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Background: The FCN1 gene encodes the ficolin-1 protein, implicated in the pathogenesis of various diseases, though its precise role in tumorigenesis remains elusive. This study aims to elucidate the prognostic significance, immune signature, and treatment response associated with FCN1 across diverse cancer types. Methods: Employing multi-omics data, we conducted a comprehensive assessment, encompassing tissue-specific and single-cell-specific expression disparities, pan-cancer expression patterns, epigenetic modifications affecting FCN1 expression, and the immune microenvironment. Our investigation primarily focused on the clinical prognostic attributes, immune profiles, potential molecular mechanisms, and candidate therapeutic agents concerning FCN1 and acute myeloid leukemia (AML). Additionally, in vitro experiments were performed to scrutinize the impact of FCN1 knockdown on cell proliferation, apoptosis, and cell cycle dynamics within the AML cell line U937 and NB4. Results: FCN1 expression exhibits widespread dysregulation across various cancers. Through both univariate and multivariate Cox regression analyses, FCN1 has been identified as an independent prognostic indicator for AML. Immunological investigations elucidate FCN1's involvement in modulating inflammatory responses within the tumor microenvironment and its correlation with treatment efficacy. Remarkably, the deletion of FCN1 influences the proliferation, apoptosis, and cell cycle dynamics of U937 cells and NB4 cells. Conclusion: These findings underscore FCN1 as a promising pan-cancer biomarker indicative of macrophage infiltration, intimately linked with the tumor microenvironment and treatment responsiveness, and pivotal for cellular mechanisms within AML cell lines.
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BACKGROUND: Cryptochrome-2 (CRY2) is a core rhythm gene that plays a crucial role in DNA damage repair. The present study investigated the potential role of CRY2 in mediating sleep deprivation-induced cognitive decline in 5xFAD mice. METHODS: To assess the effects of SD on different brain regions of the mouse brain, we used 18F FDG PET-CT. Cognitive function was evaluated using the Morris water maze test and Y-maze. Lentivirus was used for the overexpression of CRY2, and small interfering RNA (siRNA) was used for the downregulation of CRY2 to verify the effect of CRY2. We used qRTâPCR and Western blotting to identify the downstream factors of CRY2 and evaluated the cognitive function of mice to confirm the effects of these factors. RESULTS: The AD mice exhibited cognitive decline after 21 days of SD and had higher expression of CRY2 compared to AD mice with normal sleep. Overexpression of CRY2 led to decreased cognitive function in AD mice, and the downregulation of CRY2 attenuated the SD-induced cognitive decline in AD mice. CRY2 reduced the expression and function of CISH, which reduced the inhibition of STAT1 phosphorylation and led to synaptic dysfunction. CISH overexpression attenuated the impairing effect of sleep deprivation on cognitive function in AD mice. Furthermore, 18F FDG PET-CT revealed that SD significantly reduced glucose metabolism in different brain regions of AD mice. CONCLUSION: Our study demonstrated that sleep deprivation upregulated CRY2 in the hippocampus of AD mice, which resulted in synaptic dysfunction by decreasing CISH-mediated STAT1 phosphorylation.
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Disfunção Cognitiva , Criptocromos , Camundongos Transgênicos , Privação do Sono , Animais , Privação do Sono/metabolismo , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/genética , Disfunção Cognitiva/etiologia , Camundongos , Criptocromos/metabolismo , Criptocromos/genética , Masculino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Modelos Animais de Doenças , Doença de Alzheimer/metabolismo , Doença de Alzheimer/genética , Aprendizagem em Labirinto , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagemRESUMO
During the treatment of 89 pediatric patients with Acute Myeloid Leukemia (AML) at the Hematology Department of Kunming Medical University's Children's Hospital from 2020 to 2023, three patients were identified to co-express the NUP98-NSD1, FLT3-ITD, and WT1 gene mutations. The bone marrow of these three patients was screened for high-risk genetic mutations using NGS and qPCR at the time of diagnosis. The treatment was administered following the China Children's Leukemia Group (CCLG)-AML-2019 protocol. All three patients exhibited a fusion of the NUP98 exon 12 with the NSD1 exon 6 and co-expressed the FLT3-ITD and WT1 mutations; two of the patients displayed normal karyotypes, while one presented chromosomal abnormalities. During the induction phase of the CCLG-AML-2019 treatment protocol, the DAH (Daunorubicin, Cytarabine, and Homoharringtonine) and IAH (Idarubicin, Cytarabine, and Homoharringtonine) regimens, in conjunction with targeted drug therapy, did not achieve remission. Subsequently, the patients were shifted to the relapsed/refractory chemotherapy regimen C + HAG (Cladribine, Homoharringtonine, Cytarabine, and G-CSF) for two cycles, which also failed to induce remission. One patient underwent Haploidentical Hematopoietic Stem Cell Transplantation (Haplo-HSCT) and achieved complete molecular remission during a 12-month follow-up period. Regrettably, the other two patients, who did not receive transplantation, passed away. The therapeutic conclusion is that pediatric AML patients with the aforementioned co-expression do not respond to chemotherapy. Non-remission transplantation, supplemented with tailor-made pre- and post-transplant strategies, may enhance treatment outcomes.
