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1.
Front Microbiol ; 15: 1360505, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38725683

RESUMO

Introduction: Utilizing roughage resources is an effective approach to alleviate the shortage of corn-soybean feed and reducing the costs in the swine industry. Hezuo pig is one group of plateau type local Tibetan pig with strong tolerance to crude feeding. Nevertheless, current research on the roughage tolerance in Hezuo pigs and the microbiological mechanisms behind it is still minimally.This study explored the impact of various ratios of whole-plant silage (WPS) maize on the pH, cellulase activity, short-chain fatty acids (SCFAs), and intestinal microbiota in Hezuo pigs. Methods: Thirty-two Hezuo pigs were randomly divided into four groups (n = 8). The control group received a basal diet, while experimental groups I, II, and III were given diets with incremental additions of 5%, 10%, and 15% air-dried WPS maize, respectively, for 120 days. Results: The findings revealed that compared with the control group, in Group II, the pH of cecum and colon were notably decreased (p < 0.05), while acid detergent fiberdigestibility, the concentration of propionic and isobutyric acid in the cecum, and the concentration of isobutyric acid in the colon were significantly increased (p < 0.05). Also, carboxymethyl cellulase activity in the cecum in group II of Hezuo pigs was significantly higher than that in the other three groups (p < 0.05). Furthermore, the cecum microbiota showed a higher diversity in the group II of Hezuo pigs than that in the control group, as shown by the Simpson and Shannon indices. Specifically, 15 and 24 bacterial species showed a significant difference in relative abundance at the family and genus levels, respectively. Correlation analyses revealed significant associations between bacterial genera and SCFAs concentrations in the cecum. The abundance of Bacteroides and NK4A214_group was positively correlated with amounts of valeric and isovaleric acid but negatively with propionic acid (p < 0.05). The abundance of UCG-010 was positively linked with acetic acid and negatively correlated with butyric acid (p < 0.05). Actinobacillus abundance was positively associated with butyric acid levels (p < 0.05). Discussion: In conclusion, a 10% WPS maize diet improved crude fiber digestibility by lowering cecal and colonic chyme pH, enhancing intestinal cellulase activity, improving SCFA production, and increasing intestinal microbiota diversity.

2.
J Ethnopharmacol ; : 118275, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38729534

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Da-Jian-Zhong decoction (DJZD) is a herbal formula clinically used for abdominal pain and diarrhea induced by spleen-Yang deficiency syndrome. Recently, treatment of diarrhea-predominant irritable bowel syndrome (IBS-D) with DJZD has received increasing attention, but the underlying mechanism of action remains elusive. AIM OF THE STUDY: We aimed to evaluate the therapeutic effect of DJZD on IBS-D rats and to elucidate the underlying mechanisms. MATERIALS AND METHODS: An IBS-D rats model was constructed using a two-factor superposition method of neonatal maternal separation and Senna folium aqueous extract lavage. Moreover, the effect of DJZD was evaluated based on the body weight, rectal temperature, abdominal withdrawal reflex (AWR), and Bristol stool scale score (BSS). The factors that regulate the DJZD effects on IBS-D were estimated using whole microbial genome, transcriptome sequencing (RNA-Seq), flow cytometry, and quantitative reverse transcription polymerase chain reaction (RT-qPCR) analyses. RESULTS: We found that DJZD alleviated the symptoms of IBS-D rats, with the low-dose (2.4 g/kg) as the better ones, as shown by the higher body mass and lower AWR score and BSS. At the phylum level, the relative abundance of Bacteroidetes was obviously increased, and at the genus level, Bacteroides was increased, while that of Firmicutes_bacterium_424 and Ruminococcus gnavus was decreased in DJZD group. The significantly enriched GO terms after treatment with DJZD mainly included the immune response, positive regulation of activated T cell proliferation, and positive regulation of interleukin-17 (IL-17) production. Importantly, flow cytometry analysis further revealed that the T helper cell type 17/regulatory T cell (Th17/Treg) balance contributed to the DJZD-induced alleviation of IBS-D symptoms, as DJZD downregulated Th17/Treg ratio and Th17 cell-related cytokines IL-17 and IL-6 levels in the colon. CONCLUSIONS: These results demonstrate that DJZD has a good therapeutic effect on IBS-D rats, probably by maintaining the homeostasis of gut microbiota and regulating Th17/Treg balance and its related inflammatory factors.

