RESUMO

PURPOSE: Epithelial-mesenchymal transition (EMT) is a crucial pathological process that contributes to proliferative vitreoretinopathy (PVR), and research indicates that factors present in the vitreous that target cells play pivotal roles in regulating EMT. Experimental studies have confirmed that rabbit vitreous (RV) promotes EMT in human retinal pigment epithelial (RPE) cells. The long noncoding RNA (lncRNA) MALAT1 has been implicated in EMT in various diseases. Thus, this study aimed to investigate the involvement of lncRNA MALAT1 in vitreous-induced EMT in RPE cells. METHODS: MALAT1 was knocked down in ARPE-19 cells by short hairpin RNA (shRNA) transfection. Reverse transcription PCR (RT‒PCR) was used to evaluate MALAT1 expression, and Western blotting analysis was used to measure the expression of EMT-related proteins. Wound-healing, Transwell, and cell contraction assays were conducted to assess cell migration, invasion, and contraction, respectively. Additionally, cell proliferation was assessed using the CCK-8 assay, and cytoskeletal changes were examined by immunofluorescence. RESULTS: MALAT1 expression was significantly increased in ARPE-19 cells cultured with RV. Silencing MALAT1 effectively suppressed EMT and downregulated the associated factors snail1 and E-cadherin. Furthermore, silencing MALAT1 inhibited the RV-induced migration, invasion, proliferation, and contraction of ARPE-19 cells. Silencing MALAT1 also decreased RV-induced AKT and P53 phosphorylation. CONCLUSIONS: In conclusion, lncRNA MALAT1 participates in regulating vitreous-induced EMT in human RPE cells; these results provide new insight into the pathogenesis of PVR and offer a potential direction for the development of antiproliferative drugs.

Assuntos

Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Proteínas Proto-Oncogênicas c-akt , RNA Longo não Codificante , Epitélio Pigmentado da Retina , RNA Longo não Codificante/genética , Transição Epitelial-Mesenquimal/genética , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Corpo Vítreo/metabolismo , Corpo Vítreo/patologia , Coelhos , Animais , Células Cultivadas , Vitreorretinopatia Proliferativa/genética , Vitreorretinopatia Proliferativa/metabolismo , Vitreorretinopatia Proliferativa/patologia , Transdução de Sinais , Regulação da Expressão Gênica , Western Blotting

RESUMO

Porcine rotavirus (PoRV) is a significant enteric pathogen causing gastroenteritis in piglets, which causes huge economic loss to the Chinese pig industry. In this study, six porcine rotavirus A strains were isolated from three adjacent sow farms belonging to the same company within one year, which suffered severe diarrhea outbreaks. AHBZ2303 (G11P[7]) and AHBZ2305 (G9P[23]), AHBZ2304 (G9P[23]) and AHBZ2312 (G4P[6]), AHBZ2310 (G9P[23]) and AHBZ2402 (G5P[23]) were isolated from Farm A, B and C, respectively. All six isolates were related to human rotavirus through complete genome analysis, suggesting the potential cross-species infection between humans and pigs. Evolutionary analysis revealed that AHBZ2303 and AHBZ2304 likely emerged simultaneously in Farm A and B, and then AHBZ2304 was introduced to Farm A and C, leading to the emergence of AHBZ2305 and AHBZ2310. Recombination and large variation were identified for AHBZ2312 and AHBZ2402. These findings provided insights into the transmission and evolution of PoRV among farms and underscored the need for enhanced monitoring to mitigate the risk of outbreaks from novel variants.