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Leucemia Mieloide Aguda , Proteínas de Fusão Oncogênica , Proteínas WT1 , Tirosina Quinase 3 Semelhante a fms , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Tirosina Quinase 3 Semelhante a fms/genética , Masculino , Feminino , Criança , Proteínas de Fusão Oncogênica/genética , Proteínas WT1/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pré-Escolar , Citarabina/uso terapêutico , Mutação , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Transplante de Células-Tronco Hematopoéticas , Mepesuccinato de Omacetaxina/uso terapêutico , LactenteRESUMO
OBJECTIVES: To investigate the expression of microRNA-142 (miR-142) in children with autoimmune thyroid disease (AITD) and its relationship with the imbalance of helper T cell 17 (Th17) and regulatory T cell (Treg). METHODS: A total of 89 children hospitalized for AITD from January 2019 to December 2022 were prospectively selected as the study subjects, including 48 children with Graves' disease (GD group) and 41 children with Hashimoto's thyroiditis (HT group). Additionally, 55 healthy children undergoing physical examinations during the same period were selected as the control group. The differences in serum miR-142, antithyroglobulin antibody (TGAb), antithyroperoxidase antibody (TPOAb), Th17/Treg, and interleukin-17 (IL-17) expression were compared among the groups. RESULTS: The expression of miR-142, TPOAb, TGAb, Th17, Th17/Treg, and IL-17 in the GD group and HT group was higher than that in the control group, while Treg was lower than that in the control group (P<0.05). Pearson correlation analysis revealed that in the GD group, miR-142 was positively correlated with TPOAb, TGAb, Th17, Th17/Treg, and IL-17 (r=0.711, 0.728, 0.785, 0.716, 0.709, respectively; P<0.001) and negatively correlated with Treg (r=-0.725, P<0.001); in the HT group, miR-142 was positively correlated with TPOAb and TGAb (r=0.752, 0.717, respectively; P<0.001). CONCLUSIONS: miR-142 is highly expressed in children with AITD, and its expression may be related to the Th17/Treg imbalance in children with GD.
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Interleucina-17 , MicroRNAs , Linfócitos T Reguladores , Células Th17 , Humanos , MicroRNAs/sangue , Células Th17/imunologia , Criança , Masculino , Feminino , Linfócitos T Reguladores/imunologia , Interleucina-17/sangue , Doença de Hashimoto/imunologia , Doença de Hashimoto/genética , Doença de Hashimoto/sangue , Pré-Escolar , Doença de Graves/imunologia , Doença de Graves/genética , Adolescente , Autoanticorpos/sangueRESUMO
INTRODUCTION: The identification of active dietary flavonoids in food is promising for novel drug discovery. The active ingredients of duckweed (a widely recognized food and herb with abundant flavonoids) that are associated with acute myeloid leukemia (AML) have yet to be identified, and their underlying mechanisms have not been elucidated. OBJECTIVES: The objective of this study was to identify novel constituents exhibiting antileukemia activity in duckweed through the integration of chemical profiling, network pharmacology, and experimental validation. METHODS: First, high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was used to characterize the primary constituents of duckweed. Subsequently, AML cell-xenograft tumor models were used to validate the anticancer effect of duckweed extract. Furthermore, network pharmacology analysis was conducted to predict the potential active compounds and drug targets against AML. Lastly, based on these findings, two monomers (apiin and luteoloside) were selected for experimental validation. RESULTS: A total of 17 compounds, all of which are apigenin and luteolin derivatives, were identified in duckweed. The duckweed extract significantly inhibited AML cell growth in vivo. Furthermore, a total of 88 targets for duckweed against AML were predicted, with key targets including PTGS2, MYC, MDM2, VEGFA, CTNNB1, CASP3, EGFR, TP53, HSP90AA1, CCND1, MMP9, TNF, and MAPK1. GO and KEGG pathway enrichment analyses indicated that these targets were primarily involved in the apoptotic signaling pathway. Lastly, both apiin and luteoloside effectively induced apoptosis through CASP3 activation, and this effect could be partially reversed by a caspase inhibitor (Z-VAD). CONCLUSION: Duckweed extract has an antileukemic effect, and apiin derived from duckweed shows potential as a treatment for AML.
