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1.
BMC Anesthesiol ; 24(1): 218, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38956515

RESUMO

BACKGROUND: As a new type of intravenous anesthetic, ciprofol has the advantages of fast onset of action, fast recovery and high clearance rate. This study aimed to investigate the effectiveness and safety of ciprofol versus traditional propofol for anesthesia and sedation in and out of the operating room. METHODS: We searched the literature in PubMed, Web of Science, Cochrane Library, and Embase databases from January 2021 to December 2023. All clinical studies comparing the sedative effects of propofol and ciprofol, both inside and outside the operating room, were included in our trial. The main outcome measures were induction time and incidence of injection-site pain. Data are merged using risk ratio and standardized mean difference with 95% confidence interval. Subgroup analysis, meta-regression, sensitivity analysis, and publication bias were performed. The study protocol was prospectively registered with PROSPERO (CRD42023447747). RESULTS: A total of 15 randomized, controlled trials involving 2002 patients were included in this study. Compared with propofol, ciprofol has a longer induction time in the operating room but a shorter induction time in non-operating room settings. Ciprofol can effectively reduce the risk of injection-site pain and respiratory depression both inside and outside the operating room. In addition, the risk of drug-related hypotension induced with ciprofol in the operating room is lower, but the awakening time is also longer. Meta-regression analysis showed that neither age nor BMI were potential sources of heterogeneity. Funnel plot, egger and begg tests showed no significant publication bias. Sensitivity analyzes indicate that our results are robust and reliable. CONCLUSION: Ciprofol has absolute advantages in reducing the risk of injection-site pain and respiratory depression, both in and outside operating room. Intraoperative use of ciprofol reduces the risk of drug-related hypotension and may also reduce the risk of intraoperative physical movements. However, ciprofol may have longer induction and awakening time than propofol.


Assuntos
Anestésicos Intravenosos , Salas Cirúrgicas , Propofol , Propofol/efeitos adversos , Propofol/administração & dosagem , Humanos , Anestésicos Intravenosos/efeitos adversos , Anestésicos Intravenosos/administração & dosagem , Hipnóticos e Sedativos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos
2.
J Exp Clin Cancer Res ; 43(1): 181, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38937855

RESUMO

BACKGROUND: This study aimed to develop a novel six-gene expression biomarker panel to enhance the early detection and risk stratification of peritoneal recurrence and micrometastasis in locally advanced gastric cancer (LAGC). METHODS: We used genome-wide transcriptome profiling and rigorous bioinformatics to identify a six-gene expression biomarker panel. This panel was validated across multiple clinical cohorts using both tissue and liquid biopsy samples to predict peritoneal recurrence and micrometastasis in patients with LAGC. RESULTS: Through genome-wide expression profiling, we identified six mRNAs and developed a risk prediction model using 196 samples from a surgical specimen training cohort. This model, incorporating a 6-mRNA panel with clinical features, demonstrated high predictive accuracy for peritoneal recurrence in gastric cancer patients, with an AUC of 0.966 (95% CI: 0.944-0.988). Transitioning from invasive surgical or endoscopic biopsy to noninvasive liquid biopsy, the model retained its predictive efficacy (AUC = 0.963; 95% CI: 0.926-1.000). Additionally, the 6-mRNA panel effectively differentiated patients with or without peritoneal metastasis in 95 peripheral blood specimens (AUC = 0.970; 95% CI: 0.936-1.000) and identified peritoneal micrometastases with a high efficiency (AUC = 0.941; 95% CI: 0.874-1.000). CONCLUSIONS: Our study provides a novel gene expression biomarker panel that significantly enhances early detection of peritoneal recurrence and micrometastasis in patients with LAGC. The RSA model's predictive capability offers a promising tool for tailored treatment strategies, underscoring the importance of integrating molecular biomarkers with clinical parameters in precision oncology.