3.
Neuropeptides ; 106: 102436, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38733728

RESUMO

Microglial phagocytosis of myelin debris is a crucial process for promoting myelin regeneration in conditions such as multiple sclerosis (MS). Vacuolar-ATPase B2 (V-ATPase B2) has been implicated in various cellular processes, but its role in microglial phagocytosis and its potential impact on MS-related responses remain unclear. In this study, we employed BV-2 murine microglial cells to investigate the influence of V-ATPase B2 on the phagocytosis of myelin debris by microglia. The results revealed that V-ATPase B2 expression increased in response to myelin debris exposure. Overexpression of V-ATPase B2 significantly enhanced BV-2 phagocytosis of myelin debris. Additionally, V-ATPase B2 overexpression shifted microglial polarization towards an anti-inflammatory M2 phenotype, coupled with decreased lysosomal pH and enhanced lysosome degradation capacity. Moreover, endoplasmic reticulum (ER) stress inhibitor, 4-PBA, reversed the effects of V-ATPase B2 silencing on ER stress, M2 polarization, and lysosomal degradation of BV-2 cells. The MAPK pathway was inhibited upon V-ATPase B2 overexpression, contributing to heightened myelin debris clearance by BV-2 cells. Notably, MAPK pathway inhibition partially attenuated the inhibitory effects of V-ATPase B2 knockdown on myelin debris clearance. In conclusion, our findings reveal a pivotal role for V-ATPase B2 in promoting microglial phagocytosis of myelin debris by regulating microglial polarization and lysosomal function via the MAPK signaling pathway, suggesting that targeting V-ATPase B2 may hold therapeutic potential for enhancing myelin debris clearance and modulating microglial responses in MS and related neuroinflammatory disorders.

4.
Acta Biomater ; 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38734282

RESUMO

Tumor hypoxia, high oxidative stress, and low immunogenic create a deep-rooted immunosuppressive microenvironment, posing a major challenge to the therapeutic efficiency of cancer immunotherapy for solid tumor. Herein, an intelligent nanoplatform responsive to the tumor microenvironment (TME) capable of hypoxia relief and immune stimulation has been engineered for efficient solid tumor immunotherapy. The MnO2@OxA@OMV nanoreactor, enclosing bacterial-derived outer membrane vesicles (OMVs)-wrapped MnO2 nanoenzyme and the immunogenic cell death inducer oxaliplatin (OxA), demonstrated intrinsic catalase-like activity within the TME, which effectively catalyzed the endogenous H2O2 into O2 to enable a prolonged oxygen supply, thereby alleviating the tumor's oxidative stress and hypoxic TME, and expediting OxA release. The combinational action of OxA-caused ICD effect and Mn2+ from nanoreactor enabled the motivation of the cGAS-STING pathway to significantly improve the activation of STING and dendritic cells (DCs) maturation, resulting in metalloimmunotherapy. Furthermore, the immunostimulant OMVs played a crucial role in promoting the infiltration of activated CD8+ T cells into the solid tumor. Overall, the nanoreactor offers a robust platform for solid tumor treatment, highlighting the significant potential of combining relief from tumor hypoxia and immune stimulation for metalloimmunotherapy. STATEMENT OF SIGNIFICANCE: A tailor-made nanoreactor was fabricated by enclosing bacterial-derived outer membrane vesicles (OMVs) onto MnO2 nanoenzyme and loading with immunogenic cell death inducer oxaliplatin (OxA) for tumor metalloimmunotherapy. The nanoreactor possesses intrinsic catalase-like activity within the tumor microenvironment, which effectively enabled a prolonged oxygen supply by catalyzing the conversion of endogenous H2O2 into O2, thereby alleviating tumor hypoxia and expediting OxA release. Furthermore, the TME-responsive release of nutritional Mn2+ sensitized the cGAS-STING pathway and collaborated with OxA-induced immunogenic cell death (ICD). Combing with immunostimulatory OMVs enhances the uptake of nanoreactors by DCs and promotes the infiltration of activated CD8+ T cells. This nanoreactor offers a robust platform for solid tumor treatment, highlighting the significant potential of combining relief from tumor hypoxia and immune stimulation for metalloimmunotherapy.

