RESUMEN
BACKGROUND: Recurrent spontaneous miscarriage (RSM) is one of the complications during pregnancy. However, the pathogenesis of RSM is far from fully elucidated. OBJECTIVE: Since the endocytic pathway is crucial for cellular homeostasis, our study aimed to explore the roles of endocytic recycling, especially EH domain containing 1 (EHD1), a member of the endocytic recycling compartment, in RSM. STUDY DESIGN: We first investigated the expression of the endocytic pathway member EHD1 in villi from the normal and RSM groups. Then, we performed RNA sequencing and experiments in villi, HTR8 cells and BeWo cells to determine the mechanisms by which EHD1 induced RSM. Finally, placenta-specific EHD1-overexpressing mice were generated to investigate the RSM phenotype in vivo. RESULTS: EHD1 was expressed in extravillous trophoblasts (EVTs) and syncytiotrophoblast (STB) in the villi. Compared with the control group, RSM patients expressed higher EHD1. A high level of EHD1 decreased proliferation, promoted apoptosis, and reduced the migration and invasion of HTR8 cells by activating the TGFBR1-SMAD2/3 signaling pathway. The TGFBR1 antagonist LY3200882 partially reversed the EHD1 overexpression-induced changes in the cell phenotype. Besides, a high level of EHD1 also induced abnormal syncytialization, which disturbed maternal-fetal material exchanges. In a mouse model, placenta-specific overexpression of EHD1 led to the failure of spiral artery remodeling, excessive syncytialization and miscarriage. CONCLUSIONS: Increased expression of EHD1 impaired the invasion of EVTs mediated by the TGFBR1-SMAD2/3 signaling pathway and induced abnormal syncytialization of STB, which is at least partially responsible for RSM.
RESUMEN
Gout is a chronic metabolic and immune disease, and its specific pathogenesis is still unclear. When the serum uric acid exceeds its saturation in the blood or tissue fluid, it is converted to monosodium urate crystals, which lead to acute arthritis of varying degrees, urinary stones, or irreversible peripheral joint damage, and in severe cases, impairment of vital organ function. Gout flare is a clinically significant state of acute inflammation in gout. The current treatment is mostly anti-inflammatory analgesics, which have numerous side effects with limited treatment methods. Gout pathogenesis involves many aspects. Therefore, exploring gout pathogenesis from multiple perspectives is conducive to identifying more therapeutic targets and providing safer and more effective alternative treatment options for patients with gout flare. Thus, this article is of great significance for further exploring the pathogenesis of gout. The author summarizes the pathogenesis of gout from four aspects: signaling pathways, inflammatory factors, intestinal flora, and programmed cell death, focusing on exploring more new therapeutic targets.
Asunto(s)
Microbioma Gastrointestinal , Supresores de la Gota , Gota , Transducción de Señal , Ácido Úrico , Humanos , Gota/tratamiento farmacológico , Ácido Úrico/sangre , Ácido Úrico/metabolismo , Microbioma Gastrointestinal/efectos de los fármacos , Supresores de la Gota/uso terapéutico , Mediadores de Inflamación/metabolismo , Animales , Antiinflamatorios/uso terapéuticoRESUMEN
The microbial degradation of polyethylene (PE) and polypropylene (PP) resins in rivers and lakes has emerged as a crucial issue in the management of microplastics. This study revealed that as the flow rate decreased longitudinally, ammonia nitrogen (NH4+-N), heavy fraction of organic carbon (HFOC), and small-size microplastics (< 1 mm) gradually accumulated in the deep and downstream estuarine sediments. Based on their surface morphology and carbonyl index, these sediments were identified as the potential hot zone for PE/PP degradation. Within the identified hot zone, concentrations of PE/PP-degrading genes, enzymes, and bacteria were significantly elevated compared to other zones, exhibiting strong intercorrelations. Analysis of niche differences revealed that the accumulation of NH4+-N and HFOC in the hot zone facilitated the synergistic coexistence of key bacteria responsible for PE/PP degradation within biofilms. The findings of this study offer a novel insight and comprehensive understanding of the distribution characteristics and synergistic degradation potential of PE/PP in natural freshwater environments.
