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The probability of cardiovascular events has been reported lower in rheumatoid arthritis (RA) patients treated with leflunomide. However, the anti-atherosclerotic and cardiovascular protective effects and metabolism of leflunomide are not explored. In this study, we assessed the potential benefits of leflunomide on atherosclerosis and revealed the underlying mechanism. ApoE-/- mice were fed a western diet (WD) alone or supplemented with leflunomide (20 mg/kg, oral gavage, once per day) for 12 weeks. Samples of the aorta, heart, liver, serum, and macrophages were collected. We found that leflunomide significantly reduced lesion size in both en-face aortas and aortic root in WD-fed ApoE-/- mice. Leflunomide also obviously improved dyslipidemia, reduced hepatic lipid content, and improved disorders of glucose and lipid metabolism in vivo. RNA-Seq results showed that leflunomide effectively regulated the genes' expression involved in the lipid metabolism pathway. Importantly, leflunomide significantly increased the phosphorylation levels of AMPKα and acetyl-CoA carboxylase (ACC) in vivo. Furthermore, leflunomide and its active metabolite teriflunomide suppressed lipid accumulation in free fatty acid (FFA)-induced AML12 cells and improved endothelial dysfunction in palmitic acid (PA)-induced HUVECs through activating AMPK signaling and inhibiting dihydroorotate dehydrogenase (DHODH) signaling pathway. We present evidence that leflunomide and teriflunomide ameliorate atherosclerosis by regulating lipid metabolism and endothelial dysfunction. Our findings suggest a promising use of antirheumatic small-molecule drugs leflunomide and teriflunomide for the treatment of atherosclerosis and related cardiovascular diseases (CVDs).
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Antirreumáticos , Aterosclerosis , Dihidroorotato Deshidrogenasa , Leflunamida , Metabolismo de los Lípidos , Transducción de Señal , Animales , Leflunamida/uso terapéutico , Leflunamida/farmacología , Aterosclerosis/metabolismo , Aterosclerosis/tratamiento farmacológico , Ratones , Metabolismo de los Lípidos/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Dihidroorotato Deshidrogenasa/metabolismo , Antirreumáticos/farmacología , Antirreumáticos/uso terapéutico , Humanos , Proteínas Quinasas Activadas por AMP/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/metabolismo , Masculino , Ratones Endogámicos C57BL , Células Endoteliales de la Vena Umbilical Humana/metabolismoRESUMEN
The construction of coassembled peptide nanoprobes based on structural adaptation provides an effective template for stable monitoring of the molecular events in physiological and pathological processes. This also greatly expands their applications in biomedicine, such as multimodal combined diagnosis and treatment. However, the insufficient understanding of the physicochemical properties and structural features of different molecules still makes it difficult to construct the coassembled probes with mutually reinforcing functions, leading to unpredictable effects. Here, we showed how to utilize the π-π stacking network on ß-sheets formed by PD-L1-targeting peptides to capture small molecules with ferroptosis functions, thus, coassembling them into a visual probe with synergistic effects. Compared with individual components, the coassembled strategy could significantly improve the stability of the nanoprobe, inducing stronger ferroptosis effects and immune checkpoint blocking effects, and track and reflect the process. This study provides new insights into the design of multicomponent collaborative coassembly systems with biological effects.
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Ferroptosis , Péptidos , Ferroptosis/efectos de los fármacos , Humanos , Péptidos/química , Antígeno B7-H1/metabolismo , Antígeno B7-H1/química , Nanopartículas/química , Colorantes Fluorescentes/químicaRESUMEN
Peptide self-assemblies could leverage their specificity, stability, biocompatibility, and electrochemical activity to create functionalized interfaces for molecular sensing and detection. However, the dynamics within these interfaces are complex, with competing forces, including those maintaining peptide structures, recognizing analytes, and facilitating signal transmission. Such competition could lead to nonspecific interference, compromising the detection sensitivity and accuracy. In this study, a series of peptides with precise structures and controllable electron transfer capabilities were designed. Through examining their stacking patterns, the interplay between the peptides' hierarchical structures, their ability to recognize targets, and their conductivity were clarified. Among these, the EP5 peptide assembly was identified for its ability to form controllable electronic tunnels facilitated by π-stacking induced ß-sheets. EP5 could enhance the long-range conductivity, minimize nonspecific interference, and exhibit targeted recognition capabilities. Based on EP5, an electrochemical sensing interface toward the disease marker PD-L1 (programmed cell death ligand 1) was developed, suitable for both whole blood assay and in vivo companion diagnosis. It opens a new avenue for crafting electrochemical detection interfaces with specificity, sensitivity, and compatibility.