5.
Food Chem ; 450: 139472, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38705103

RESUMO

In this study, the electrospinning technique was used to co-encapsulate Quercetin (Qu) and Lactiplantibacillus plantarum 1-24-LJ in PVA-based nanofibers, and the effect of bioactive films on fish preservation was evaluated at the first time. The findings indicated that both Lpb. plantarum 1-24-LJ and Qu were successfully in the fibers, and co-loaded fibers considerably outperformed single-loaded fiber in terms of bacterial survival and antioxidant activity. Following fish preservation using the loaded fibers, significant reductions were observed in TVB-N, TBARS, and microbial complexity compared to the control group. Additionally, the co-loaded fibers more effectively reduced the counts of H2S-producing bacteria and Pseudomonas. In the future, fibers with both active substances and LAB hold promise as a novel approach for fish preservation.

6.
Elife ; 122024 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-38738857

RESUMO

Enhanced protein synthesis is a crucial molecular mechanism that allows cancer cells to survive, proliferate, metastasize, and develop resistance to anti-cancer treatments, and often arises as a consequence of increased signaling flux channeled to mRNA-bearing eukaryotic initiation factor 4F (eIF4F). However, the post-translational regulation of eIF4A1, an ATP-dependent RNA helicase and subunit of the eIF4F complex, is still poorly understood. Here, we demonstrate that IBTK, a substrate-binding adaptor of the Cullin 3-RING ubiquitin ligase (CRL3) complex, interacts with eIF4A1. The non-degradative ubiquitination of eIF4A1 catalyzed by the CRL3IBTK complex promotes cap-dependent translational initiation, nascent protein synthesis, oncogene expression, and cervical tumor cell growth both in vivo and in vitro. Moreover, we show that mTORC1 and S6K1, two key regulators of protein synthesis, directly phosphorylate IBTK to augment eIF4A1 ubiquitination and sustained oncogenic translation. This link between the CRL3IBTK complex and the mTORC1/S6K1 signaling pathway, which is frequently dysregulated in cancer, represents a promising target for anti-cancer therapies.


Assuntos
Fator de Iniciação 4A em Eucariotos , Alvo Mecanístico do Complexo 1 de Rapamicina , Transdução de Sinais , Ubiquitinação , Humanos , Fator de Iniciação 4A em Eucariotos/metabolismo , Fator de Iniciação 4A em Eucariotos/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Animais , Biossíntese de Proteínas , Linhagem Celular Tumoral , Camundongos , Receptores de Interleucina-17
7.
Nanoscale ; 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38712434

RESUMO

Introducing a donor-acceptor (D-A) unit is an effective approach to facilitate charge transfer in polymeric carbon nitride (PCN) and enhance photocatalytic performance. However, the introduction of hetero-molecules can lead to a decrease in crystallinity, limiting interlayer charge transfer and inhibiting further improvement. In this study, we constructed a novel D-A type carbon nitride with significantly higher crystallinity and a bi-directional charge transfer channel, which was achieved through 2,5-thiophenedicarboxylic acid (2,5-TDCA)-assisted self-assembly followed by KCl-templated calcination. The thiophene and cyano groups introduced serve as the electron donor and acceptor, respectively, enhancing in-plane electron delocalization. Additionally, introduced potassium ions are intercalated among the adjacent layers of carbon nitride, creating an interlayer charge transfer channel. Moreover, the highly ordered structure and improved crystallinity further facilitate charge transfer. As a result, the as-prepared photocatalyst exhibits superior photocatalytic hydrogen evolution (PHE) activity of 7.449 mmol h-1 g-1, which is 6.03 times higher than that of pure carbon nitride. The strategy of developing crystalline D-A-structured carbon nitride with controlled in-plane and interlayer charge transfer opens new avenues for the design of carbon nitride with enhanced properties for PHE.

8.
Clin Exp Pharmacol Physiol ; 51(6): e13861, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38724488

RESUMO

Relevant studies have indicated the association of HCG18 with tumour occurrence and progression. In this study, we observed that PM2.5 can enhance the growth of lung adenocarcinoma cells by modulating the expression of HCG18. Further investigations, including overexpression and knockout experiments, elucidated that HCG18 suppresses miR-195, which in turn upregulates the expression of ATG14, resulting in the upregulation of autophagy. Consequently, exposure to PM2.5 leads to elevated HCG18 expression in lung tissues, which in turn increases Atg14 expression and activates autophagy pathways through inhibition of miR-195, thereby contributing to oncogenesis.


