our aim in this study was to investigate the interconnection between microglia polarization and TREM2 in neuroinflammation. Our results suggested that IFN-ß could modulate TREM2 expression to alter the polarization state of microglia, thereby reducing LPS-induced neuroinflammation. Therefore, TREM2 is a novel potential therapeutic target for neuroinflammation.

9.
Cell Death Discov ; 9(1): 315, 2023 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-37626060

RESUMO

Neutrophil extracellular traps (NETs) are involved in the activation and dysfunction of multiple overlapping and interacting pathways, including the immune response to injury, inflammation, and coagulation, which contribute to the pathogenesis of sepsis-induced acute lung injury (SI-ALI). However, how NETs mediate the relationship between inflammation and coagulation has not been fully clarified. Here, we found that NETs, through stimulator of interferon genes (STING) activation, induced endothelial cell damage with abundant production of tissue factor (TF), which magnified the dysregulation between inflammatory and coagulant responses and resulted in poor prognosis of SI-ALI model mice. Disruption of NETs and inhibition of STING improved the outcomes of septic mice and reduced the inflammatory response and coagulation. Furthermore, Toll-like receptor 2 (TLR2) on the surface of endothelial cells was involved in the interaction between NETs and the STING pathway. Collectively, these findings demonstrate that NETs activate the coagulant cascade in endothelial cells in a STING-dependent manner in the development of SI-ALI.

10.
Clin Transl Med ; 13(1): e1170, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36629024

RESUMO

Sepsis is a persistent systemic inflammatory condition involving multiple organ failures resulting from a dysregulated immune response to infection, and one of the hallmarks of sepsis is endothelial dysfunction. During its progression, neutrophils are the first line of innate immune defence against infection. Aside from traditional mechanisms, such as phagocytosis or the release of inflammatory cytokines, reactive oxygen species and other antibacterial substances, activated neutrophils also release web-like structures composed of tangled decondensed DNA, histone, myeloperoxidase and other granules called neutrophil extracellular traps (NETs), which can efficiently ensnare bacteria in the circulation. In contrast, excessive neutrophil activation and NET release may induce endothelial cells to shift toward a pro-inflammatory and pro-coagulant phenotype. Furthermore, neutrophils and NETs can degrade glycocalyx on the endothelial cell surface and increase endothelium permeability. Consequently, the endothelial barrier collapses, contributing to impaired microcirculatory blood flow, tissue hypoperfusion and life-threatening organ failure in the late phase of sepsis.


Assuntos
Armadilhas Extracelulares , Sepse , Humanos , Neutrófilos/metabolismo , Armadilhas Extracelulares/metabolismo , Células Endoteliais , Microcirculação , Sepse/metabolismo
11.
Clin Transl Med ; 13(9): e1389, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37715457

RESUMO

Neutrophil extracellular traps (NETs), released by polymorphonuclear neutrophils (PMNs), exert a robust antimicrobial function in infectious diseases such as sepsis. NETs also contribute to the pathogenesis and exacerbation of sepsis. Although the lung is highly vulnerable to infections, few studies have explored the role of NETs in sepsis-induced acute lung injury (SI-ALI). We demonstrate that NETs induce SI-ALI via enhanced ferroptosis in alveolar epithelial cells. Our findings reveal that the excessive release of NETs in patients and mice with SI-ALI is accompanied by upregulation of ferroptosis depending on METTL3-induced m6A modification of hypoxia-inducible factor-1α (HIF-1α) and subsequent mitochondrial metabolic reprogramming. In addition to conducting METTL3 overexpression and knockdown experiments in vitro, we also investigated the impact of ferroptosis on SI-ALI caused by NETs in a caecum ligation and puncture (CLP)-induced SI-ALI model using METTL3 condition knockout (CKO) mice and wild-type mice. Our results indicate the crucial role of NETs in the progression of SI-ALI via NET-activated METTL3 m6A-IGF2BP2-dependent m6A modification of HIF-1α, which further contributes to metabolic reprogramming and ferroptosis in alveolar epithelial cells.