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STUDY OBJECTIVE: The use of hydroxyethyl starch 130/0.4 has been linked to renal injury in critically ill patients, but its impact on surgical patients remains uncertain. DESIGN: A retrospective cohort study. SETTING: This study was conducted at one tertiary care hospital in China. PATIENTS: We evaluated the records of 51,926 Chinese adults who underwent noncardiac surgery from 2013 to 2022. Patients given a combination of hydroxyethyl starch 130/0.4 and crystalloids were propensity-matched at a 1: 1 ratio of baseline characteristics to patients given only crystalloids (11,725 pairs). INTERVENTIONS: Eligible patients were divided into those given a combination of hydroxyethyl starch 130/0.4 and crystalloid during surgery and a reference crystalloid group consisting of patients who were not given any colloid. MEASUREMENTS: The primary outcome was the incidence of acute kidney injury. Secondarily, acute kidney injury stage, need for renal replacement therapy, intensive care unit transfer rate, and duration of postoperative hospitalization were considered. MAIN RESULTS: After matching, hydroxyethyl starch use [8.5 (IQR: 7.5-10.0) mL/kg] did not increase the incidence of acute kidney injury compared with that in the crystalloid group [2.0 vs. 2.2%, OR: 0.90 (0.74-1.08), P = 0.25]. Nor did hydroxyethyl starch use worsen acute kidney injury stage [OR 0.90 (0.75-1.08), P = 0.26]. No significant differences between the fluid groups were observed in renal replacement therapy [OR 0.60 (0.41-0.90), P = 0.02)] or intensive care unit transfers [OR 1.02 (0.95-1.09), P = 0.53] after Bonferroni correction. Even in a subset of patients at high risk of renal injury, hydroxyethyl starch use was not associated with worse outcomes. CONCLUSIONS: Hydroxyethyl starch 130/0.4 use was not significantly associated with a greater incidence of postoperative acute kidney injury compared to receiving crystalloid solutions only.
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Injúria Renal Aguda , Soluções Cristaloides , Derivados de Hidroxietil Amido , Complicações Pós-Operatórias , Pontuação de Propensão , Humanos , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/induzido quimicamente , Derivados de Hidroxietil Amido/efeitos adversos , Derivados de Hidroxietil Amido/administração & dosagem , Estudos Retrospectivos , Feminino , Masculino , Pessoa de Meia-Idade , China/epidemiologia , Soluções Cristaloides/administração & dosagem , Soluções Cristaloides/efeitos adversos , Idoso , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Incidência , Substitutos do Plasma/efeitos adversos , Substitutos do Plasma/administração & dosagem , Adulto , Terapia de Substituição Renal/estatística & dados numéricos , Tempo de Internação/estatística & dados numéricos , Procedimentos Cirúrgicos Operatórios/efeitos adversosRESUMO
OBJECTIVES: The activation of astrocytes is an important process in the formation of chronic pain. This study aims to observe the activation of A1 reactive astrocytes in the medullary dorsal horn in the rat model of trigeminal neuralgia, and to explore the mechanism of central sensitization caused by A1 reactive astrocyte. METHODS: The adult male rats were randomly divided into a sham group and a chronic constriction injury of infraorbital nerve (ION-CCI) group. The facial mechanical pain threshold and thermal withdrawal latency were measured before the operation and on the 1st, 3rd, 7th, 10th, and 14th day after the operation. After pain behavior observation, the expression of glial fibrillary acidic protein (GFAP) in the medullary dorsal horn was observed by immunohistochemistry and immunofluorescence colocalization of GFAP, complement 3 (C3)/S100A10, and 4', 6-diamidino-2-phenylindole (DAPI) was analyzed. Primary astrocytes were cultured and randomly divided into a naive group and a DHK group. The DHK group was treated with 1 mmol/L of astrocyte activation inhibitor dihydrokainic acid (DHK). Fura-2/AM was used to stain the astrocytes and the calcium wave of the 2 groups under the stimulation of high potassium was recorded and compared. The expression of C3 was detected by Western blotting. RESULTS: The facial mechanical pain threshold and thermal withdrawal latency of the ION-CCI group were significantly lower than those of the sham group (both P<0.05). There were a large number of GFAP positive astrocytes in the medullary dorsal horn of the ION-CCI group. The fluorescence intensity of GFAP in the ION-CCI group was higher than that in the sham group (P<0.05). GFAP and C3/S100A10 were co-expressed in astrocytes. Compared with the sham group, the fluorescence intensity of C3 and the protein expression of C3 in the ION-CCI group were increased (both P<0.05). The expression of C3 in ION-CCI group was significantly increased (P<0.05). Compared with the naive group, the C3 protein expression was significantly decreased in the DHK group (P<0.05). The intensity of calcium fluorescence was increased after high potassium stimulation in both groups. Furthermore, the peak and increase amplitude of calcium fluorescence in the naive group were much higher than those in the DHK group (both P<0.05). CONCLUSIONS: A1 reactive astrocytes in the medullary dorsal horn of trigeminal neuralgia model rats are increased significantly, which may participate in central sensitization of trigeminal neuralgia by impacting astrocyte calcium wave.