Assuntos
Biomarcadores Tumorais , Perfilação da Expressão Gênica , Micrometástase de Neoplasia , Recidiva Local de Neoplasia , Neoplasias Peritoneais , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Biópsia Líquida/métodos , Feminino , Micrometástase de Neoplasia/genética , Masculino , Neoplasias Peritoneais/secundário , Neoplasias Peritoneais/genética , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica/métodos , Pessoa de Meia-Idade , Transcriptoma , Idoso
3.
Am J Cancer Res ; 14(5): 2124-2140, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38859826

RESUMO

Alpha-fetoprotein-producing gastric cancer (AFPGC) is a rare and aggressive subtype of gastric cancer associated with poor prognosis. This study aimed to investigate the recurrent metastatic patterns and prognostic factors in AFPGC patients undergoing radical surgical resection. Data from 241 AFPGC patients diagnosed between January 2017 and January 2020 who underwent surgical resection were analyzed across multiple centers. Recurrence patterns, metastatic sites, and survival outcomes were evaluated. Univariate and multivariate analyses were performed to identify risk factors for recurrent metastasis, overall survival (OS), and disease-free survival (DFS). There is an annual increase in the proportion of AFPGC cases, rising from 3.45% in 2017 to 7.88% in 2023. Higher serum AFP level was associated with increased likelihood of lymph node metastasis (P=0.006), deeper invasion depth (P=0.000) and greater tumor diameter (P=0.036). Independent predictors of recurrent metastasis included T4 infiltration, lymph node metastasis, tumor diameter >5 cm, poorly differentiated-undifferentiated pathology, preoperative AFP>1000 ng/mL, and postoperative increasing trend in AFP levels. The 5-year OS and DFS rates were 36.5% and 34.2%, respectively, with poorer survival linked to higher preoperative AFP levels and postoperative increasing trend in AFP level. Independent risk factors for poor OS and DFS included T4 infiltration, lymph node metastasis, poorly differentiated-undifferentiated pathology, preoperative AFP>1000 ng/mL, and postoperative increasing trend in AFP. Serum AFP level can serve as a potential predictive and prognostic biomarker. Identifying independent risk factors informs risk stratification and personalized treatment for AFPGC patients.

4.
Am J Cancer Res ; 14(5): 2272-2286, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38859846

RESUMO

OBJECTIVE: To establish nomogram models for predicting the overall survival (OS) and cancer-specific survival (CSS) of gastric cancer liver metastasis (GCLM) patients. METHODS: Data from the Surveillance, Epidemiology, and End Results (SEER) database for 5,451 GCLM patients diagnosed between 2010 and 2015 were analyzed. The cohort was divided into a training set (3,815 cases) and an internal validation set (1,636 cases). External validation included 193 patients from the Fourth Hospital of Hebei Medical University and 171 patients from the People's Hospital of Shijiazhuang City, spanning 2016-2018. Multivariable Cox regression analysis identified eight independent prognostic factors for OS and CSS in GCLM patients, including age, histological type, grade, tumor size, surgery, chemotherapy, bone metastasis, and lung metastasis. Two nomogram models were developed based on these factors and evaluated using time-dependent receiver operating characteristic curve analysis, calibration curves, and decision curve analysis. RESULTS: Internal validation showed that the nomogram models outperformed the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system in predicting 1-year, 2-year, and 3-year OS and CSS in GCLM patients (1-year OS: 0.801 vs. 0.593, P < 0.001; 1-year CSS: 0.807 vs. 0.598, P < 0.001; 2-year OS: 0.803 vs. 0.630, P < 0.001; 2-year CSS: 0.802 vs. 0.633, P < 0.001; 3-year OS: 0.824 vs. 0.691, P < 0.001; 3-year CSS: 0.839 vs. 0.692, P < 0.001). CONCLUSION: This study developed and validated nomogram models using SEER database data to predict OS and CSS in GCLM patients. These models offer improved prognostic accuracy over traditional staging systems, aiding in clinical decision-making.

5.
Cell Rep Med ; 5(5): 101573, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38776874

RESUMO

Epstein-Barr virus (EBV) is linked to various malignancies and autoimmune diseases, posing a significant global health challenge due to the lack of specific treatments or vaccines. Despite its crucial role in EBV infection in B cells, the mechanisms of the glycoprotein gp42 remain elusive. In this study, we construct an antibody phage library from 100 EBV-positive individuals, leading to the identification of two human monoclonal antibodies, 2B7 and 2C1. These antibodies effectively neutralize EBV infection in vitro and in vivo while preserving gp42's interaction with the human leukocyte antigen class II (HLA-II) receptor. Structural analysis unveils their distinct binding epitopes on gp42, different from the HLA-II binding site. Furthermore, both 2B7 and 2C1 demonstrate potent neutralization of EBV infection in HLA-II-positive epithelial cells, expanding our understanding of gp42's role. Overall, this study introduces two human anti-gp42 antibodies with potential implications for developing EBV vaccines targeting gp42 epitopes, addressing a critical gap in EBV research.