Assuntos
Lesão Pulmonar Aguda , Ferroptose , Sepse , Animais , Camundongos , Sepse/complicações , Sepse/genética , Lesão Pulmonar Aguda/genética , Regulação para Cima , Adenosina
12.
Nat Metab ; 5(6): 1045-1058, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37277610

RESUMO

Hypothalamic AgRP/NPY neurons are key players in the control of feeding behaviour. Ghrelin, a major orexigenic hormone, activates AgRP/NPY neurons to stimulate food intake and adiposity. However, cell-autonomous ghrelin-dependent signalling mechanisms in AgRP/NPY neurons remain poorly defined. Here we show that calcium/calmodulin-dependent protein kinase ID (CaMK1D), a genetic hot spot in type 2 diabetes, is activated upon ghrelin stimulation and acts in AgRP/NPY neurons to mediate ghrelin-dependent food intake. Global Camk1d-knockout male mice are resistant to ghrelin, gain less body weight and are protected against high-fat-diet-induced obesity. Deletion of Camk1d in AgRP/NPY, but not in POMC, neurons is sufficient to recapitulate above phenotypes. In response to ghrelin, lack of CaMK1D attenuates phosphorylation of CREB and CREB-dependent expression of the orexigenic neuropeptides AgRP/NPY in fibre projections to the paraventricular nucleus (PVN). Hence, CaMK1D links ghrelin action to transcriptional control of orexigenic neuropeptide availability in AgRP neurons.


Assuntos
Diabetes Mellitus Tipo 2 , Grelina , Camundongos , Animais , Masculino , Grelina/metabolismo , Proteína Relacionada com Agouti/genética , Proteína Relacionada com Agouti/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Neuropeptídeo Y/genética , Neuropeptídeo Y/metabolismo , Neurônios/metabolismo , Obesidade/metabolismo , Camundongos Knockout , Ingestão de Alimentos , Proteína Quinase Tipo 1 Dependente de Cálcio-Calmodulina/metabolismo
13.
Shock ; 57(6): 161-171, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35759299

RESUMO

ABSTRACT: As a global major health problem and a leading cause of death, sepsis is defined as a failure of homeostasis, which is mainly initiated by an infection and followed by sustained excessive inflammation until immune suppression. Despite advances in the identification and management of clinical sepsis, morbidity, and mortality remain high. In addition, clinical trials have failed to yield promising results. In recent years, the mechanism of regulated cell death (RCD) in sepsis has attracted more and more attention, because these dying cells could release a large number of danger signals which contribute to inflammatory responses and exacerbation of sepsis, providing a new direction for us to make treatment strategy. Here we summarize mechanisms of several forms of RCD in sepsis including necroptosis, pyroptosis, ferroptosis. In conclusion, targeting RCD is considered a promising approach to treat sepsis.


Assuntos
Ferroptose , Sepse , Humanos , Inflamação , Necroptose , Piroptose , Sepse/terapia
14.
Front Genet ; 13: 907145, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35860471

RESUMO

Background: Acute kidney injury (AKI) is a common clinical syndrome with limited methods of treatment and diagnosis. Although several molecules associated with AKI have been discovered, molecular mechanisms underlying AKI still remain unclear. Weighted gene co-expression network analysis (WGCNA) is a novel method to uncover the relationship between co-expression genes and clinical traits at the system level. Methods: First, by employing WGCNA in transcriptional data on 30 patients with well/poor functioning kidney graft, we identified two co-expression modules that were significantly related to serum creatinine (SCr). Second, based on the modules, potential small molecular compound candidates for developing targeted therapeutics were obtained by connectivity map analysis. Furthermore, multiple validations of expression in space/time were carried out with two classical AKI models in vivo and other five databases of over 152 samples. Results: Two of the 14 modules were found to be closely correlated with SCr. Function enrichment analysis illustrated that one module was enriched in the immune system, while the other was in the metabolic process. Six key renal function-related genes (RFRGs) were finally obtained. Such genes performed well in cisplatin-induced or cecal ligation and puncture-induced AKI mouse models. Conclusion: The analysis suggests that WGCNA is a proper method to connect clinical traits with genome data to find novel targets in AKI. The kidney tissue with worse renal function tended to develop a "high immune but low metabolic activity" expression pattern. Also, ACSM2A, GLYAT, CORO1A, DPEP1, ALDH7A1, and EPHX2 are potential targets of molecular diagnosis and treatment in AKI.