Asunto(s)
Bacterias , Biodegradación Ambiental , Sedimentos Geológicos , Polietileno , Polipropilenos , Contaminantes Químicos del Agua , Polipropilenos/química , Polietileno/química , Polietileno/metabolismo , Contaminantes Químicos del Agua/metabolismo , Contaminantes Químicos del Agua/química , Sedimentos Geológicos/microbiología , Sedimentos Geológicos/química , Bacterias/metabolismo , Bacterias/genética , Microplásticos/toxicidad , Microplásticos/metabolismo , Agua Dulce/microbiología , EstuariosRESUMEN
Gouty nephropathy (GN) is a metabolic disease with persistently elevated blood uric acid levels. The main manifestations of GN are crystalline kidney stones, chronic interstitial nephritis, and renal fibrosis. Understanding the mechanism of the occurrence and development of GN is crucial to the development of new drugs for prevention and treatment of GN. Currently, most studies exploring the pathogenesis of GN are primarily based on animal and cell models. Numerous studies have shown that inflammation, oxidative stress, and programmed cell death mediated by uric acid and sodium urate are involved in the pathogenesis of GN. In this article, we first review the mechanisms underlying the abnormal intrinsic immune activation and programmed cell death in GN and then describe the characteristics and methods used to develop animal and cell models of GN caused by elevated uric acid and deposited sodium urate crystals. Finally, we propose potential animal models for GN caused by abnormally high uric acid levels, thereby provide a reference for further investigating the methods and mechanisms of GN and developing better prevention and treatment strategies.
RESUMEN
Observational investigations recommend that mineral supplements were associated with a higher risk of polycystic ovary syndrome (PCOS) and its risk factors (insulin resistance, hyperandrogenism, and obesity), but the relationship with risk of PCOS, hyperandrogenism, obesity, and insulin resistance was unclear. This study was to investigate the potential causal impact of genetically predicted levels of magnesium (Mg), calcium (Ca), selenium (Se), zinc (Zn), iron (Fe), and omega-3 (ω-3) on polycystic ovary syndrome (PCOS) and its associated risk factors. A two-sample Mendelian randomization (MR) analysis was conducted. The genetic variations obtained from GWAS of individuals with European ancestry were found to be associated with the genetically predicted levels of Ca, Mg, Zn, Se, Fe, or ω-3. The data obtained from the FinnGen Consortium and MAGIC were utilized for the outcome of GWAS. The study found that there was a correlation between genetically predicted higher levels of Se and a reduced risk of insulin resistance, with a decrease of 2.2% according to random-effect IVW (OR 0.978, 95% CI 0.960-0.996, p = 0.015). The association between genetically determined mineral levels and PCOS was found to be limited, with an odds ratio (OR) ranging from 0.875 (95% CI: 0.637-1.202, p value = 0.411) for Ca. Limited scientific proof was found for the efficacy of other genetically determined mineral levels on hyperandrogenism, obesity, and insulin resistance. These findings suggested a causal relationship between genetically predicted higher levels of Se and a reduced risk of insulin resistance. Nonetheless, there is limited evidence supporting a causal association between various genetically determined mineral levels and the risk factors associated with PCOS.