RESUMO

Introduction: Intra-aortic balloon pump (IABP) is sometimes coupled with Venoarterial extracorporeal membrane oxygenation (VA-ECMO) to treat patients with cardiogenic shock. In this study, we attempted to evaluate the association of the IABP approach on survival and vascular complication rates in adults with cardiogenic shock undergoing VA-ECMO. Methods: We performed a systematic search of original studies on VA-ECMO with and without IABP in PubMed, EMBASE, and the Cochrane Library. Results: A total of 42 studies with 8,759 patients were included. The pooled in-hospital deaths of patients on VA-ECMO with and without IABP were 2,962/4,807 (61.61%) versus 2,666/3,952 (67.45%). VA-ECMO with IABP presents lower in-hospital mortality (risk ratio, 0.88; 95% CI, 0.86-0.91; P < 0.00001). In addition, IABP was associated with lower in-hospital mortality of patients with postcardiotomy cardiogenic shock and ischaemic heart disease. (risk ratio, 0.93; 95% CI, 0.87-0.98; P = 0.01; risk ratio, 0.85; 95% CI, 0.82-0.89; P < 0.00001). There was no significant difference in in-hospital morbidity in neurological, gastrointestinal, limb-related, bleeding, and infection complications between patients on VA-ECMO with and without IABP. Discussion: In these observational studies, concomitant use of IABP and VA-ECMO in adult patients with cardiogenic shock was associated with reduced in-hospital mortality. Systematic Review Registration: PROSPERO [CRD42017069259].

RESUMO

Phenformin, a biguanide compound, has attracted increased attention due to its prominent antitumor activity. As a multi­target agent, the antitumor effects of phenformin involve a wide range of factors, including inhibition of mitochondrial complex I, activation of AMP­activated protein kinase, impact on the tumor microenvironment, suppression of cancer stem cells and others. In addition, phenformin has been shown to markedly augment the effectiveness of various clinical treatment methods, including radiotherapy, chemotherapy, targeted therapy and immunotherapy. It is noteworthy that breakthrough progress has been made in the treatment of cancer with phenformin with application in clinical trials for the treatment of melanoma. Phenformin not only reduces the lesion area of patients, but also enhances the efficacy of dalafinib/trimetinib. In the present review, the novel breakthroughs in the antitumor effects and mechanisms of phenformin were discussed. In addition, the current review focuses on the clinical development value of phenformin, striving to provide new insights into the future research direction of phenformin in the field of tumor treatment.

Assuntos

Neoplasias , Fenformin , Microambiente Tumoral , Humanos , Fenformin/farmacologia , Fenformin/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Animais , Melanoma/tratamento farmacológico

RESUMO

Lard is highly appreciated for its flavor. However, it has not been elucidated how to consume lard while at the same time eliminating its adverse effects on postpartum cognitive function. Female mice were divided into three groups (n = 10): soybean oil (SO), lard oil (LO), and a mixture of soybean oil and lard at a ratio of 1:1 (LS). No significant difference was observed between the SO and LS groups in behavioral testing of the maternal mice, but the LO group was significantly worse compared with these two groups. Moreover, the SO and LS supplementation increased docosahexaenoic acid (DHA) and total n-3 polyunsaturated fatty acid (PUFA) levels in the brain and short-chain fatty acid (SCFA)-producing bacteria in feces, thereby mitigating neuroinflammation and lowering the p-ERK(1/2)/ERK(1/2), p-CREB/CREB, and BDNF levels in the brain compared to the LO group. Collectively, the LS group inhibited postpartum cognitive impairment by regulating the brain fatty acid composition, neuroinflammation, gut microbiota, and the SCFA/ERK(1/2)/CREB/BDNF signaling pathway compared to lard.

Assuntos

Fator Neurotrófico Derivado do Encéfalo , Encéfalo , Disfunção Cognitiva , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Ácidos Graxos Voláteis , Período Pós-Parto , Óleo de Soja , Animais , Feminino , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Camundongos , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Ácidos Graxos Voláteis/metabolismo , Óleo de Soja/farmacologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Ácidos Graxos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos

RESUMO

Porcine epidemic diarrhea virus (PEDV) is a major causative pathogen of a highly contagious, acute enteric viral disease. This study evaluated the emergence of nine variants in Jiangsu and Anhui provinces of China from 2020 to 2023. S gene-based phylogenetic analysis indicated that three variants belong to the G1c subgroup, while the other six strains are clustered within the G2c subgroup. Recombination analyses supported that three variants of the G1c subgroup were likely derived from recombination of parental variants FR0012014 and a donor variant AJ1102. In addition, there are novel mutations on amino acid 141-148 and these likely resulted in changes in antigenicity in the three variants. These results illustrated that the study provides novel insights into the epidemiology, evolution, and transmission of PEDV in China.