Assuntos
Anticorpos Monoclonais , Epitopos , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Humanos , Herpesvirus Humano 4/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , Anticorpos Monoclonais/imunologia , Epitopos/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Camundongos , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Proteínas Virais/imunologia , Linfócitos B/imunologia
6.
PLoS One ; 19(4): e0298153, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38603661

RESUMO

OBJECTIVE: The Da Vinci Robot is the most advanced micro-control system in endoscopic surgical instruments and has gained a lot of valuable experience today. However, the technical feasibility and oncological safety of the robot over open surgery are still uncertain. This work is to systematically evaluate the efficacy of the unilateral axillary approach for robotic surgery compared to open surgery for differentiated thyroid carcinoma. METHODS: PubMed, Embase, Cochrane Library, and Web of Science databases were utilized to search for relevant literatures of robotic thyroid surgery using unilateral axillary approach compared to open thyroid surgery, and a meta-analysis was performed using RevMan software version 5.3. Statistical analysis was performed through Mantle-Haenszel and inverse variance methods. RESULTS: Twelve studies with a total of 2660 patients were included in the meta-analysis. The results showed that compared with the open group, the robotic group had a longer total thyroidectomy time, shorter hospital stay, less intraoperative bleeding, more postoperative drainage, fewer retrieved central lymph nodes, and higher cosmetic satisfaction (all P < 0.05). In contrast, temporary and permanent laryngeal recurrent nerve injury, temporary and permanent hypoparathyroidism or hypocalcemia, brachial plexus nerve injury, number of retrieved central lymph nodes, number of retrieved lymph nodes in the lateral cervical region, number of lymph node metastases in the lateral cervical region, hematoma, seroma, lymphatic leak, stimulated thyroglobulin (sTg) and unstimulated thyroglobulin (uTg), and the number and recurrence rate of patients with sTg <1ng/ml were not statistically different between the two groups (P > 0.05). CONCLUSIONS: The unilateral axillary approach for robotic thyroid surgery may achieve outcomes similar to those of open surgery. Further validation is required in a prospective randomized controlled trial.


Assuntos
Adenocarcinoma , Procedimentos Cirúrgicos Robóticos , Robótica , Neoplasias da Glândula Tireoide , Humanos , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Tireoglobulina , Estudos Prospectivos , Neoplasias da Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/patologia , Robótica/métodos , Tireoidectomia/efeitos adversos , Adenocarcinoma/cirurgia , Estudos Retrospectivos , Esvaziamento Cervical
7.
J Agric Food Chem ; 72(17): 9818-9827, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38647087

RESUMO

The feces of healthy middle-aged and old people were first transplanted into d-galactose-induced aging mice to construct humanized aging mice with gut microbiota (FMTC) to confirm the antiaging effect of probiotics produced from centenarians. The mouse model was then treated with centenarian-derived Bifidobacterium bifidum (FMTL), Lactobacillus casei (FMTB), and their mixtures (FMTM), and young mice were used as the control. Compared with the FMTC group, the results demonstrated that the probiotics and their combinations alleviated neuronal damage, increased antioxidant capacity, decreased inflammation, and enhanced cognitive and memory functions in aging mice. In the gut microbiota, the relative abundance of Lactobacillus, Ligilactobacillus, and Akkermansia increased and that of Desulfovibrio and Colidextribacter decreased in the FMTM group compared with that in the FMTC group. The three probiotic groups displayed significant changes in 15 metabolites compared with the FMTC group, with 4 metabolites showing increased expression and 11 metabolites showing decreased expression. The groups were graded as Control > FMTM > FMTB > FMTL > FMTC using a newly developed comprehensive quantitative scoring system that thoroughly analyzed the various indicators of this study. The beneficial antiaging effects of probiotics derived from centenarians were quantitatively described using a novel perspective in this study; it is confirmed that both probiotics and their combinations exert antiaging effects, with the probiotic complex group exhibiting a larger effect.