Assuntos
Adenocarcinoma de Pulmão , Proteínas Relacionadas à Autofagia , Autofagia , Progressão da Doença , Neoplasias Pulmonares , MicroRNAs , Material Particulado , MicroRNAs/genética , MicroRNAs/metabolismo , Humanos , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/metabolismo , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Material Particulado/efeitos adversos , Autofagia/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo , Proliferação de Células/genética , Células A549 , Linhagem Celular Tumoral , Proteínas Adaptadoras de Transporte Vesicular
9.
Artigo em Inglês | MEDLINE | ID: mdl-38726776

RESUMO

BACKGROUND: Breast Cancer (BC) is a female malignancy with a high mortality rate. Novel diagnostic and prognostic biomarkers are valuable for reducing BC mortality. Our study is designed to undrape the precise role of the LINC00466/miR-4731-5p/EPHA2 axis in BC.

Methods: The Cancer Genome Atlas (TCGA) sequencing dataset was utilized to compare the levels of LINC00466. The levels of LINC00466, miR-4731-5p, and EPHA2 were tested by qRTPCR. Cell proliferation and cycle were detected by CCK-8 assay and flow cytometer. In vivo role of LINC00466 was tested by Xenograft nude models. Binding sites were predicted by TargetScan and Starbase. The binding relationship was employed by Dual-luciferase reporter gene assay and RNA pull-down assay.

Results: LINC00466 was increased in human breast cancer tissues. LINC00466 was negatively associated with miR-4731-5p and positively correlated with EPHA2 in human breast cancer tissues. Down-regulation of LINC00466 suppressed the proliferation and arrested the cell cycle of breast cancer cells, and inhibited tumor growth in vivo.

Conclusion: LINC00466 promoted BC development via mediating the miR-4731-5p/EPHA2 axis, which has the potential value as a promising therapeutic target in BC.

10.
Talanta ; 275: 126194, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38703481

RESUMO

Lung cancer staging is crucial for personalized treatment and improved prognosis. We propose a novel bimodal diagnostic approach that integrates LIBS and Raman technologies into a single platform, enabling comprehensive tissue elemental and molecular analysis. This strategy identifies critical staging elements and molecular marker signatures of lung tumors. LIBS detects concentration patterns of elemental lines including Mg (I), Mg (II), Ca (I), Ca (II), Fe (I), and Cu (II). Concurrently, Raman spectroscopy identifies changes in molecular content, such as phenylalanine (1033 cm-1), tyrosine (1174 cm-1), tryptophan (1207 cm-1), amide III (1267 cm-1), and proteins (1126 cm-1 and 1447 cm-1), among others. The bimodal information is fused using a decision-level Bayesian fusion model, significantly enhancing the performance of the convolutional neural network architecture in classification algorithms, with an accuracy of 99.17 %, sensitivity of 99.17 %, and specificity of 99.88 %. This study provides a powerful new tool for the accurate staging and diagnosis of lung tumors.

11.
J Adv Res ; 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38704090

RESUMO

BACKGROUND: Central nervous system (CNS) injury causes severe organ damage due to both damage resulting from the injury and subsequent cell death. However, there are currently no effective treatments for countering the irreversible loss of cell function. Parthanatos is a poly (ADP-ribose) polymerase 1 (PARP-1)-dependent form of programmed cell death that is partly responsible for neural cell death. Consequently, the mechanism by which parthanatos promotes CNS injury has attracted significant scientific interest. AIM OF REVIEW: Our review aims to summarize the potential role of parthanatos in CNS injury and its molecular and pathophysiological mechanisms. Understanding the role of parthanatos and related molecules in CNS injury is crucial for developing effective treatment strategies and identifying important directions for future in-depth research. KEY SCIENTIFIC CONCEPTS OF REVIEW: Parthanatos (from Thanatos, the personification of death according to Greek mythology) is a type of programmed cell death that is initiated by the overactivation of PARP-1. This process triggers a cascade of reactions, including the accumulation of poly(ADP-ribose) (PAR), the nuclear translocation of apoptosis-inducing factor (AIF) after its release from mitochondria, and subsequent massive DNA fragmentation caused by migration inhibitory factor (MIF) forming a complex with AIF. Secondary molecular mechanisms, such as excitotoxicity and oxidative stress-induced overactivation of PARP-1, significantly exacerbate neuronal damage following initial mechanical injury to the CNS. Furthermore, parthanatos is not only associated with neuronal damage but also interacts with various other types of cell death. This review focuses on the latest research concerning the parthanatos cell death pathway, particularly considering its regulatory mechanisms and functions in CNS damage. We highlight the associations between parthanatos and different cell types involved in CNS damage and discuss potential therapeutic agents targeting the parthanatos pathway.