RESUMO

Purpose: This study aims to explore the metabolic signature of aging retina and identify the potential metabolic biomarkers for the diagnosis of retinal aging. Methods: Retinal samples were collected from both young (two months) and aging (14 months) mice to conduct an unbiased metabolic profiling. Liquid chromatography-tandem mass spectrometry analysis was conducted to screen for the metabolic biomarkers and altered signaling pathways associated with retinal aging. Results: We identified 166 metabolites differentially expressed between young and aged retinas using a threshold of orthogonal projection to latent structures discriminant analysis variable importance in projection >1 and P < 0.05. These metabolites were significantly enriched in several metabolic pathways, including purine metabolism, citrate cycle, phenylalanine, tyrosine and tryptophan biosynthesis, glycerophospholipid metabolism, and alanine, aspartate and glutamate metabolism. Among these significantly enriched pathways, glycerophospholipid metabolites emerged as promising candidates for retinal aging biomarkers. We assessed the potential of these metabolites as biomarkers through an analysis of their sensitivity and specificity, determined by the area under the receiver-operating characteristic (ROC) curves. Notably, the metabolites like PC (15:0/22:6), PC (17:0/14:1), LPC (P-16:0), PE (16:0/20:4), and PS (17:0/16:1) demonstrated superior performance in sensitivity, specificity, and accuracy in predicting retinal aging. Conclusions: This study sheds light on the molecular mechanisms underlying retinal aging by identifying distinct metabolic profiles and pathways. These findings provide a valuable foundation for developing future clinical applications in diagnosing, identifying, and treating age-related retinal degeneration. Translational Relevance: This study sheds light on novel metabolic profiles and biomarkers in aging retinas, potentially paving the way for targeted interventions in preventing, diagnosing, and treating age-related retinal degeneration and other retinal diseases.

Assuntos

Envelhecimento , Biomarcadores , Camundongos Endogâmicos C57BL , Retina , Espectrometria de Massas em Tandem , Animais , Envelhecimento/metabolismo , Retina/metabolismo , Camundongos , Biomarcadores/metabolismo , Cromatografia Líquida , Curva ROC , Redes e Vias Metabólicas , Metaboloma , Metabolômica/métodos

RESUMO

Genomic instability stands out as a pivotal hallmark of cancer, and PARP inhibitors (PARPi) emerging as a groundbreaking class of targeted therapy drugs meticulously crafted to inhibit the repair of DNA single-strand breaks(SSB) in tumor cells. Currently, PARPi have been approved for the treatment of ovarian cancer, pancreatic cancer, breast cancer, and prostate cancer characterized by homologous recombination(HR) repair deficiencies due to mutations in BRCA1/2 or other DNA repair associated genes and acquiring the designation of breakthrough therapy. Nonetheless, PARPi exhibit limited efficacy in the majority of HR-proficient BRCA1/2 wild-type cancers. At present, the synergistic approach of combining PARPi with agents that induce HR defects, or with chemotherapy and radiotherapy to induce substantial DNA damage, significantly enhances the efficacy of PARPi in BRCA wild-type or HR-proficient patients, supporting extension the use of PARPi in HR proficient patients. Therefore, we have summarized the effects and mechanisms of the combined use of drugs with PARPi, including the combination of PARPi with HR defect-inducing drugs such as ATRi, CHKi, HR indirectly inducing drugs like VEGFRi, CDKi, immune checkpoint inhibitors and drugs instigating DNA damage such as chemotherapy or radiotherapy. In addition, this review discusses several ongoing clinical trials aimed at analyzing the clinical application potential of these combined treatment strategies.