Assuntos
Envelhecimento , Bifidobacterium bifidum , Fezes , Galactose , Microbioma Gastrointestinal , Lacticaseibacillus casei , Probióticos , Animais , Lacticaseibacillus casei/metabolismo , Humanos , Camundongos , Probióticos/administração & dosagem , Probióticos/farmacologia , Bifidobacterium bifidum/fisiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Fezes/microbiologia , Fezes/química , Masculino , Transplante de Microbiota Fecal , Pessoa de Meia-Idade , Feminino , Idoso , Camundongos Endogâmicos C57BL , Bactérias/classificação , Bactérias/isolamento & purificação , Bactérias/genética , Bactérias/metabolismo
8.
Bioorg Med Chem ; 105: 117716, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38608329

RESUMO

In this study, a series of new formylpiperazine-derived ferroptosis inhibitors were designed and synthesized based on the structure of a known ferroptosis inhibitor, ferrostatin-1 (Fer-1). The anti-ferroptosis activity of these synthetic compounds in human umbilical vein endothelial cells (HUVECs) induced by Erastin was evaluated. It was found that some of the new compounds, especially compound 26, showed potent anti-ferroptosis activity, as evidenced by its ability to restore cell viability, reduce iron accumulation, scavenge reactive oxygen species, maintain mitochondrial membrane potential, increase GSH levels, decrease LPO and MDA content, and upregulate GPX4 expression. Moreover, compound 26 exhibited superior microsomal stability than Fer-1. The present results suggest that compound 26 is a promising lead compound for the development of new ferroptosis inhibitors for the treatment of vascular diseases.


Assuntos
Sobrevivência Celular , Cicloexilaminas , Desenho de Fármacos , Ferroptose , Células Endoteliais da Veia Umbilical Humana , Piperazinas , Humanos , Ferroptose/efeitos dos fármacos , Piperazinas/farmacologia , Piperazinas/síntese química , Piperazinas/química , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Relação Estrutura-Atividade , Cicloexilaminas/farmacologia , Cicloexilaminas/química , Cicloexilaminas/síntese química , Sobrevivência Celular/efeitos dos fármacos , Estrutura Molecular , Fenilenodiaminas/farmacologia , Fenilenodiaminas/química , Fenilenodiaminas/síntese química , Relação Dose-Resposta a Droga , Espécies Reativas de Oxigênio/metabolismo , Compostos Ferrosos/farmacologia , Compostos Ferrosos/química , Compostos Ferrosos/síntese química , Potencial da Membrana Mitocondrial/efeitos dos fármacos
9.
RSC Med Chem ; 15(4): 1198-1209, 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38665835

RESUMO

Ferroptosis is a nonapoptotic, iron-catalyzed form of regulated cell death. It has been shown that high glucose (HG) could induce ferroptosis in vascular endothelial cells (VECs), consequently contributing to the development of various diseases. This study synthesized and evaluated a series of novel ferrostatin-1 (Fer-1) derivatives fused with a benzohydrazide moiety to prevent HG-induced VEC ferroptosis. Several promising compounds showed similar or improved inhibitory effects compared to positive control Fer-1. The most effective candidate 12 exhibited better protection against erastin-induced ferroptosis and high glucose-induced ferroptosis in VECs. Mechanistic studies revealed that compound 12 prevented mitochondrial damage, reduced intracellular ROS accumulation, upregulated the expression of GPX4, and decreased the amounts of ferrous ion, LPO and MDA in VECs. However, compound 12 still exhibited undesirable microsomal stability like Fer-1, suggesting the need for further optimization. Overall, the present findings highlight ferroptosis inhibitor 12 as a potential lead compound for treating ferroptosis-associated vascular diseases.

10.
Free Radic Biol Med ; 216: 106-117, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38461872

RESUMO

Oxidized low density lipoprotein (oxLDL)-induced endothelial oxidative damage promotes the development of atherosclerosis. Caveolae play an essential role in maintaining the survival and function of vascular endothelial cell (VEC). It is reported that the long coiled-coil protein NECC2 is localized in caveolae and is associated with neural cell differentiation and adipocyte formation, but its role in VECs needs to be clarified. Our results showed NECC2 expression increased in the endothelium of plaque-loaded aortas and oxLDL-treated HUVECs. Down-regulation of NECC2 by NECC2 siRNA or compound YF-307 significantly inhibited oxLDL-induced VEC apoptosis and the adhesion factors expression. Remarkably, inhibition of NECC2 expression in the endothelium of apoE-/- mice by adeno-associated virus (AAV)-carrying NECC2 shRNA or compound YF-307 alleviated endothelium injury and restricted atherosclerosis development. The immunoprecipitation results confirmed that NECC2 interacted with Tyk2 and caveolin-1(Cav-1) in VECs, and NECC2 further promoted the phosphorylation of Cav-1 at Tyr14 b y activating Tyk2 phosphorylation. On the other hand, inhibiting NECC2 levels suppressed oxLDL-induced phosphorylation of Cav-1, uptake of oxLDL by VECs, accumulation of intracellular reactive oxygen species and activation of NF-κB. Our findings suggest that NECC2 may contribute to oxLDL-induced VEC injury and atherosclerosis via modulating Cav-1 phosphorylation through Tyk2. This work provides a new concept and drug target for treating atherosclerosis.