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Dor Crônica , Neuralgia do Trigêmeo , Masculino , Animais , Ratos , Astrócitos , Cálcio , PotássioRESUMO
STUDY DESIGN: Basic science study using a hemisection spinal cord injury (SCI) model. OBJECTIVE: We sought to assess the effect of blocking osteopontin (OPN) upregulation on motor function recovery and pain behavior after SCI and to further investigate the possible downstream target of OPN in the injured spinal cord. SUMMARY OF BACKGROUND DATA: OPN is a noncollagenous extracellular matrix protein widely expressed across different tissues. Its expression substantially increases following SCI. A previous study suggested that this protein might contribute to locomotor function recovery after SCI. However, its neuroprotective potential was not fully explored, nor were the underlying mechanisms. MATERIALS AND METHODS: We constructed a SCI mouse model and analyzed the expression of OPN at different time points and the particular cell distribution in the injured spinal cord. Then, we blocked OPN upregulation with lentivirus-delivering siRNA targeting OPN specifically and examined its effect on motor function impairment and neuropathic pain after SCI. The underlying mechanisms were explored in the OPN-knockdown mice model and cultured vascular endothelial cells. RESULTS: The proteome study revealed that OPN was the most dramatically increased protein following SCI. OPN in the spinal cord was significantly increased three weeks after SCI. Suppressing OPN upregulation through siRNA exacerbated motor function impairment and neuropathic pain. In addition, SCI resulted in an increase in vascular endothelial growth factor (VEGF), AKT phosphorylation, and angiogenesis within the spinal cord, all of which were curbed by OPN reduction. Similarly, OPN knockdown suppressed VEGF expression, AKT phosphorylation, cell migration, invasion, and angiogenesis in cultured vascular endothelial cells. CONCLUSION: OPN demonstrates a protective influence against motor function impairment and neuropathic pain following SCI. This phenomenon may result from the proangiogenetic effect of OPN, possibly due to activation of the VEGF and/or AKT pathways.
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Neuralgia , Osteopontina , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal , Medula Espinal , Animais , Masculino , Camundongos , Angiogênese , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Neovascularização Fisiológica/fisiologia , Neovascularização Fisiológica/efeitos dos fármacos , Neuralgia/etiologia , Neuralgia/metabolismo , Neuralgia/prevenção & controle , Osteopontina/metabolismo , Recuperação de Função Fisiológica/fisiologia , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/fisiopatologia , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
INTRODUCTION: Local anesthetic-induced neurotoxicity contributes to perioperative nerve damage; however, the underlying mechanisms remain unclear. Here, we investigated the role of the paraventricular thalamus (PVT)-nucleus accumbens (NAc) projections in neurotoxicity induced by ropivacaine, a local anesthetic agent. METHODS: Ropivacaine (58 mg/kg, intraperitoneal administration) was used to construct the local anesthetic systemic toxicity (LAST) mice model. We first identified neural projections from the PVT to the NAc through the expression of a retrograde tracer and virus. The inhibitory viruses (rAAV-EF1α-DIO-hm4D(Gi)-mCherry-WPREs: AAV2/retro and rAAV-CaMKII-CRE-WPRE-hGh: AAV2/9) were injected into the mice model to assess the effects of the specific inhibition of the PVT-NAc pathway on neurological behaviors in the presence of clozapine-N-oxide. The inhibition of the PVT-NAc pathway was evaluated by immunofluorescence staining of c-Fos-positive neurons and Ca2+ signals in CaMKIIa neurons. RESULTS: We successfully identified a circuit connecting the PVT and NAc in C57BL/6 mice. Ropivacaine administration induced the activation of the PVT-NAc pathway and seizures. Specific inhibition of NAc-projecting CaMKII neurons in the PVT was sufficient to inhibit the neuronal activity in the NAc, which subsequently decreased ropivacaine-induced neurotoxicity. CONCLUSION: These results reveal the presence of a dedicated PVT-NAc circuit that regulates local anesthetic-induced neurotoxicity and provide a potential mechanistic explanation for the treatment and prevention of LAST.