RESUMO

BACKGROUND AND OBJECTIVES: Prosociality refers to voluntary behaviors that intend to benefit others. Most of the existing literature suggests that older adults tend to act more prosocially compared to younger adults, whereas some studies show that older adults might not be that prosocial under certain conditions. The current study aimed to summarize the mixed findings and quantify the age difference in prosociality by conducting a qualitative systematic review and a quantitative meta-analysis. RESEARCH DESIGN AND METHODS: Literature search was conducted based on 5 databases. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed and this review was registered at PROSPERO (CRD42022333373). RESULTS: Based on the qualitative synthesis of 51 studies, older adults (n = 109,911) were more prosocial than younger adults (n = 68,501). The meta-analysis of 46 studies further supported this age effect (Hedges' g = 0.31, 95% confidence interval [0.24, 0.37]), and this age effect might be moderated by the types of prosociality. We discovered a moderate age effect in sharing (Hedges' g = 0.53), but a nonsignificant age effect in helping (Hedges' g = 0.11), comforting (Hedges' g = -0.20), or mixed prosociality (Hedges' g = 0.15). Additionally, the age effect was only significant when older adults had higher socioeconomic status than younger adults. DISCUSSION AND IMPLICATIONS: Future research should develop more comprehensive measures of prosociality, examine more variables that influence aging and prosociality, and investigate the neural mechanism(s) of prosociality to achieve a thorough understanding of the age difference in prosociality.

Assuntos

Comportamento Social , Humanos , Idoso , Fatores Etários , Adulto , Adulto Jovem , Envelhecimento/psicologia , Altruísmo , Masculino , Feminino

RESUMO

The electrospun nanofiber system is correlated with high efficacy of drug delivery. This study aims to investigate the effect of nanofiber-based delivery of evodiamine, an indole alkaloid derived from Rutaceae plants Evodia rutaecarpa (Juss.) Benth, on intrahepatic cholangiocarcinoma (ICC), as well as to explore the molecular mechanisms. An electrospun nanofiber system carrying evodiamine was generated. Compared to evodiamine treatment alone, the nano-evodiamine exhibited more pronounced effects on suppressing proliferation, colony formation, invasiveness, migration, apoptosis resistance, cell cycle progression, and in vivo tumorigenesis of two ICC cell lines (HUCC-T1 and RBE). ICC cells exhibited increased expression of histone deacetylase 4 (HDAC4) while decreased tropomyosin 1 (TPM1). HDAC4 suppressed TPM1 expression by removing H3K9ac modifications from its promoter. Nano-evodiamine reduced HDAC4 protein levels in ICC cells, thus promoting transcription and expression of TPM1. Either overexpression of HDAC4 or downregulation of TPM1 negated the tumor-suppressive effects of nano-evodiamine. Collectively, this study demonstrates that the electrospun nanofiber system enhances the efficiency of evodiamine. Additionally, evodiamine suppresses the malignant properties of ICC cells. The findings may provide fresh insights into the application of electrospun nanofiber system for drug delivery and the effects of evodiamine on tumor suppression.

Assuntos

Colangiocarcinoma , Sistemas de Liberação de Medicamentos , Histona Desacetilases , Nanofibras , Tropomiosina , Tropomiosina/genética , Tropomiosina/metabolismo , Humanos , Colangiocarcinoma/patologia , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/genética , Histona Desacetilases/metabolismo , Histona Desacetilases/genética , Linhagem Celular Tumoral , Quinazolinas/farmacologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/genética , Transcrição Gênica/efeitos dos fármacos , Transcrição Gênica/genética , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Terapia de Alvo Molecular , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteínas Repressoras