15.
Int J Biol Sci ; 18(8): 3337-3357, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35637949

RESUMO

Neutrophil extracellular traps (NETs) production is a major strategy employed by polymorphonuclear neutrophils (PMNs) to fight against microbes. NETs have been implicated in the pathogenesis of various lung injuries, although few studies have explored NETs in sepsis-associated acute lung injury (SI-ALI). Here, we demonstrate a major contribution of NETs to the pathology of sepsis-associated ALI by inducing ferroptosis of alveolar epithelial cells. Using both in vitro and in vivo studies, our findings show enhanced NETs accumulation in sepsis-associated ALI patients and mice, as well as the closely related upregulation of ferroptosis, the induction of which depends on METTL3-induced m6A modification of GPX4. Using a CLP-induced sepsis-associated ALI mouse model established with METTL3-/- versus WT mice, in addition to METTL3 knockout and overexpression in vitro, we elucidated and confirmed the critical role of ferroptosis in NETs-induced ALI. These findings support a role for NETs-induced METTL3 modification and the subsequent induction of ferroptosis in the pathogenesis of sepsis-associated ALI.


Assuntos
Lesão Pulmonar Aguda , Armadilhas Extracelulares , Ferroptose , Sepse , Lesão Pulmonar Aguda/patologia , Células Epiteliais Alveolares , Animais , Humanos , Metiltransferases , Camundongos , Sepse/complicações , Sepse/patologia
16.
Front Oncol ; 12: 927262, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35875149

RESUMO

Background: Opioids are widely used during primary debulking surgery (PDS) for ovarian cancers, and a high mu-opioid receptor (MOR) expression predicts worse cancer outcomes. However, the impact of MOR expression on survival outcomes in ovarian cancers is still not clear. Methods: A retrospective cohort study was conducted in patients who underwent PDS in ovarian cancer patients. MOR expression was measured in tumor and normal tissue. Primary outcomes were overall survival (OS) and disease-free survival (DFS). Secondary outcomes included perineural invasion (PNI), intraoperative sufentanil consumption, length of stay (LOS), and verbal numerical rating scale (VNRS) on postoperative day 1 (POD1), POD3, and POD5. Results: After propensity score matching, a total of 366 patients were finally enrolled in this study. There were no significant differences in OS rates in patients with high versus low levels of MOR (1-year OS: 82.9% versus 83.3%, 3-year: 57.8% versus 59.1%, 5-year: 22.4% versus 23.1%,respectively) in the ovarian cancers. There were no significant differences in DFS between the groups. Intraoperative sufentanil consumption was higher in the MOR high-expression group compared with the MOR low-expression group. Tumors expressing high levels of MOR showed higher rates of PNI. VNRS in the MOR high-expression group was higher on POD1. Conclusion: MOR is not an independent predictor of worse survival in ovarian cancers but is associated with high rates of perineural invasion.

17.
Cell Death Discov ; 8(1): 375, 2022 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-36030287

RESUMO

Neutrophil extracellular traps (NETs) assist pathogen clearance, while excessive NETs formation is associated with exacerbated inflammatory responses and tissue injury in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Autophagy is generally considered to be a protective process, but autophagy dysfunction is harmful. Whether and how NETs affect autophagic flux during sepsis-induced ALI are currently unknown. Here, we confirmed that the level of NETs was increased in ARDS patients and mice models, which led to impairment of autophagic flux and deterioration of the disease. Mechanistically, NETs activated METTL3 mediated m6A methylation of Sirt1 mRNA in alveolar epithelial cells, resulting in abnormal autophagy. These findings provide new insights into how NETs contribute to the development of sepsis-associated ALI/ARDS.