Assuntos
Aterosclerose , Animais , Camundongos , Apolipoproteínas/efeitos adversos , Apolipoproteínas/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerose/metabolismo , Endotélio/metabolismo , Lipoproteínas LDL/metabolismo , Estresse Oxidativo
11.
Cell Biochem Funct ; 42(2): e3985, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38509716

RESUMO

Autophagy is a process in which cells degrade intracellular substances and play a variety of roles in cells, such as maintaining intracellular homeostasis, preventing cell overgrowth, and removing pathogens. It is highly conserved during the evolution of eukaryotic cells. So far, the study of autophagy is still a hot topic in the field of cytology. Ferroptosis is an iron-dependent form of cell death, accompanied by the accumulation of reactive oxygen species and lipid peroxides. With the deepening of research, it has been found that ferroptosis, like autophagy, is involved in the occurrence and development of cardiovascular diseases. The relationship between autophagy and ferroptosis is complex, and the association between the two in cardiovascular disease remains to be clarified. This article reviews the mechanism of autophagy and ferroptosis and their correlation, and discusses the relationship between them in cardiovascular diseases, which is expected to provide new and important treatment strategies for cardiovascular diseases.


Assuntos
Doenças Cardiovasculares , Ferroptose , Humanos , Ferro/metabolismo , Morte Celular , Espécies Reativas de Oxigênio/metabolismo , Autofagia
12.
Cell Biochem Funct ; 42(2): e3955, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38379220

RESUMO

Heart diseases remain the primary cause of human mortality in the world. Although conventional therapeutic opportunities fail to halt or recover cardiac fibrosis, the promising clinical results and therapeutic efficacy of engineered chimeric antigen receptor (CAR) T cell therapy show several advancements. However, the current models of CAR-T cells need further improvement since the T cells are associated with the triggering of excessive inflammatory cytokines that directly affect cardiac functions. Thus, the current study highlights the critical function of heart immune cells in tissue fibrosis and repair. The study also confirms CAR-T cell as an emerging therapeutic for treating cardiac fibrosis, explores the current roadblocks to CAR-T cell therapy, and considers future outlooks for research development.


Assuntos
Receptores de Antígenos Quiméricos , Humanos , Receptores de Antígenos Quiméricos/uso terapêutico , Imunoterapia Adotiva/métodos , Linfócitos T
13.
bioRxiv ; 2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38328117

RESUMO

Neuroblastoma is a leading cause of death in childhood cancer cases. Unlike adult malignancies, which typically develop from aged cells through accumulated damage and mutagenesis, neuroblastoma originates from neural crest cells with disrupted differentiation. This distinct feature provides novel therapeutic opportunities beyond conventional cytotoxic methods. Previously, we reported that the mitochondrial uncoupler NEN (niclosamide ethanolamine) activated mitochondria respiration to reprogram the epigenome, promoting neuronal differentiation. In the current study, we further combine NEN with retinoic acid (RA) to promote neural differentiation both in vitro and in vivo. The treatment increased the expression of RA signaling and neuron differentiation-related genes, resulting in a global shift in the transcriptome towards a more favorable prognosis. Overall, these results suggest that the combination of a mitochondrial uncoupler and the differentiation agent RA is a promising therapeutic strategy for neuroblastoma.

14.
Mini Rev Med Chem ; 2024 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-38284727

RESUMO

Since ferroptosis was reported in 2012, its application prospects in various diseases have been widely considered, initially as a treatment direction for tumors. Recent studies have shown that ferroptosis is closely related to the occurrence and development of atherosclerosis. The primary mechanism is to affect the occurrence and development of atherosclerosis through intracellular iron homeostasis, ROS and lipid peroxide production and metabolism, and a variety of intracellular signaling pathways. Inhibition of ferroptosis is effective in inhibiting the development of atherosclerosis, and it can bring a new direction for treating atherosclerosis. In this review, we discuss the mechanism of ferroptosis and focus on the relationship between ferroptosis and atherosclerosis, summarize the different types of ferroptosis inhibitors that have been widely studied, and discuss some issues worthy of attention in the treatment of atherosclerosis by targeting ferroptosis.