RESUMO

Rationale: Current treatments for ocular angiogenesis primarily focus on blocking the activity of vascular endothelial growth factor (VEGF), but unfavorable side effects and unsatisfactory efficacy remain issues. The identification of novel targets for anti-angiogenic treatment is still needed. Methods: We investigated the role of tsRNA-1599 in ocular angiogenesis using endothelial cells, a streptozotocin (STZ)-induced diabetic model, a laser-induced choroidal neovascularization model, and an oxygen-induced retinopathy model. CCK-8 assays, EdU assays, transwell assays, and matrigel assays were performed to assess the role of tsRNA-1599 in endothelial cells. Retinal digestion assays, Isolectin B4 (IB4) staining, and choroidal sprouting assays were conducted to evaluate the role of tsRNA-1599 in ocular angiogenesis. Transcriptomic analysis, metabolic analysis, RNA pull-down assays, and mass spectrometry were utilized to elucidate the mechanism underlying angiogenic effects mediated by tsRNA-1599. Results: tsRNA-1599 expression was up-regulated in experimental ocular angiogenesis models and endothelial cells in response to angiogenic stress. Silencing of tsRNA-1599 suppressed angiogenic effects in endothelial cells in vitro and inhibited pathological ocular angiogenesis in vivo. Mechanistically, tsRNA-1599 exhibited little effect on VEGF signaling but could cause reduced glycolysis and NAD+/NADH production in endothelial cells by regulating the expression of HK2 gene through interacting with YBX1, thus affecting endothelial effects. Conclusions: Targeting glycolytic reprogramming of endothelial cells by a tRNA-derived small RNA represents an exploitable therapeutic approach for ocular neovascular diseases.

Assuntos

Neovascularização de Coroide , Células Endoteliais , Glicólise , Animais , Glicólise/efeitos dos fármacos , Camundongos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Neovascularização de Coroide/tratamento farmacológico , Neovascularização de Coroide/metabolismo , Humanos , Proteína 1 de Ligação a Y-Box/metabolismo , Proteína 1 de Ligação a Y-Box/genética , Inibidores da Angiogênese/farmacologia , Hexoquinase/metabolismo , Hexoquinase/genética , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Camundongos Endogâmicos C57BL , Masculino , Modelos Animais de Doenças , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/metabolismo , Retinopatia Diabética/genética , Células Endoteliais da Veia Umbilical Humana , Pequeno RNA não Traduzido/genética , Pequeno RNA não Traduzido/metabolismo

RESUMO

Under a full straw returning system, the relationship between soil bacterial community diversity and straw decomposition, yield, and the combined application of slow-release nitrogen and urea remains unclear. To evaluate these effects and provide an effective strategy for sustainable agricultural production, a 2-year field positioning trial was conducted using maize as the research object. Six experimental treatments were set up: straw returning + no nitrogen fertilizer (S1N0), straw returning + slow-release nitrogen fertilizer:urea = 0:100% (S1N1), straw returning + slow-release nitrogen fertilizer:urea = 30%:70% (S1N2), straw returning + slow-release nitrogen fertilizer:urea = 60%:40% (S1N3), straw returning + slow-release nitrogen fertilizer:urea = 90%:10% (S1N4), and straw removal + slow-release nitrogen fertilizer:urea = 30%:70% (S0N2). Significant differences (p < 0.05) were observed between treatments for Proteobacteria, Acidobacteriota, Myxococcota, and Actinobacteriota at the jointing stage; Proteobacteria, Acidobacteriota, Myxococcota, Bacteroidota, and Gemmatimonadota at the tasseling stage; and Bacteroidota, Firmicutes, Myxococcota, Methylomirabilota, and Proteobacteria at the maturity stage. The alpha diversity analysis of the soil bacterial community showed that the number of operational taxonomic units (OTUs) and the Chao1 index were higher in S1N2, S1N3, and S1N4 compared with S0N2 at each growth stage. Additionally, the alpha diversity measures were higher in S1N3 and S1N4 compared with S1N2. The beta diversity analysis of the soil bacterial community showed that the bacterial communities in S1N3 and S1N4 were more similar or closely clustered together, while S0N2 was further from all treatments across the three growth stages. The cumulative straw decomposition rate was tested for each treatment, and data showed that S1N3 (90.58%) had the highest decomposition rate. At the phylum level, straw decomposition was positively correlated with Proteobacteria, Actinobacteriota, Myxococcota, and Bacteroidota but significantly negatively correlated with Acidobacteriota. PICRUSt2 function prediction results show that the relative abundance of bacteria in soil samples from each treatment differed significantly. The maize yield of S1N3 was 15597.85 ± 1477.17 kg/hm2, which was 12.80 and 4.18% higher than that of S1N1 and S0N2, respectively. In conclusion, a combination of slow-release nitrogen fertilizer and urea can enhance the straw decomposition rate and maize yield by improving the soil bacterial community and structure within a full straw returning system.