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Astrocyte swelling is implicated in various neurological disorders. However, whether astrocyte swelling contributes to neuropathic pain remains elusive. This study elucidates the pivotal role of the nuclear factor of activated T-cells 5 (NFAT5) emerges as a master regulator of astrocyte swelling in the spinal dorsal horn (SDH) during neuropathic pain. Despite the ubiquitous expression of NFAT5 protein in SDH cell types, it selectively induces swelling specifically in astrocytes, not in microglia. Mechanistically, NFAT5 directly controls the expression of the water channel aquaporin-4 (AQP4), a key regulator exclusive to astrocytes. Additionally, aurora kinase B (AURKB) orchestrates NFAT5 phosphorylation, enhancing its protein stability and nuclear translocation, thereby regulating AQP4 expression. The findings establish NFAT5 as a crucial regulator for neuropathic pain through the modulation of astrocyte swelling. The AURKB-NFAT5-AQP4 pathway in astrocytes emerges as a potential therapeutic target to combat neuropathic pain.
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Astrócitos , Neuralgia , Humanos , Astrócitos/metabolismo , Microglia/metabolismo , Fosforilação , Neuralgia/metabolismo , Fatores de Transcrição/metabolismoRESUMO
BACKGROUND: Preliminary clinical trials of adamgammadex, a new cyclodextrin-based selective reversal agent, have demonstrated its efficacy in reversing neuromuscular block by rocuronium. METHODS: This multicentre, randomised, double-blind, positive-controlled, non-inferiority phase III clinical trial compared the efficacy and safety of adamgammadex and sugammadex. We randomised 310 subjects to receive adamgammadex (4 mg kg-1) or sugammadex (2 mg kg-1) at reappearance of the second twitch of the train-of-four (TOF), and standard safety data were collected. RESULTS: For the primary outcome, the proportion of patients with TOF ratio ≥0.9 within 5 min was 98.7% in the adamgammadex group vs 100% in the sugammadex group, with a point estimate and 95% confidence interval (CI) of 1.3% (-4.6%, +1.3%); the lower limit was greater than the non-inferiority margin of -10%. For the key secondary outcome, the median (inter quartile range) time from the start of administration of adamgammadex or sugammadex to recovery of TOF ratio to 0.9 was 2.25 (1.75, 2.75) min and 1.75 (1.50, 2.00) min, respectively. The difference was 0.50 (95% CI: 0.25, 0.50); the upper limit was lower than the non-inferiority margin of 5 min. In addition, there were no inferior results observed in secondary outcomes. Adamgammadex had a lower incidence of adverse drug reactions compared with sugammadex (anaphylactic reaction, recurarisation, decreased heart rate, and laryngospasm; P=0.047). CONCLUSIONS: Adamgammadex was non-inferior to sugammadex with a possible lower incidence of adverse drug reactions compared with sugammadex. Adamgammadex may have a potential advantage in terms of its overall risk-benefit profile. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2000039525. Registered October 30, 2020. https://www.chictr.org.cn/showproj.html?proj=56825.