15.
Cell Death Dis ; 15(1): 89, 2024 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-38272889

RESUMO

As a highly heterogeneous tumor, pancreatic ductal adenocarcinoma (PDAC) exhibits non-uniform responses to therapies across subtypes. Overcoming therapeutic resistance stemming from this heterogeneity remains a significant challenge. Here, we report that Vitamin D-resistant PDAC cells hijacked Vitamin D signaling to promote tumor progression, whereas epigenetic priming with glyceryl triacetate (GTA) and 5-Aza-2'-deoxycytidine (5-Aza) overcame Vitamin D resistance and shifted the transcriptomic phenotype of PDAC toward a Vitamin D-susceptible state. Increasing overall H3K27 acetylation with GTA and reducing overall DNA methylation with 5-Aza not only elevated the Vitamin D receptor (VDR) expression but also reprogrammed the Vitamin D-responsive genes. Consequently, Vitamin D inhibited cell viability and migration in the epigenetically primed PDAC cells by activating genes involved in apoptosis as well as genes involved in negative regulation of cell proliferation and migration, while the opposite effect of Vitamin D was observed in unprimed cells. Studies in genetically engineered mouse PDAC cells further validated the effects of epigenetic priming for enhancing the anti-tumor activity of Vitamin D. Using gain- and loss-of-function experiments, we further demonstrated that VDR expression was necessary but not sufficient for activating the favorable transcriptomic phenotype in respond to Vitamin D treatment in PDAC, highlighting that both the VDR and Vitamin D-responsive genes were prerequisites for Vitamin D response. These data reveal a previously undefined mechanism in which epigenetic state orchestrates the expression of both VDR and Vitamin D-responsive genes and determines the therapeutic response to Vitamin D in PDAC.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animais , Camundongos , Vitamina D/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Azacitidina/farmacologia , Epigênese Genética , Perfilação da Expressão Gênica , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica
16.
Chem Biodivers ; 21(2): e202301371, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38069597

RESUMO

In the present study, a novel derivative, IOP-LA, was prepared by hybridizing antioxidant lipoic acid (LA) and our recently reported antioxidative marine phidianidine B-inspired indole/1,2,4-oxadiazole derivative. Our results demonstrated that IOP-LA could protect vascular endothelial cells (VECs) from oxidized low-density lipoprotein (oxLDL)-induced oxidative stress by activating the Nrf2 pathway, inhibit the production of atherosclerotic plaque, and promote the stability of atherosclerotic plaque in apoE-/- mice. Moreover, the protective effect of IOP-LA was superior to LA at the same concentration. Mechanistic studies revealed that IOP-LA significantly inhibited the increase of reactive oxygen species (ROS) levels and the translocation of nuclear factor kappa-B (NF-κB) nuclear induced by oxLDL through the nuclear factor erythroid2-related factor 2 (Nrf2) pathway. In summary, the data demonstrate that IOP-LA, as a new antioxidant, protects VECs from oxLDL-induced oxidative stress by activating the Nrf2 pathway. It is worth noting that this study provides a promising lead compound for the prevention and treatment of atherosclerosis.


Assuntos
Aterosclerose , Placa Aterosclerótica , Ácido Tióctico , Animais , Camundongos , Ácido Tióctico/farmacologia , Ácido Tióctico/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Placa Aterosclerótica/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Células Endoteliais , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo
17.
Gerontology ; 70(1): 76-89, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37883929