RESUMO

It has been suggested that dietary intake of lipids and fatty acids may influence cognitive function, however, the effect of lard intake during pregnancy and postpartum periods on cognitive function of mother remains to be elucidated. We investigated the effect and mechanism of consuming soybean oil (SO), the mixed oil of lard and soybean oil at the ratio of 1:1 (LS) and lard oil (LO) during the pregnancy and postpartum periods on cognitive function of the maternal mice. All pregnant C57BL/6JNifdc mice were fed with soybean oil diet during day 0-10 (the day when vaginal plugs appeared in female mice was recorded as day 0), and then randomly assigned to SO, LS and LO groups (n = 10) from day 11 to day 44. The time in center zone and the number of times to enter in center zone were significantly higher in the SO group than in the LO group detected by the open-field test. The levels of neuroglial cells, NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome complex and pyroptosis related proteins in brain of the LO group were significantly higher than those in the SO group. RNA-sequencing results showed that the calcium signaling pathway related genes in brain, including Adcy8, Ntsr1, Trhr, Oxtr, Htr5b and Camk2d levels significantly higher in the LO group than in the SO group. Lipidomic analysis indicated that PG 18:2_18:2, PG 20:5_22:6, and CL 12:0_16:0_22:3_22:5 of glycerophospholipid metabolism in brain significantly connected with Htr5b of calcium signaling pathway. In conclusion, the intake of lard during the pregnancy and postpartum periods is detrimental to the cognitive function of maternal mice, which probably due to changes in the composition of fatty acid in the brain, thereby activating neuroinflammation via calcium signaling pathway in brain.

RESUMO

A near-resonant excitation strategy is proposed and implemented in a 4-µm-thick GaN microcavity to realize an exciton-polariton condensate/lasing with low threshold. Strong exciton-photon coupling is demonstrated, and polariton lasing is realized with an ultra-low threshold excitation power density of about 13.3 W/cm2 at room temperature. Such an ultra-low threshold is ascribed to the implementation of the near-resonant optical excitation strategy, which enables acceleration of the exciton and polariton relaxation and suppression of the heat generation in the cavity, thereby reducing the energy loss and enhance the cavity excitation efficiency.

RESUMO

Noncoding RNAs (ncRNAs) do not participate in protein-coding. Ferroptosis is a newly discovered form of cell death mediated by reactive oxygen species and lipid peroxidation. Recent studies have shown that ncRNAs such as microRNAs, long noncoding RNAs, circular RNAs, and ferroptosis are involved in the occurrence and development of osteosarcoma (OS). Studies have confirmed that ncRNAs participate in the development of OS by regulating the ferroptosis. However, systematic summary on this topic are still lacking. This review summarises the potential role of ncRNAs in the diagnosis, treatment, drug resistance, and prognosis of OS and the basis for diagnosing, preventing, and treating clinical OS and developing effective drugs. This review summarises the latest research progress on ncRNAs that regulate ferroptosis in OS, attempts to clarify the molecular mechanisms by which ncRNAs regulate ferroptosis in the pathogenesis of OS, and elaborates on the involvement of ferroptosis in OS from the perspective of ncRNAs.