12.
Artigo em Inglês | MEDLINE | ID: mdl-38695237

RESUMO

AIMS: This study aimed to explore the change trend and group heterogeneity of psychosocial adjustment level and to determine its influencing factors among young and middle-aged patients with first-episode acute myocardial infarction (AMI). METHODS AND RESULTS: The Psychosocial Adjustment Scale of Illness was used to assess the psychosocial adjustment level of the patients at 1, 3, and 6 months after discharge, respectively. Data were analyzed using Pearson correlation analysis, generalized estimating equations, and growth mixed models. A total of 233 patients were included, and their psychosocial adjustment scores at the three-time points were 57.18 ± 15.50, 36.17 ± 15.02, and 24.22 ± 12.98, respectively. The trajectories of changes in patients' psychosocial adjustment levels were divided into three latent categories: moderate adjustment improvement group (72.5%), low adjustment improvement group (16.3%), and persistent maladjustment group (11.2%). Among them, predictors of the persistent maladjustment group included no spouse, low monthly family income per capita, normal body mass index, never smoking, never exercising, combined with hyperlipidemia, low social support, submission coping, and high perceived stress. CONCLUSIONS: The psychosocial adjustment level of young and middle-aged patients with first-episode AMI showed an upward trend within 6 months after discharge, and there was group heterogeneity in the change trajectory of psychosocial adjustment level. It is suggested that a multi-center, large-sample longitudinal study should be carried out in the future, and the time of follow-up investigation should be extended to further clarify the change trajectory and influencing factors of psychosocial adjustment of patients with different subtypes, to provide the theoretical basis for formulating targeted intervention programs.

13.
Biochem Biophys Res Commun ; 716: 150002, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38697011

RESUMO

Type 2 diabetes mellitus (T2DM) significantly impairs the functionality and number of endothelial progenitor cells (EPCs) and resident endothelial cells, critical for vascular repair and regeneration, exacerbating the risk of vascular complications. GLP-1 receptor agonists, like dulaglutide, have emerged as promising therapeutic agents due to their multifaceted effects, including the enhancement of EPC activity and protection of endothelial cells. This study investigates dulaglutide's effects on peripheral blood levels of CD34+ and CD133+ cells in a mouse model of lower limb ischemia and its protective mechanisms against high-glucose-induced damage in endothelial cells. Results demonstrated that dulaglutide significantly improves blood flow, reduces tissue damage and inflammation in ischemic limbs, and enhances glycemic control. Furthermore, dulaglutide alleviated high-glucose-induced endothelial cell damage, evident from improved tube formation, reduced reactive oxygen species accumulation, and restored endothelial junction integrity. Mechanistically, dulaglutide mitigated mitochondrial fission in endothelial cells under high-glucose conditions, partly through maintaining SIRT1 expression, which is crucial for mitochondrial dynamics. This study reveals the potential of dulaglutide as a therapeutic option for vascular complications in T2DM patients, highlighting its role in improving endothelial function and mitochondrial integrity.

15.
Nano Lett ; 2024 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-38739468

RESUMO

Accumulated reactive oxygen species (ROS) and their resultant vascular dysfunction in androgenic alopecia (AGA) hinder hair follicle survival and cause permanent hair loss. However, safe and effective strategies to rescue hair follicle viability to enhance AGA therapeutic efficiency remain challenging. Herein, we fabricated a quercetin-encapsulated (Que) and polydopamine-integrated (PDA@QLipo) nanosystem that can reshape the perifollicular microenvironment to initial hair follicle regeneration for AGA treatment. Both the ROS scavenging and angiogenesis promotion abilities of PDA@QLipo were demonstrated. In vivo assays revealed that PDA@QLipo administrated with roller-microneedles successfully rejuvenated the "poor" perifollicular microenvironment, thereby promoting cell proliferation, accelerating hair follicle renewal, and facilitating hair follicle recovery. Moreover, PDA@QLipo achieved a higher hair regeneration coverage of 92.5% in the AGA mouse model than minoxidil (87.8%), even when dosed less frequently. The nanosystem creates a regenerative microenvironment by scavenging ROS and augmenting neovascularity for hair regrowth, presenting a promising approach for AGA clinical treatment.