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Técnicas Electroquímicas , Técnicas Electroquímicas/métodos , Humanos , Conformación Proteica en Lámina beta , Péptidos/química , Antígeno B7-H1/análisis , Antígeno B7-H1/sangre , Electrones , AnimalesRESUMEN
BACKGROUND: Hepatic ischemia/reperfusion (I/R) injury is a major cause of complications in clinical liver surgery. AXL receptor tyrosine kinase (AXL) is a member of the TAM receptor tyrosine kinase family (TYRO3, AXL, and MERTK). Our previous study has shown that AXL expression was markedly upregulated in liver transplantation patients. However, the underlying mechanism of AXL in hepatic I/R injury remains unclear. METHODS: A mouse liver warm I/R model and a primary hepatocyte hypoxia/reoxygenation model were established to investigate the role of AXL activation and ferroptosis in hepatic I/R injury by pretreating with recombinant mouse growth arrest-specific protein 6 (AXL activator) or R428 (AXL inhibitor). Moreover, we used LY294002 (phosphatidylinositol 3-kinase [PI3K] inhibitor) to evaluate the relationship between the PI3K/AKT (the Ser and Thr kinase AKT) pathway and ferroptosis in hepatic I/R injury. RESULTS: Hepatic I/R injury decreased phosphorylation AXL expression and enhanced ferroptosis in liver transplantation patients and hepatic I/R-subjected mice. AXL activation attenuated lipid peroxidation and ferroptosis in hepatic I/R injury in vivo and in vitro. Inhibition of AXL activation exacerbated liver pathological damage and liver dysfunction, as well as iron accumulation and lipid peroxidation in hepatic I/R injury. Mechanistically, activated growth arrest-specific protein 6/AXL and its downstream PI3K/AKT signaling pathway inhibited ferroptosis during hepatic I/R injury. CONCLUSIONS: AXL activation protects against hepatic I/R injury by preventing ferroptosis through the PI3K/AKT pathway. This study is the first investigation on the AXL receptor and ferroptosis, and activating AXL to mitigate ferroptosis may be an innovative therapeutic strategy to combat hepatic I/R injury.
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Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the epidermal growth factor precursor homologous domain A (EGF-A) of low-density lipoprotein receptor (LDLR) in the liver and triggers the degradation of LDLR via the lysosomal pathway, consequently leading to an elevation in plasma LDL-C levels. Inhibiting PCSK9 prolongs the lifespan of LDLR and maintains cholesterol homeostasis in the body. Thus, PCSK9 is an innovative pharmacological target for treating hypercholesterolemia and atherosclerosis. In this study, we discovered that E28362 was a novel small-molecule PCSK9 inhibitor by conducting a virtual screening of a library containing 40,000 compounds. E28362 (5, 10, 20 µM) dose-dependently increased the protein levels of LDLR in both total protein and the membrane fraction in both HepG2 and AML12 cells, and enhanced the uptake of DiI-LDL in AML12 cells. MTT assay showed that E28362 up to 80 µM had no obvious toxicity in HepG2, AML12, and HEK293a cells. The effects of E28362 on hyperlipidemia and atherosclerosis were evaluated in three different animal models. In high-fat diet-fed golden hamsters, administration of E28362 (6.7, 20, 60 mg·kg-1·d-1, i.g.) for 4 weeks significantly reduced plasma total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C) and PCSK9 levels, and reduced liver TC and TG contents. In Western diet-fed ApoE-/- mice (20, 60 mg·kg-1·d-1, i.g.) and human PCSK9 D374Y overexpression mice (60 mg·kg-1·d-1, i.g.), administration of E28362 for 12 weeks significantly decreased plasma LDL-C levels and the area of atherosclerotic lesions in en face aortas and aortic roots. Moreover, E28362 significantly increased the protein expression level of LDLR in the liver. We revealed that E28362 selectively bound to PCSK9 in HepG2 and AML12 cells, blocked the interaction between LDLR and PCSK9, and induced the degradation of PCSK9 through the ubiquitin-proteasome pathway, which finally resulted in increased LDLR protein levels. In conclusion, E28362 can block the interaction between PCSK9 and LDLR, induce the degradation of PCSK9, increase LDLR protein levels, and alleviate hyperlipidemia and atherosclerosis in three distinct animal models, suggesting that E28362 is a promising lead compound for the treatment of hyperlipidemia and atherosclerosis.