Assuntos

Neoplasias Ósseas , Ferroptose , MicroRNAs , Osteossarcoma , RNA Circular , RNA Longo não Codificante , Ferroptose/genética , Osteossarcoma/genética , Osteossarcoma/patologia , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Neoplasias Ósseas/metabolismo , Animais , Regulação Neoplásica da Expressão Gênica

RESUMO

As a clinical anti-glioma agent, the therapeutic effect of carmustine (BCNU) was largely decreased because of the drug resistance mediated by O6-alkylguanine-DNA alkyltransferase (AGT) and the blood-brain barrier (BBB). To overcome these obstacles, we synthesized a BCNU-loaded hypoxia/esterase dual stimulus-activated nanomicelle, abbreviated as T80-HACB/BCNU NPs. In this nano-system, Tween 80 acts as the functional coating on the surface of the micelle to facilitate transport across the BBB. Hyaluronic acid (HA) with active tumor-targeting capability was linked with the hypoxia-sensitive AGT inhibitors (O6-azobenzyloxycarbonyl group) via an esterase-activated ester bond. The obtained T80-HACB/BCNU NPs had an average particle size of 232.10 ± 10.66 nm, the zeta potential of -18.13 ± 0.91 mV, and it showed high drug loading capacity, eximious biocompatibility and dual activation of hypoxia/esterase drug release behavior. The obtained T80-HACB/BCNU NPs showed enhanced cytotoxicity against hypoxic T98G and SF763 cells with IC50 at 132.2 µM and 133.1 µM, respectively. T80 modification improved the transportation of the micelle across an in vitro BBB model. The transport rate of the T80-HACB/Cou6 NPs group was 12.37 %, which was 7.6-fold (p<0.001) higher than the micelle without T80 modification. T80-HACB/BCNU NPs will contribute to the development of novel CENUs chemotherapies with high efficacy.

Assuntos

Antineoplásicos Alquilantes , Carmustina , Hipóxia Celular , Nanopartículas , Elastase Pancreática , Polissorbatos , Polissorbatos/química , Micelas , Elastase Pancreática/química , Elastase Pancreática/metabolismo , Carmustina/síntese química , Carmustina/química , Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/farmacologia , Nanopartículas/química , Nanopartículas/toxicidade , Ácido Hialurônico/química , Humanos , Linhagem Celular Tumoral , Dextranos/química , Sistemas de Liberação de Medicamentos , Apoptose/efeitos dos fármacos

RESUMO

Background: Concerns over the security of laparoscopic radical operation for gallbladder cancer (GBC) persist. This systematic review and meta-analysis attempted to compare the safety and efficacy of laparoscopic surgery (LS) versus open surgery (OS) in the treatment of GBC. Methods: The PubMed, EMBASE, and Web of Science were searched from inception to July 18, 2022. Literature search, quality assessment, and data extraction were completed independently and in duplicate. Effect-size estimates expressed as weighted mean difference (WMD) or odds ratio (OR) with 95% confidence interval (CI) were derived under the random-effects model. Results: A total of 27 independent studies including 2,868 participants were meta-analyzed. Significance was noted for intraoperative blood loss (WMD: -117.194, 95% CI: -170.188 to 64.201, P<0.001), harvested lymph nodes (WMD: -1.023, 95% CI: -1.776 to -0.269, P=0.008), postoperative hospital stay (WMD: -3.555, 95% CI: -4.509 to -2.601, P<0.001), postoperative morbidity (OR: 0.596, 95% CI: 0.407 to 0.871, P=0.008), overall survival rate at 2-year (OR: 1.524, 95% CI: 1.143 to 2.031, P=0.004), T2 survival at 1-year (OR: 1.799, 95% CI: 1.777 to 2.749, P<0.01) and 2-year (OR: 2.026, 95% CI: 1.392 to 2.949, P<0.001), as well as T3 survival at 1-year (OR: 2.669, 95% CI: 1.564 to 4.555, P<0.001) and 2-year (OR: 2.300, 95% CI: 1.308 to 4.046, P=0.004). Subgroup analyses revealed that ethnicity, incidental GBC, sample size, and follow-up period were possible sources of heterogeneity. There was a low probability of publication bias for all outcomes except postoperative morbidity. Conclusions: Our findings indicated that LS statistically had better 2-year survival rates, less intraoperative bleeding, shorter hospitalization times, and lower rates of complications than OS. However, the superiority and even the safety of LS still remain an open question due to the impact of incidental GBC, unaccounted heterogeneity, publication bias, lymph node dissection, and port-site metastasis.