16.
J Gene Med ; 26(5): e3689, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38676365

RESUMO

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy characterized by a poor prognosis and closely linked to tumor stemness. However, the key molecules that regulate ICC stemness remain elusive. Although Y-box binding protein 1 (YBX1) negatively affects prognosis in various cancers by enhancing stemness and chemoresistance, its effect on stemness and cisplatin sensitivity in ICC remains unclear. METHODS: Three bulk and single-cell RNA-seq datasets were analyzed to investigate YBX1 expression in ICC and its association with stemness. Clinical samples and colony/sphere formation assays validated the role of YBX1 in stemness and sensitivity to cisplatin. AZD5363 and KYA1979K explored the interaction of YBX1 with the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) and WNT/ß-catenin pathways. RESULTS: YBX1 was significantly upregulated in ICC, correlated with worse overall survival and shorter postoperative recurrence time, and was higher in chemotherapy-non-responsive ICC tissues. The YBX1-high group exhibited significantly elevated stemness scores, and genes linked to YBX1 upregulation were enriched in multiple stemness-related pathways. Moreover, YBX1 expression is significantly correlated with several stemness-related genes (SOX9, OCT4, CD133, CD44 and EPCAM). Additionally, YBX1 overexpression significantly enhanced the colony- and spheroid-forming abilities of ICC cells, accelerated tumor growth in vivo and reduced their sensitivity to cisplatin. Conversely, the downregulation of YBX1 exerted the opposite effect. The transcriptomic analysis highlighted the link between YBX1 and the PI3K/AKT and WNT/ß-catenin pathways. Further, AZD5363 and KYA1979K were used to clarify that YBX1 promoted ICC stemness through the regulation of the AKT/ß-catenin axis. CONCLUSIONS: YBX1 is upregulated in ICC and promotes stemness and cisplatin insensitivity via the AKT/ß-catenin axis. Our study describes a novel potential therapeutic target for improving ICC prognosis.


Assuntos
Colangiocarcinoma , Cisplatino , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Proteína 1 de Ligação a Y-Box , beta Catenina , Animais , Feminino , Humanos , Masculino , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , beta Catenina/metabolismo , beta Catenina/genética , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , Colangiocarcinoma/mortalidade , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Células-Tronco Neoplásicas/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Via de Sinalização Wnt , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína 1 de Ligação a Y-Box/metabolismo , Proteína 1 de Ligação a Y-Box/genética
17.
Food Funct ; 15(8): 4614-4626, 2024 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-38590249

RESUMO

The role of vitamin D (VD) in non-alcoholic fatty liver disease (NAFLD) remains controversial, possibly due to the differential effects of various forms of VD. In our study, Sod1 gene knockout (SKO) mice were utilized as lean NAFLD models, which were administered 15 000 IU VD3 per kg diet, or intraperitoneally injected with the active VD analog calcipotriol for 12 weeks. We found that VD3 exacerbated hepatic steatosis in SKO mice, with an increase in the levels of Cd36, Fatp2, Dgat2, and CEBPA. However, calcipotriol exerted no significant effect on hepatic steatosis. Calcipotriol inhibited the expression of Il-1a, Il-1b, Il-6, Adgre1, and TNF, with a reduction of NFκB phosphorylation in SKO mice. No effect was observed by either VD3 or calcipotriol on hepatocyte injury and hepatic fibrosis. Co-immunofluorescence stains of CD68, a liver macrophage marker, and VDR showed that calcipotriol reduced CD68 positive cells, and increased the colocalization of VDR with CD68. However, VD3 elevated hepatocyte VDR expression, with no substantial effect on the colocalization of VDR with CD68. Finally, we found that VD3 increased the levels of serum 25(OH)D3 and 24,25(OH)2D3, whereas calcipotriol decreased both. Both VD3 and calcipotriol did not disturb serum calcium and phosphate levels. In summary, our study found that VD3 accentuated hepatic steatosis, while calcipotriol diminished inflammation levels in SKO mice, and the difference might stem from their distinct cellular selectivity in activating VDR. This study provides a reference for the application of VD in the treatment of lean NAFLD.