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Osteoporosis is particularly prevalent among postmenopausal women and the elderly. In the present study, we investigated the effect of the novel small molecule E0924G (N-(4-methoxy-pyridine-2-yl)-5-methylfuran-2-formamide) on osteoporosis. E0924G significantly increased the protein expression levels of osteoprotegerin (OPG) and runt-related transcription factor 2 (RUNX2), and thus significantly promoted osteogenesis in MC3T3-E1 cells. E0924G also significantly decreased osteoclast differentiation and inhibited bone resorption and F-actin ring formation in receptor activator of NF-κB ligand (RANKL)-induced osteoclasts from RAW264.7 macrophages. Importantly, oral administration of E0924G in both ovariectomized (OVX) rats and SAMP6 senile mice significantly increased bone mineral density and decreased bone loss compared to OVX controls or SAMR1 mice. Further mechanistic studies showed that E0924G could bind to and then activate peroxisome proliferator-activated receptor delta (PPARδ), and the pro-osteoblast effect and the inhibition of osteoclast differentiation induced by E0924G were significantly abolished when PPARδ was knocked down or inhibited. In conclusion, these data strongly suggest that E0924G has the potential to prevent OVX-induced and age-related osteoporosis by dual regulation of bone formation and bone resorption through activation of the PPARδ signaling pathway.
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Resorción Ósea , Osteogénesis , Ovariectomía , PPAR delta , Transducción de Señal , Animales , Ratones , Resorción Ósea/tratamiento farmacológico , Resorción Ósea/prevención & control , Resorción Ósea/metabolismo , Ratas , PPAR delta/metabolismo , Femenino , Osteogénesis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Estructura Molecular , Células RAW 264.7 , Osteoporosis/tratamiento farmacológico , Osteoporosis/prevención & control , Osteoporosis/metabolismo , Relación Dosis-Respuesta a Droga , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/química , Ratas Sprague-Dawley , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Diferenciación Celular/efectos de los fármacosRESUMEN
During the construction of coalbed methane extraction wells, cementing cement sheath is crucial for the stability and sealing of surface wells. One effective method to enhance these properties is the addition of lignosulfonate. However, the mechanism of the effect of calcium lignosulfonate on the whole process of cement hydration is still unclear. In this paper, the water distribution and variation characteristics of calcium lignosulfonate modified cement paste were revealed by low-field nuclear magnetic resonance technology, and the hydration ion experiment of modified cement was carried out to obtain the variation characteristics of hydration ions of modified cementing cement. Finally, the formation mechanism of hydration products was clarified by analyzing the phase change of modified cement stone. The results indicate that the cement paste's hydration process can be divided into four stages: dissolution, crystallization, acceleration, and decline. During the dissolution stage, calcium lignosulfonate's air entraining effect maintains the cement paste in a stable suspension state. In the crystallization stage, calcium lignosulfonate's electro-repulsion delays the formation of hydration products and the hydration process. During the acceleration stage, the addition of calcium lignosulfonate reduces bound water formation in the cement slurry's flocculation structure, and the released filled water participates more in the hydration reaction, reducing the total relaxation signal's increasing trend. In the decline stage, the cement paste has solidified, and the system's water is primarily in the porous medium. The research results have practical guiding significance for the addition of calcium lignosulfonate in cementing operations.