RESUMO

Background: Postoperative complications in adhesive small bowel obstruction (ASBO) significantly escalate healthcare costs and prolong hospital stays. This study endeavors to construct a nomogram that synergizes computed tomography (CT) body composition data with inflammatory-nutritional markers to forecast postoperative complications in ASBO. Methods: The study's internal cohort consisted of 190 ASBO patients recruited from October 2017 to November 2021, subsequently partitioned into training (n = 133) and internal validation (n = 57) groups at a 7:3 ratio. An additional external cohort comprised 52 patients. Body composition assessments were conducted at the third lumbar vertebral level utilizing CT images. Baseline characteristics alongside systemic inflammatory responses were meticulously documented. Through univariable and multivariable regression analyses, risk factors pertinent to postoperative complications were identified, culminating in the creation of a predictive nomogram. The nomogram's precision was appraised using the concordance index (C-index) and the area under the receiver operating characteristic (ROC) curve. Results: Postoperative complications were observed in 65 (48.87%), 26 (45.61%), and 22 (42.31%) patients across the three cohorts, respectively. Multivariate analysis revealed that nutrition risk score (NRS), intestinal strangulation, skeletal muscle index (SMI), subcutaneous fat index (SFI), neutrophil-lymphocyte ratio (NLR), and lymphocyte-monocyte ratio (LMR) were independently predictive of postoperative complications. These preoperative indicators were integral to the nomogram's formulation. The model, amalgamating body composition and inflammatory-nutritional indices, demonstrated superior performance: the internal training set exhibited a 0.878 AUC (95% CI, 0.802-0.954), 0.755 accuracy, and 0.625 sensitivity; the internal validation set displayed a 0.831 AUC (95% CI, 0.675-0.986), 0.818 accuracy, and 0.812 sensitivity. In the external cohort, the model yielded an AUC of 0.886 (95% CI, 0.799-0.974), 0.808 accuracy, and 0.909 sensitivity. Calibration curves affirmed a strong concordance between predicted outcomes and actual events. Decision curve analysis substantiated that the model could confer benefits on patients with ASBO. Conclusion: A rigorously developed and validated nomogram that incorporates body composition and inflammatory-nutritional indices proves to be a valuable tool for anticipating postoperative complications in ASBO patients, thus facilitating enhanced clinical decision-making.

RESUMO

Glutamate (Glu) is a predominant excitatory neurotransmitter that acts on glutamate receptors to transfer signals in the central nervous system. Abnormally elevated extracellular glutamate levels is closely related to the generation and transition of epileptic seizures. However, there lacks of investigation regarding the role of extracellular glutamate homeostasis dysregulated by astrocyte in neuronal epileptic discharges. According to this, we propose a novel neuron-astrocyte computational model (NAG) by incorporating extracellular Glu concentration dynamics from three aspects of regulatory mechanisms: (1) the Glu uptake through astrocyte EAAT2; (2) the binding and release Glu via activating astrocyte mGluRs; and (3) the Glu free diffusion in the extracellular space. Then the proposed model NAG is analyzed theoretically and numerically to verify the effect of extracellular Glu homeostasis dysregulated by such three regulatory mechanisms on neuronal epileptic discharges. Our results demonstrate that the neuronal epileptic discharges can be aggravated by the downregulation expression of EAAT2, the aberrant activation of mGluRs, and the elevated Glu levels in extracellular micro-environment; as well as various discharge states (including bursting, mixed-mode spiking, and tonic firing) can be transited by their combination. Furthermore, we find that such factors can also alter the bifurcation threshold for the generation and transition of epileptic discharges. The results in this paper can be helpful for researchers to understand the astrocyte role in modulating extracellular Glu homeostasis, and provide theoretical basis for future related experimental studies.