Assuntos
Calcitriol , Calcitriol/análogos & derivados , Colecalciferol , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Calcitriol/farmacologia , Camundongos , Colecalciferol/farmacologia , Masculino , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Fígado/metabolismo , Fígado/efeitos dos fármacos , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Inflamação/tratamento farmacológico , Camundongos Endogâmicos C57BL , Humanos , Modelos Animais de Doenças
18.
Diabetes Metab Syndr Obes ; 17: 1621-1634, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38616991

RESUMO

Objective: To investigate the impact of sarcopenia on the 10-year risk of atherosclerotic cardiovascular disease (ASCVD) among individuals with type 2 diabetes mellitus (T2DM). Methods: This study included the clinical, laboratory, and body composition data of 1491 patients with T2DM who were admitted to the Department of Endocrinology and Metabolism at Tianjin Union Medical Center from July 2018 to July 2023. The China-PAR model was utilized to evaluate cardiovascular disease risk. Associations between ASCVD risk and various clinical parameters were analyzed, and the relationship between body composition parameters and ASCVD risk was assessed using logistic regression. Results: The analysis revealed that T2DM patients with sarcopenia had a higher 10-year ASCVD risk compared to those without sarcopenia, with reduced muscle mass independently predicting an increased risk of cardiovascular disease. This association was significant among female T2DM patients, while male T2DM patients with sarcopenia showed a marginally higher median ASCVD risk compared to their non-sarcopenic counterparts. ASCVD risk inversely correlated with body muscle parameters and positively correlated with fat content parameters. Specifically, height- and weight-adjusted fat mass (FM, FM%, FMI) were identified as risk factors for ASCVD. Conversely, muscle parameters adjusted for weight and fat (ASM%, SMM%, FFM%, ASM/FM, SMM/FM, FMM/FM) were protective against ASCVD risk. These findings highlight the critical role of sarcopenia in influencing cardiovascular disease risk among Chinese patients with T2DM, as predicted by the China-PAR model. Conclusion: This study highlights the importance of sarcopenia in T2DM patients, not only as an indicator of ASCVD risk, but possibly as an independent risk factor in this demographics.

19.
J Math Biol ; 88(6): 65, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38630136

RESUMO

First-principles-based modelings have been extremely successful in providing crucial insights and predictions for complex biological functions and phenomena. However, they can be hard to build and expensive to simulate for complex living systems. On the other hand, modern data-driven methods thrive at modeling many types of high-dimensional and noisy data. Still, the training and interpretation of these data-driven models remain challenging. Here, we combine the two types of methods to model stochastic neuronal network oscillations. Specifically, we develop a class of artificial neural networks to provide faithful surrogates to the high-dimensional, nonlinear oscillatory dynamics produced by a spiking neuronal network model. Furthermore, when the training data set is enlarged within a range of parameter choices, the artificial neural networks become generalizable to these parameters, covering cases in distinctly different dynamical regimes. In all, our work opens a new avenue for modeling complex neuronal network dynamics with artificial neural networks.


Assuntos
Aprendizagem , Redes Neurais de Computação , Dinâmica não Linear
20.
Mater Today Bio ; 26: 101054, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38633865

RESUMO

The hypoxic tumor microenvironment (TME) of osteosarcoma (OS) is the Achilles' heel of oxygen-dependent photodynamic therapy (PDT), and tremendous challenges are confronted to reverse the hypoxia. Herein, we proposed a "reducing expenditure of O2 and broadening sources" dual-strategy and constructed ultrasmall IrO2@BSA-ATO nanogenerators (NGs) for decreasing the O2-consumption and elevating the O2-supply simultaneously. As O2 NGs, the intrinsic catalase (CAT) activity could precisely decompose the overexpressed H2O2 to produce O2 in situ, enabling exogenous O2 infusion. Moreover, the cell respiration inhibitor atovaquone (ATO) would be at the tumor sites, effectively inhibiting cell respiration and elevating oxygen content for endogenous O2 conservation. As a result, IrO2@BSA-ATO NGs systematically increase tumor oxygenation in dual ways and significantly enhance the antitumor efficacy of PDT. Moreover, the extraordinary photothermal conversion efficiency allows the implementation of precise photothermal therapy (PTT) under photoacoustic guidance. Upon a single laser irradiation, this synergistic PDT, PTT, and the following immunosuppression regulation performance of IrO2@BSA-ATO NGs achieved a superior tumor cooperative eradicating capability both in vitro and in vivo. Taken together, this study proposes an innovative dual-strategy to address the serious hypoxia problem, and this microenvironment-regulable IrO2@BSA-ATO NGs as a multifunctional theranostics platform shows great potential for OS therapy.

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