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OBJECTIVE: Type 2 diabetes mellitus (T2DM) is a common chronic metabolic disease. Peroxisome proliferator-activated receptors (PPARs) play crucial roles in regulating glucolipid metabolism. Previous studies showed that E17241 could ameliorate atherosclerosis and lower fasting blood glucose levels in ApoE-/- mice. In this work, we investigated the role of E17241 in glycolipid metabolism in diabetic KKAy mice. APPROACH AND RESULTS: We confirmed that E17241 is a powerful pan-PPAR agonist with a potent agonistic activity on PPARγ, a high activity on PPARα, and a moderate activity on PPARδ. E17241 also significantly increased the protein expression of ATP-binding cassette transporter 1 (ABCA1), a crucial downstream target gene for PPARs. E17241 clearly lowered plasma glucose levels, improved OGTT and ITT, decreased islet cholesterol content, improved ß-cell function, and promoted insulin secretion in KKAy mice. Moreover, E17241 could significantly lower plasma total cholesterol and triglyceride levels, reduce liver lipid deposition, and improve the adipocyte hypertrophy and the inflammatory response in epididymal white adipose tissue. Further mechanistic studies indicated that E17241 boosts cholesterol efflux and insulin secretion in an ABCA1 dependent manner. RNA-seq and qRT-PCR analysis demonstrated that E17241 induced different expression of PPAR target genes in liver and adipose tissue differently from the PPARγ agonist rosiglitazone. In addition, E17241 treatment was also demonstrated to have an exhilarating cardiorenal benefits. CONCLUSIONS: Our results demonstrate that E17241 regulates glucolipid metabolism in KKAy diabetic mice while having cardiorenal benefits without inducing weight gain. It is a promising drug candidate for the treatment of T2DM.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Dislipidemias , Hiperglucemia , Ratones , Animales , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , PPAR gamma/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Dislipidemias/tratamiento farmacológico , Hígado/metabolismo , Hiperglucemia/tratamiento farmacológico , Colesterol/metabolismo , Tejido Adiposo Blanco/metabolismoRESUMEN
To meet the demand for precision medicine, researchers are committed to developing novel strategies to reduce systemic toxicity and side effects in cancer treatment. Targeting peptides are widely applied due to their affinity and specificity, and their ability to be high-throughput screened, chemically synthesized and modified. More importantly, peptides can form ordered self-assembled structures through non-covalent supramolecular interactions, which can form nanostructures with different morphologies and functions, playing crucial roles in targeted diagnosis and treatment. Among them, in targeted immunotherapy, utilizing targeting peptides to block the binding between immune checkpoints and ligands, thereby activating the immune system to eliminate cancer cells, is an advanced therapeutic strategy. In this mini-review, we summarize the screening, self-assembly, and biomedical applications of targeting peptide-based nanomaterials. Furthermore, this mini-review summarizes the potential and optimization strategies of targeting peptides.
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Nanoestructuras , Neoplasias , Péptidos/química , Nanoestructuras/química , Medicina de Precisión , Neoplasias/tratamiento farmacológico , Neoplasias/diagnósticoRESUMEN
Atherosclerosis (AS) is the root cause of cardiovascular diseases. Ferroptosis is characterized by highly iron-dependent lipid peroxidation and has been reported to play an important role in the pathogenesis of AS. Visualization of the ferroptosis process in atherosclerotic plaques is of great importance for diagnosing and treating AS. In this work, the rationally designed fluorescent probe FAS1 exhibited excellent advantages including large Stokes shift, sensitivity to environmental viscosity, good photostability, and improved water solubility. It also could co-locate with commercial lipid droplets (LDs) probes (BODIPY 493/503) well in RAW264.7 cells treated by the ferroptosis inducer. After self-assembly into nanoparticles and then encapsulation with macrophage membranes, the engineered FAS1@MM NPs could successfully target the atherosclerotic plaques in Western diet-induced apolipoprotein E knockout (ApoE-/-) mice and reveal the association of ferroptosis with AS through fluorescence imaging in vivo. This study may provide additional insights into the roles of ferroptosis in the diagnosis and treatment of AS.