RESUMO

INTRODUCTION: Recent research on the gut deepens people's understanding of the role of gut microbe-metabolites in longevity. However, most of the longevity population is female, and the gut microbe-metabolites associated with longevity in women remain unknown. Here, we hypothesize that the gut microbe-metabolite levels differed between the longevity women (LW, age ≥90) and the elderly women (EW, 60 < age <90). METHODS: We performed a cross-sectional study of 22 women in Guangxi longevity areas. 16S rRNA full-length sequencing, bioinformatic analysis, and nuclear magnetic resonance hydrogen spectra were determined to analyze the gut microbiota, microbial pathways, and fecal metabolites. We evaluated significant differences and relationships in gut microbe-metabolites and microbial pathways using the Mann-Whitney test and Spearman correlation, respectively. RESULTS: The EW experienced gut dysbiosis characterized by a higher Firmicutes/Bacteroidetes (F/B) value. The LW showed a higher abundance of Bacteroides and Alistipes, which might support health maintenance. Moreover, LW enriched alanine, aspartate, and glutamate metabolism, histidine metabolism, and pyruvate metabolism, leading to major changes in histidine, fumaric acid, acetate, valine, and aspartate. Interestingly, the most valuable metabolic pathway based on differential fecal metabolites confirmed the KEGG microbial pathway "alanine, aspartate, and glutamate metabolism" enriched in LW. Impressively, Bacteroides and Alistipes were positively correlated with alanine, aspartate, and glutamate metabolism, thus improving the level of aspartate, which could be a particular pathway related to longevity. CONCLUSION: The enriched gut genus and microbial pathways in LW showed a significant correlation, which might mediate the production of metabolites related to longevity.


Assuntos
Ácido Aspártico , Microbioma Gastrointestinal , Idoso , Humanos , Feminino , China , Estudos Transversais , Histidina , RNA Ribossômico 16S/genética , Alanina , Glutamatos
18.
ESC Heart Fail ; 11(1): 574-580, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37909849

RESUMO

Patients with multiple myeloma (MM) are likely to achieve poor therapeutic response when organs are involved. We produced anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cells, which are in a trial for patients with relapsed/refractory MM. One enrolled patient developed severe heart failure, highly suspected as light chain cardiac amyloidosis. He exhibited increased N-terminal pro-brain natriuretic peptide with a peak of 32 299 ng/mL and heart failure with an ejection fraction of 30%. Anti-BCMA CAR-T cells were administered following lymphodepletion. The patient achieved cardiac response within 1 week with a decrease in N-terminal pro-brain natriuretic peptide by 80%, an increase in ejection fraction from 30% to 56%, and a haematological response with negative minimal residual disease at 1 month and a complete response at 1 year. To date, this patient has maintained good health without heart failure or haematological relapse. Herein, we show the efficacy of anti-BCMA CAR-T cells in patients with MM and severe heart failure.


Assuntos
Insuficiência Cardíaca , Mieloma Múltiplo , Receptores de Antígenos Quiméricos , Masculino , Humanos , Mieloma Múltiplo/terapia , Mieloma Múltiplo/tratamento farmacológico , Receptores de Antígenos Quiméricos/uso terapêutico , Antígeno de Maturação de Linfócitos B/uso terapêutico , Peptídeo Natriurético Encefálico , Recidiva Local de Neoplasia/tratamento farmacológico , Insuficiência Cardíaca/terapia , Insuficiência Cardíaca/tratamento farmacológico
19.
Oncol Lett ; 26(5): 468, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37780546

RESUMO

[This retracts the article DOI: 10.3892/ol.2019.11002.].

20.
J Chromatogr A ; 1710: 464417, 2023 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-37778098

RESUMO

Liquid chromatography-tandem with high-resolution mass spectrometry (LCHRMS) has proven challenging for annotating multiple small molecules within complex matrices due to the complexities of chemical structure and raw LCHRMS data, as well as limitations in previous literatures and reference spectra related to those molecules. In this study, we developed a molecular networking assisted automatic database screening (MN/auto-DBS) strategy to examine the combined effect of MS1 exact mass screening and MS2 similarity analysis. We compiled all previously reported compounds from the relevant literatures. With the development of a Python software, the in-house database (DB) was created by automatically calculating the m/z and data from experimental MS1 hits were rapid screened with DB. We then performed a feature-based molecular network analysis on the auto-MS2 data for supplementary identification of unreported compounds, including clustered FBMN and annotated GNPS compounds. Finally, the results from both strategies were merged and manually curated for correct structural assignment. To demonstrate the applicability of MN/auto-DBS, we selected the Huangqi-Danshen herb pair (HD), commonly used in prescriptions or patent medicines to treat diabetic nephropathy and cerebrovascular disease. A total of 223 compounds were annotated, including 65 molecules not previously reported in HD, such as aromatic polyketides, coumarins, and diarylheptanoids. Using MN/auto-DBS, we can profile and mine a wide range of complex matrices for potentially new compounds.


Assuntos
Software , Espectrometria de Massas em Tandem , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida , Bases de Dados de Compostos Químicos , Bases de Dados Factuais , Cromatografia Líquida de Alta Pressão/métodos
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