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Bloqueio Neuromuscular , Fármacos Neuromusculares não Despolarizantes , gama-Ciclodextrinas , Humanos , Sugammadex/efeitos adversos , Rocurônio , Bloqueio Neuromuscular/métodos , gama-Ciclodextrinas/efeitos adversos , Fármacos Neuromusculares não Despolarizantes/efeitos adversos , Androstanóis/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologiaRESUMO
The E2A-PBX1 gene fusion is a common translocation in B-cell acute lymphoblastic leukaemia. Patients harbouring the E2A-PBX1 fusion gene typically exhibit an intermediate prognosis. Furthermore, minimal residual disease has unsatisfactory prognostic value in E2A-PBX1 B-cell acute lymphoblastic leukaemia. However, the mechanism of E2A-PBX1 in the occurrence and progression of B-cell acute lymphoblastic leukaemia is not well understood. Here, we mainly review the roles of E2A and PBX1 in the differentiation and development of B lymphocytes, the mechanism of E2A-PBX1 gene fusion in B-cell acute lymphoblastic leukaemia, and the potential therapeutic approaches.
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Proteínas de Fusão Oncogênica , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Linfócitos B/patologia , Linfócitos B/metabolismo , Prognóstico , Fator de Transcrição 1 de Leucemia de Células Pré-B/genética , Diferenciação Celular , Proteínas de HomeodomínioRESUMO
Pain management remains among the most common and largely unmet clinical problems today. Local anesthetics play an indispensable role in pain management. The main limitation of traditional local anesthetics is the limited duration of a single injection. To address this problem, catheters are often placed or combined with other drugs in clinical practice to increase the time that local anesthetics act. However, this method does not meet the needs of clinical analgesics. Therefore, many researchers have worked to develop local anesthetic extended-release types that can be administered in a single dose. In recent years, drug extended-release systems have emerged dramatically due to their long duration and efficacy, providing more possibilities for the application of local anesthetics. This paper summarizes the types of local anesthetic drug delivery systems and their clinical applications, discusses them in the context of relevant studies on local anesthetics, and provides a summary and outlook on the development of local anesthetic extended-release agents.
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Anestésicos Locais , Manejo da Dor , Anestesia Local , Analgésicos , Sistemas de Liberação de MedicamentosRESUMO
Neuropathic pain often leads to negative emotions, which in turn can enhance the sensation of pain. This study aimed to investigate the molecular mechanisms mediating neuropathic pain and negative emotions. Chronic constriction injury (CCI) rats were used as model animals and behavioral tests were conducted to assess pain and negative emotions. Then, the rat anterior cingulate cortex (ACC) was analyzed using UPLC-MS/MS and subsequently integrated with our previously published transcriptome data. Metabolomics analysis revealed that 68 differentially expressed metabolites (DEMs) were identified, mainly in amino acid metabolites and fatty acyls. Combined with our previously published transcriptome data, we predicted two genes that potentially exhibited associations with these metabolites, respectively Apolipoprotein L domain containing 1 (Apold1) and WAP four-disulfide core domain 1 (Wfdc1). Taken together, our results indicated that peripheral nerve injury contributing to neuropathic pain and pain-related depression may be associated with these metabolites and genes. This research provides new insights into the molecular regulatory mechanism, which could serve as a reference for the treatment of neuropathic pain and pain-related depression.
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BACKGROUND: Chloride is the most abundant anion in the human extracellular fluid and plays a crucial role in maintaining homeostasis. Previous studies have demonstrated that hypochloremia can act as an independent risk factor for adverse outcomes in various clinical settings. However, the association of variances of serum chloride with long-term mortality risk in general populations has been rarely investigated. OBJECTIVE: This study aims to assess the association of serum chloride with all-cause and cause-specific mortality in the general American adult population. METHODS: Data were collected from 10 survey cycles (1999-2018) of the National Health and Nutrition Examination Survey. All-cause mortality, cardiovascular disease (CVD) mortality, cancer mortality, and respiratory disease mortality data were obtained by linkage to the National Death Index