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Aterosclerosis , Ferroptosis , Placa Aterosclerótica , Ratones , Animales , Placa Aterosclerótica/diagnóstico por imagen , Aterosclerosis/metabolismo , Macrófagos/metabolismo , Membrana Celular/metabolismoRESUMEN
BACKGROUND: Liver metastasis (LM) is one of the most common distant metastases of gastric cancer (GC). However, the mechanisms underlying the LM of GC (GC-LM) remain poorly understood. This study aimed to identify the tumour-secreted protein associated with GC-LM and to investigate the mechanisms by which this secreted protein remodels the liver microenvironment to promote GC-LM. METHODS: Data-independent acquisition mass spectrometry (DIA-MS), mRNA expression microarray, quantitative real-time PCR, enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) were performed to identify and validate the GC-secreted proteins associated with GC-LM. A modified intrasplenic injection mouse model of LM was used to evaluate the progression and tumour burden of LM in vivo. Flow cytometry, immunofluorescence (IF), western blots (WB) and IHC were performed to validate the pre-metastatic niche (PMN) formation in the pre-modelling mouse models. mRNA sequencing of PMA-treated THP-1 cells with or without lipopolysaccharide binding protein (LBP) treatment was used to identify the functional target genes of LBP in macrophages. Co-immunoprecipitation (Co-IP), WB, ELISA, IF and Transwell assays were performed to explore the underlying mechanism of LBP in inducing intrahepatic PMN formation. RESULTS: LBP was identified as a critical secreted protein associated with GC-LM and correlated with a worse prognosis in patients with GC. LBP activated the TLR4/NF-κB pathway to promote TGF-ß1 secretion in intrahepatic macrophages, which, in turn, activated hepatic satellite cells (HSCs) to direct intrahepatic fibrotic PMN formation. Additionally, TGF-ß1 enhanced the migration and invasion of incoming metastatic GC cells in the liver. Consequently, selective targeting of the TGF-ß/Smad signaling pathway with galunisertib demonstrated its efficacy in effectively preventing GC-LM in vivo. CONCLUSIONS: The results of this study provide compelling evidence that serological LBP can serve as a valuable diagnostic biomarker for the early detection of GC-LM. Mechanistically, GC-derived LBP mediates the crosstalk between primary GC cells and the intrahepatic microenvironment by promoting TGF-ß1 secretion in intrahepatic macrophages, which induces intrahepatic fibrotic PMN formation to promote GC-LM. Importantly, selectively targeting the TGF-ß/Smad signaling pathway with galunisertib represents a promising preventive and therapeutic strategy for GC-LM.
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Neoplasias Hepáticas , Neoplasias Gástricas , Animales , Humanos , Ratones , Neoplasias Hepáticas/genética , ARN Mensajero , Transducción de Señal , Neoplasias Gástricas/patología , Factor de Crecimiento Transformador beta1/metabolismo , Microambiente TumoralRESUMEN
BACKGROUND: The prognostic significance of neural invasion (NI) in gastric cancer (GC) has not been established. This study is to investigate the characteristic and prognostic value of NI in GC. METHODS: 592 patients who had undergone gastrectomy for GC were retrospectively analyzed. NI was defined when cancer cells infiltrated into the perineurium or neural fascicles by hematoxylin and eosin staining of surgical specimens. NI and the other clinical factors were analyzed. RESULTS: NI was detected in 270 of the 592 patients. NI was associated with tumor size, site, depth of invasion, lymph node metastasis, TNM stage, D dissection, tumor differentiation, Lauren classification, and blood vessel invasion. NI was associated with the overall survival. Multivariate analysis indicated that NI was not an independent prognostic factor for total patients, while NI independently predicted prognosis for age < 60 and lymph node metastasis negative patients by subgroup analysis. Concomitant existence of NI with tumor size ≥3cm, TNM stage III, or diffused Lauren classification independently predicted prognosis. CONCLUSIONS: The frequency of NI is high in GC patients and increases with disease progression. NI is related to poor survival in GC patients who underwent curative gastrectomy and provides independent prognostic value for young and lymph node metastasis negative patients.