18.
Front Oncol ; 11: 686877, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34222012

RESUMO

BACKGROUND: The use of opioids in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) is associated with shorter survival and not dependent on the expression of the mu-opioid receptor (MOR). The role of opioid use and MOR expression in stage I-III PDAC has not been investigated. METHODS: We conducted retrospective study in patients with stage I-III PDAC. MOR expression and OPRM1 gene expression in tumour tissue and non-tumour tissue was measured. Primary endpoints were overall survival (OS) and disease-free survival (DFS). Secondary endpoints included perineural invasion, intraoperative sufentanil consumption, and length of stay. We performed a subgroup group analysis to evaluate the interaction between levels of MOR expression, amount of opioids use (high versus low) and its association with survival. RESULTS: A total of 236 patients were enrolled in this study.There were no significantly difference in OS rates in patients with high versus low levels of MOR (1-year OS: 65.2% versus 70.6%, P=0.064; 3-year: 31.4% versus 35.8%, P=0.071; 5-year: 19.4% versus. 16.2%, P=0.153, respectively) in the tumours. The DFS rates between the groups were no significantly difference. Of note, a high expression of MOR combined with high opioid consumption was associated with poor prognosis in stage I-III PDAC patients. Tumor expressing high levels of MOR show higher rates of perineural invasion. CONCLUSION: MOR is not an independent predictor of poor survival in stage I-III PDAC but associated with perineural invasion. Patients requiring high amounts of opioids intraoperatively show worse outcome if they are expressing high levels of MOR.

19.
Front Cell Infect Microbiol ; 11: 653228, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33816356

RESUMO

Patients with sepsis commonly suffer from coagulation dysfunction and lead to the formation of thrombus. During the development of sepsis, neutrophils migrate from the circulating blood to infected tissues and mediate the formation of neutrophil extracellular traps (NETs) that kill pathogens. However, the overactivation of neutrophils can promote the formation of immunothrombosis and even cause disseminated intravascular coagulation (DIC), which damages microcirculation. The outcome of sepsis depends on early recognition and intervention, so clinical evaluation of NETs function may be a valuable biomarker for early diagnosis of sepsis. The interaction of NETs with platelets, complement, and endothelium mediates the formation of immunothrombosis in sepsis. Inhibiting the formation of NETs is also considered to be one of the potential treatments for sepsis. In this review, we will discuss the key role of neutrophils and NETs in sepsis and septic thrombosis, in order to reveal new mechanisms for thrombosis treatment of sepsis.


Assuntos
Armadilhas Extracelulares , Sepse , Trombose , Plaquetas , Humanos , Neutrófilos
20.
Front Oncol ; 11: 689832, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35070949

RESUMO

BACKGROUND: Intravenous lidocaine has been shown to reduce opioid consumption and is associated with favourable outcomes after surgery. In this study, we explored whether intraoperative lidocaine reduces intraoperative opioid use and length of stay (LOS) and improves long-term survival after primary debulking surgery for ovarian cancer and explored the correlation between SCN9A expression and ovarian cancer prognosis. METHODS: This retrospective study included patients who underwent primary debulking surgery(PDS) for ovarian cancer from January 2015 to December 2018. The patients were divided into non-lidocaine and lidocaine [bolus injection of 1.5 mg/kg lidocaine at the induction of anaesthesia followed by a continuous infusion of 2 mg/(kg∙h) intraoperatively] groups. Intraoperative opioid consumption, the verbal numeric rating scale (VNRS) at rest and LOS were recorded. Propensity score matching was used to minimize bias, and disease-free survival (DFS) and overall survival (OS) were compared between the two groups. RESULTS: After propensity score matching(PSM), the demographics were not significantly different between the groups. The intraoperative sufentanil consumption in the lidocaine group was significantly lower than that in the non-lidocaine group (Mean: 35.6 µg vs. 43.2 µg, P=0.035). LOS was similar between the groups (12.0 days vs. 12.4 days, P=0.386). There was a significant difference in DFS between the groups (32.3% vs. 21.6%, P=0.015), and OS rates were significantly higher in the lidocaine group than in the non-lidocaine group (35.2% vs. 25.6%, P=0.042). Multivariate analysis indicated that intraoperative lidocaine infusion was associated with prolonged OS and DFS. CONCLUSION: Intraoperative intravenous lidocaine infusion appears to be associated with improved OS and DFS in patients undergoing primary debulking surgery for ovarian cancer. Our study has the limitations of a retrospective review. Hence, our results should be confirmed by a prospective randomized controlled trial.

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