through December 31, 2019. After adjusting for demographic factors and relevant lifestyle, laboratory items, and comorbid factors, weighted Cox proportional risk models were constructed to estimate hazard ratios and 95% CIs for all-cause and cause-specific mortality. RESULTS: A total of 51,060 adult participants were included, and during a median follow-up of 111 months, 7582 deaths were documented, 2388 of CVD, 1639 of cancer, and 567 of respiratory disease. The weighted Kaplan-Meier survival analyses showed consistent highest mortality risk in individuals with the lowest quartiles of serum chloride. The multivariate-adjusted hazard ratios from lowest to highest quartiles of serum chloride (≤101.2, 101.3-103.2, 103.2-105.0, and ≥105.1 mmol/L) were 1.00 (95% CI reference), 0.77 (95% CI 0.67-0.89), 0.72 (95% CI 0.63-0.82), and 0.77 (95% CI 0.65-0.90), respectively, for all-cause mortality (P for linear trend<.001); 1.00 (95% CI reference), 0.63 (95% CI 0.51-0.79), 0.56 (95% CI 0.43-0.73), and 0.67 (95% CI 0.50-0.89) for CVD mortality (P for linear trend=.004); 1.00 (95% CI reference), 0.67 (95% CI 0.54-0.84), 0.65 (95% CI 0.50-0.85), and 0.65 (95% CI 0.48-0.87) for cancer mortality (P for linear trend=.004); and 1.00 (95% CI reference), 0.68 (95% CI 0.41-1.13), 0.59 (95% CI 0.40-0.88), and 0.51 (95% CI 0.31-0.84) for respiratory disease mortality (P for linear trend=.004). The restricted cubic spline analyses revealed the nonlinear and L-shaped associations of serum chloride with all-cause and cause-specific mortality (all P for nonlinearity<.05), in which lower serum chloride was prominently associated with higher mortality risk. The associations of serum chloride with mortality risk were robust, and no significant additional interaction effect was detected for all-cause mortality and CVD mortality (P for interaction>.05). CONCLUSIONS: In American adults, decreased serum chloride concentrations were independently associated with increased all-cause mortality, CVD mortality, cancer mortality, and respiratory disease mortality. Our findings suggested that serum chloride may serve as a promising cost-effective health indicator in the general adult population. Further studies are warranted to explore the potential pathophysiological mechanisms underlying the association between serum chloride and mortality.
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Doenças Cardiovasculares , Neoplasias , Adulto , Humanos , Cloretos , Causas de Morte , Inquéritos Nutricionais , Estudos ProspectivosRESUMO
BACKGROUND: The arm circumference is a feasible and reliable indicator in evaluating the nutritional status of children. However, its application in general adults has yet to be thoroughly investigated. OBJECTIVE: This study aimed to evaluate the association between mid-upper arm circumferences (MUACs) and mortality in general adults. METHODS: The nationally representative cohort from the National Health and Nutrition Examination Survey (1999-2018) was analyzed with mortality information obtained through linkage to the National Death Index. The baseline MUACs were collected as exposure. Survey-weighted Cox proportional hazard regressions were performed to estimate the hazard ratios (HRs) and 95% confidential intervals (CIs) of mortality risk for individuals with different MUACs. Restricted cubic spline analyses were performed to examine the nonlinear association of MUAC with all-cause and cause-specific mortality. RESULTS: A total of 52,159 participants were included in this study. During a median follow-up time of 117 months, 7157 deaths were documented, with leading causes of cardiovascular disease (CVD), cancer, and respiratory disease. Individuals in the first quartile (Q1) of MUAC tended to have higher all-cause mortality risk than the rest after full adjustment. Similarly, CVD mortality risk in Q1 was higher than that in the second quartile (Q2) and the third quartile (Q3); respiratory mortality risk in Q1 was higher than in Q2. MUAC was non-linearly associated with all-cause mortality and CVD mortality. Individuals in Q1 MUAC (≤ 29.3) tended to have higher all-cause mortality risk, with HRs (95% CIs) estimated to be 0.76 (0.67-0.87) for Q2 (29.4, 32.5), 0.69 (0.59-0.81) for Q3 (32.6, 36.0), and 0.59 (0.46-0.75) for Q4 (≥ 36.1) after adjustment of demographic, lifestyle, and comorbidity covariates. Similarly, compared with Q1, HRs (95% CIs) for CVD mortality were estimated to be 0.73 (0.58-0.93) for Q2 and 0.57 (0.43-0.47) for Q3; HRs (95% CIs) for respiratory mortality was estimated to be 0.57 (95% CI, 0.37-0.87) for Q2 with other differences not significant. CONCLUSION: The MUAC was inversely associated with long-term mortality in general adults in the United States and may serve as a valuable measurement in adult health evaluations.