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Neoplasias Gástricas , Humanos , Neoplasias Gástricas/cirugía , Metástasis Linfática , Pronóstico , Estudios Retrospectivos , Gastrectomía , Ganglios LinfáticosRESUMEN
Drug resistance is a considerable obstacle to gastric cancer (GC) treatment. The current work aimed to elucidate the functional mechanism of CD109 in 5-fluorouracil (5-FU) resistance in GC. In this study, we demonstrated that CD109 was extremely heightened in 5-FU-resistant GC cells. CD109 deficiency lessened the IC50 value, impaired cell viability and metastatic capability, and induced cell apoptosis after 5-FU treatment in cells. In addition, we found that PAX5 bound p300 increased the enrichment of H3K27ac at the promoter region of the CD109 gene, which resulted in the upregulation of CD109 in GC. Moreover, we also revealed that CD109 triggered 5-FU resistance via activating the JNK/MAPK signaling. Blockage of JNK/MAPK signaling using JNK inhibitor, SP600125, abolished CD109 upregulation-induced changes of IC50 values, cell viability, metastasis and apoptosis in NCI-N87/5-FU and SNU-1/5-FU cells. Importantly, CD109 silencing enhanced the therapeutic efficacy of 5-FU, leading to reduced tumor growth in vivo. In conclusion, our results unveiled that H3K27 acetylation activated-CD109 enhanced 5-FU resistance of GC cells via modulating the JNK/MAPK signaling pathway, which might provide an attractive therapeutic target for GC.
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Fluorouracilo , Neoplasias Gástricas , Humanos , Fluorouracilo/farmacología , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Acetilación , Línea Celular Tumoral , Apoptosis , Sistema de Señalización de MAP Quinasas , Resistencia a Antineoplásicos , Proliferación Celular , Proteínas de Neoplasias , Antígenos CD/genética , Antígenos CD/metabolismo , Proteínas Ligadas a GPI/metabolismoRESUMEN
Abnormal 5-methylcytosine (m5C) methylation has been proved to be closely related to gastric carcinogenesis, progression, and prognosis. Dysregulated long noncoding RNAs (lncRNAs) participate in a variety of biological processes in cancer. However, to date, m5C-methylated lncRNAs are rarely researched in gastric cancer (GC). Here, we found that RNA cytosine-C(5)-methyltransferase (NSUN2) was upregulated in GC and high NSUN2 expression was associated with poor prognosis. NR_033928 was identified as an NSUN2-methylated and upregulated lncRNA in GC. Functionally, NR_033928 upregulated the expression of glutaminase (GLS) by interacting with IGF2BP3/HUR complex to promote GLS mRNA stability. Increased glutamine metabolite, α-KG, upregulated NR_033928 expression by enhancing its promoter 5-hydroxymethylcytosine (hm5C) demethylation. In conclusion, our results revealed that NSUN2-methylated NR_033928 promoted GC progression and might be a potential prognostic and therapeutic target for GC.
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ARN Largo no Codificante , Neoplasias Gástricas , Humanos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Glutamina , Glutaminasa/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proliferación Celular/genéticaRESUMEN
Background: Recently, the use of immunochemotherapy in the treatment of advanced gastric cancer (GC) has been increasing and programmed cell death protein 1 (PD-1) inhibitors combined with chemotherapy has become the first-line treatment for advanced GC. However, few studies with small sample sizes have examined this treatment regimen to assess its effectiveness and safety in the neoadjuvant treatment phase of resectable local advanced GC. Materials and methods: Herein, we systematically searched PubMed, Cochrane CENTRAL, and Web of Science for clinical trials on neoadjuvant immunochemotherapy (nICT) in advanced GC. The primary outcomes were effectiveness [evaluated by major pathological response (MPR) and pathological complete response (pCR)] and safety [assessed by grade 3-4 treatment-related adverse events (TRAEs) and postoperative complications]. A meta-analysis of non-comparative binary results was performed to aggregate the primary outcomes. Direct comparative analysis was used to compare pooled results of neoadjuvant chemotherapy (nCT) with nICT. The outcomes emerged as risk ratios (RR). Results: Five articles with 206 patients were included, and all of them were from the Chinese population. The pooled pCR and MPR rates were 26.5% (95% CI: 21.3%-33.3%) and 49.0% (95% CI: 42.3%-55.9%), while grade 3-4 TRAEs and post-operative complication rates were 20.0% (95% CI: 9.1%-39.8%) and 30.1% (95% CI: 23.1%-37.9%), respectively. Direct comparison showed that with the exception of grade 3-4 TRAEs and postoperative complications, all outcomes including pCR, MPR, and R0 resection rate favoured nICT to nCT. Conclusion: nICT is a promising strategy for use as an advisable neoadjuvant treatment for patients with advanced GC in Chinese population. However, more phase III randomized controlled trials (RCTs) will be required to further consolidate the efficacy and safety of this regimen.
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Inmunoterapia , Terapia Neoadyuvante , Neoplasias Gástricas , Humanos , Pueblos del Este de Asia , Proyectos Piloto , Complicaciones Posoperatorias , Neoplasias Gástricas/terapiaRESUMEN
BACKGROUND: The aim of this retrospective matched-paired cohort study was to clarify the effectiveness of preserving the vagus nerve in totally laparoscopic radical distal gastrectomy (TLDG). METHODS: One hundred eighty-three patients with gastric cancer who underwent TLDG between February 2020 and March 2022 were included and followed up. Sixty-one patients with preservation of the vagal nerve (VPG) in the same period were matched (1:2) to conventional sacrificed (CG) cases for demographics, tumor characteristics, and tumor node metastasis stage. The evaluated variables included intraoperative and postoperative indices, symptoms, nutritional status, and gallstone formation at 1 year after gastrectomy between the two groups. RESULTS: Although the operation time was significantly increased in the VPG compared with the CG (198.0 ± 35.2 vs. 176.2 ± 35.2 min, P < 0.001), the mean time of gas passage in the VPG was significantly lower than that in the CG (68.1 ± 21.7 h vs. 75.4 ± 22.6 h, P = 0.038). The overall postoperative complication rate was similar between the two groups (P = 0.794). There was no statistically significant difference between the two groups hospital stay, total number of harvested lymph nodes, and mean number of examined lymph nodes at each station. During follow-up, the morbidity of gallstones or cholecystitis (8.2% vs. 20.5%, P = 0.036), chronic diarrhea (3.3% vs. 14.8%, P = 0.022), and constipation (4.9% vs. 16.4%, P = 0.032) were significantly lower in the VPG than in the CG in this study. Moreover, injury to the vagus nerve was found to be an independent risk factor for gallstone formation or cholecystitis and chronic diarrhea in univariate analysis and multivariate analysis. CONCLUSION: The vagus nerve plays an imperative role in gastrointestinal motility, and hepatic and celiac branch preservation mainly exerts efficacy and safety in patients who undergo TLDG.
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Colecistitis , Cálculos Biliares , Laparoscopía , Neoplasias Gástricas , Humanos , Estudios Retrospectivos , Estudios de Cohortes , Cálculos Biliares/cirugía , Gastrectomía/efectos adversos , Neoplasias Gástricas/cirugía , Neoplasias Gástricas/patología , Laparoscopía/efectos adversos , Nervio Vago/patología , Colecistitis/cirugía , Diarrea/cirugía , Resultado del TratamientoRESUMEN
Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases. Silencing information regulator 1 (SIRT1) was demonstrated to modulate cholesterol and lipid metabolism in NAFLD. Here, a novel SIRT1 activator, E1231, was studied for its potential improvement effects on NAFLD. C57BL/6J mice were fed a high-fat and high-cholesterol diet (HFHC) for 40 weeks to create a NAFLD mouse model, and E1231 was administered by oral gavage (50 mg/kg body weight, once/day) for 4 weeks. Liver-related plasma biochemistry parameter tests, Oil Red O staining, and hematoxylin-eosin staining results showed that E1231 treatment ameliorated plasma dyslipidemia, plasma marker levels of liver damage (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), liver total cholesterol (TC) and triglycerides (TG) contents, and obviously decreased hepatic steatosis score and NAFLD Activity Score (NAS) in the NAFLD mouse model. Western blot results showed that E1231 treatment significantly regulated lipid-metabolism-related protein expression. In particular, E1231 treatment increased SIRT1, PGC-1α, and p-AMPKα protein expression but decreased ACC and SCD-1 protein expression. Additionally, in vitro studies demonstrated that E1231 inhibited lipid accumulation and improved mitochondrial function in free-fatty-acid-challenged hepatocytes, and required SIRT1 activation. In conclusion, this study illustrated that the SIRT1 activator E1231 alleviated HFHC-induced NAFLD development and improved liver injury by regulating the SIRT1-AMPKα pathway, and might be a promising candidate compound for NAFLD treatment.