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Doenças Cardiovasculares , Doenças Respiratórias , Criança , Humanos , Adulto , Estados Unidos/epidemiologia , Braço , Estudos Prospectivos , Causas de Morte , Inquéritos NutricionaisRESUMO
Background: The optimal local treatment for HCC with tumor diameter ≥ 5 cm is not well established. This research evaluated the effectiveness of external beam radiation therapy (EBRT) versus transcatheter arterial chemoembolization (TACE) for HCC with tumor diameter ≥ 5 cm. Methods: A total of 1210 HCC patients were enrolled in this study, including 302 and 908 patients that received EBRT and TACE, respectively. Propensity score matching (PSM) was used to identify patient pairs with similar baseline characteristics. Overall survival (OS) was the primary study endpoint. Results: We identified 428 patients using 1:1 PSM for survival comparison. Compared with the TACE group, the EBRT group had a significantly longer median OS (mOS) before (14.9 vs. 12.3 months, p = 0.0085) and after (16.8 vs. 11.4 months, p = 0.0026) matching. In the subgroup analysis, compared with the TACE group, the EBRT group had a significantly longer mOS for HCC with tumor diameters of 5-7 cm (34.1 vs. 14.3 months, p = 0.04) and 7-10 cm (34.4 vs. 10 months, p = 0.00065), whereas for HCC with tumor diameters ≥ 10 cm, no significant difference in mOS was observed (11.2 vs. 11.2 months, p = 0.83). In addition, the multivariable Cox analysis showed that Child-A, alkaline phosphatase < 125 U/L, and EBRT were independent prognostic indicators for longer survival. Conclusion: EBRT is more effective than TACE as the primary local treatment for HCC with tumor diameter ≥ 5 cm, especially for HCC with tumor diameter of 5-10 cm.
Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Terapia Combinada , Estudos RetrospectivosRESUMO
BACKGROUND: The unmet needs in treating acute myeloid leukemia(AML) promote us to look for more effective and less toxic therapies. In this study, we discovered that Yinzhihuang injection(YZHI), a traditional Chinese patent medicine for hepatitis treatment, suppressed the growth of AML cells. METHOD: Anti-proliferative activities of YZHI were measured by CCK-8 assay. Cell cycle arrest was evaluated by PI staining, and apoptosis was evaluated by annexin V/PI staining. To explore the cell cycle arrest and cell death mechanism induced by YZHI, we assessed a series of assays, including measurements of the protein expression and cellular ATP. The anti-tumor activity was further demonstrated in nude mice. RESULTS: Flow cytometric and biochemical analysis revealed that YZHI caused cell cycle arrest and induced apoptosis in the AML HL-60 cells. Mechanistically, YZHI activated AMPK by promoting phosphorylation of the kinase. The active AMPK negatively regulated the downstream target mTORC1, leading to the inhibition of cell proliferation and induction of apoptosis. Pretreatment with the AMPK inhibitor compound C rescued YZHI induced apoptosis and partially restored cell proliferation of HL-60. Consistent with the data in vitro, YZHI obviously suppressed subcutaneous xenograft growth in nude mice. CONCLUSIONS: In a word, our data suggest that YZHI can be repurposed for the treatment of AML, which is worthy of further clinical evaluation.
Assuntos
Proteínas Quinases Ativadas por AMP , Leucemia Mieloide Aguda , Animais , Camundongos , Humanos , Camundongos Nus , Apoptose , Leucemia Mieloide Aguda/patologiaRESUMO
INTRODUCTION: The aim of this study was to investigate the role of thymidine kinase 1 (TK1) levels in hepatocellular carcinoma (HCC) prognosis and to develop a nomogram for predicting HCC prognosis. METHOD: In this study, 1066 HCC patients were enrolled between August 2018 and April 2022. TK1 levels were measured within one week before enrollment, and the relationship with HCC prognosis was evaluated. Next, all patients were randomly assigned to the training set (70%, n = 746) and the validation set (30%, n = 320). We used multivariate Cox analysis to find independent prognostic factors in the training set to construct a nomogram. The predictive power of the nomogram was assessed using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). The optimal critical value of TK1 was determined as 2.35 U/L using X-tile software. RESULT: Before and after propensity score matching (PSM), the median overall survival (mOS) of the low-TK1 group (< 2.35 U/L) remained significantly longer than that of the high-TK1 group (≥ 2.35 U/L) (48.1 vs 16.5 months, p < 0.001; 75.7 vs 19.8 months, p = 0.001). Moreover, multivariate Cox analysis showed that the low TK1 level was an independent positive prognostic indicator. Additionally, the area under the ROC curve for predicting the 1-year, 2-year, and 3-year survival rates was 0.770, 0.758, and 0.805, respectively. CONCLUSIONS: TK1 could serve as a prognostic marker for HCC. In addition, the nomogram showed good predictive capability for HCC prognosis.