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Glioma is a highly challenging human malignancy and conventional drugs typically exhibit low blood-brain barrier (BBB) permeability as well as poor tumor targeting. To complicate matters further, recent advances in research on oncology have highlighted the dynamic and complex cellular networks within the immunosuppressive tumor microenvironment (TME) that complicate glioma treatment. Therefore, precise and efficient targeting of tumor tissue, whilst reversing immunosuppression, may provide an ideal strategy for the treatment of gliomas. Here, by using the "one-bead-one-component" combinatorial chemistry approach, we designed and screened a peptide that can specifically target brain glioma stem cells (GSCs), which was further engineered into glycopeptide-functionalized multifunctional micelles. We demonstrated that the micelles can carry DOX and effectively penetrate the BBB to achieve targeted killing of glioma cells. Meanwhile, mannose confers a unique tumor immune microenvironment modulating function to the micelles, which can activate the anti-tumor immune response function of tumor-associated macrophages and is expected to be further applied in vivo. This study highlights that glycosylation modification of targeted peptides specific to cancer stem cells (CSCs) may serve as an effective tool to improve the therapeutic outcome of brain tumor patients.
Asunto(s)
Neoplasias Encefálicas , Glioma , Humanos , Glicopéptidos , Micelas , Línea Celular Tumoral , Glioma/tratamiento farmacológico , Neoplasias Encefálicas/tratamiento farmacológico , Péptidos/uso terapéutico , Microambiente TumoralRESUMEN
BACKGROUND: N6-methyladenosine (m6 A) modification is the most common modification that occurs in eukaryotes. Although substantial effort has been made in the prevention and treatment of gastric cancer (GC) in recent years, the prognosis of GC patients remains unsatisfactory. The regulatory mechanism between m6 A modification and GC development needs to be elucidated. In this study, we examined m6 A modification and the downstream mechanism in GC. METHODS: Dot blotting assays, The Cancer Genome Atlas analysis, and quantitative real-time PCR (qRT-PCR) were used to measure the m6 A levels in GC tissues. Methylated RNA-immunoprecipitation sequencing and RNA sequencing were performed to identify the targets of m6 A modification. Western blotting, Transwell, wound healing, and angiogenesis assays were conducted to examine the role of centromere protein F (CENPF) in GC in vitro. Xenograft, immunohistochemistry, and in vivo metastasis experiments were conducted to examine the role of CENPF in GC in vivo. Methylated RNA-immunoprecipitation-qPCR, RNA immunoprecipitation-qPCR and RNA pulldown assays were used to verify the m6 A modification sites of CENPF. Gain/loss-of-function and rescue experiments were conducted to determine the relationship between CENPF and the mitogen-activated protein kinase (MAPK) signaling pathway in GC cells. Coimmunoprecipitation, mass spectrometry, qRT-PCR, and immunofluorescence assays were performed to explore the proteins that interact with CENPF and elucidate the regulatory mechanisms between them. RESULTS: CENPF was upregulated in GC and facilitated the metastasis of GC both in vitro and in vivo. Mechanistically, increased m6 A modification of CENPF was mediated by methyltransferase 3, and this modified molecule could be recognized by heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1), thereby promoting its mRNA stability. In addition, the metastatic phenotype of CENPF was dependent on the MAPK signaling pathway. Furthermore, CENPF could bind to FAK and promote its localization in the cytoplasm. Moreover, we discovered that high expression of CENPF was related to lymphatic invasion and overall survival in GC patients. CONCLUSIONS: Our findings revealed that increased m6 A modification of CENPF facilitates the metastasis and angiogenesis of GC through the CENPF/FAK/MAPK and epithelial-mesenchymal transition axis. CENPF expression was correlated with the clinical features of GC patients; therefore, CENPF may serve as a prognostic marker of GC.