Asunto(s)
Estudio de Asociación del Genoma Completo , Resistencia a la Insulina , Análisis de la Aleatorización Mendeliana , Minerales , Síndrome del Ovario Poliquístico , Síndrome del Ovario Poliquístico/genética , Síndrome del Ovario Poliquístico/epidemiología , Síndrome del Ovario Poliquístico/sangre , Humanos , Femenino , Minerales/metabolismo , Resistencia a la Insulina/genética , Factores de Riesgo , Polimorfismo de Nucleótido Simple , Obesidad/genética , Obesidad/epidemiologíaRESUMEN
OBJECTIVE: This meta-analysis was designed to provide new insights into the relationship between Helicobacter pylori (H. pylori) infection and recurrent aphthous stomatitis (RAS). MATERIALS AND METHODS: We included and evaluated studies on H. pylori infection and RAS from PubMed, EMBASE, Cochrane Library, and Web of Science databases published up to January 31, 2023. The characteristics of these studies were collected, and the quality was evaluated by Newcastle-Ottawa Scale (NOS). The random effects model was used to calculate the pooled odds ratio (OR) and 95% confidence interval (CI). To further explore the sources of heterogeneity, meta-regression analysis and subgroup analyses were performed. Funnel plot, Egger's test, and Begg's test were used to assess publication bias. RESULTS: In total, fifteen case-control studies with 1137 individuals (601 cases and 536 controls) were included. The H. pylori was found to be significantly associated with RAS (OR: 1.83 95% CI: 1.41-2.37, P = 0.001). In the subgroup analyses, studies that used PCR (OR: 2.03 95% CI: 1.31-3.15) or UBT (OR: 1.83 95% CI: 1.13-2.96) yielded a significant positive association, while a non-significant association (OR: 1.12 95% CI: 0.61-2.08) was found from studies that used ELISA method. Sensitivity analyses showed that the results were robust. No significant publication bias was found. CONCLUSIONS: The current evidence does not rule out an association between H. pylori and RAS. The effect of H. pylori on RAS varies in detection methods and sources of sample. Large samples, multiple clinical studies, and improved methods are still needed to determine the exact effect of H. pylori on RAS. CLINICAL SIGNIFICANCE: H. pylori infection may be a risk factor for the pathogenesis of RAS.
Asunto(s)
Infecciones por Helicobacter , Helicobacter pylori , Estomatitis Aftosa , Humanos , Estomatitis Aftosa/complicaciones , Factores de RiesgoRESUMEN
The imbalance of bone homeostasis has become a major public medical problem amid the background of an aging population, which is closely related to the occurrence of osteoporosis, osteoarthritis, and fractures. Presently, most drugs used in the clinical treatment of bone homeostasis imbalance are bisphosphonates, calcitonin, estrogen receptor modulators, and biological agents that inhibit bone resorption or parathyroid hormone analogs that promote bone formation. However, there are many adverse reactions. Therefore, it is necessary to explore potential drugs. Quercetin, as a flavonol compound with various biological activities, is widely distributed in plants. Studies have found that quercetin can regulate bone homeostasis through multiple pathways and targets. An in-depth exploration of the pharmacological mechanism of quercetin is of great significance for the development of new drugs. This review discusses the therapeutic mechanisms of quercetin on bone homeostasis, such as regulating the expression of long non-coding RNA, signaling pathways of bone metabolism, various types of programmed cell death, bone nutrients supply pathways, anti-oxidative stress, anti-inflammation, and activation of Sirtuins. We also summarize recent progress in improving quercetin bioavailability and propose some issues worth paying attention to, which may help guide future research efforts.
Asunto(s)
Conservadores de la Densidad Ósea , Osteoporosis , Humanos , Anciano , Quercetina/farmacología , Quercetina/uso terapéutico , Osteoporosis/metabolismo , Conservadores de la Densidad Ósea/farmacología , Conservadores de la Densidad Ósea/uso terapéutico , Difosfonatos/efectos adversos , HomeostasisRESUMEN
BACKGROUND: Many epidemiologic investigations have explored the relationship between viatmins and polycystic ovary syndrome (PCOS). However, the effectiveness of vitamin, vitamin-like nutrient, or mineral supplementation in reducing the risk of PCOS remains a subject of debate. AIM: To investigate the impact of plasma levels of vitamins A, B12, D, E, and K on PCOS and key pathways implicated in its development, namely, insulin resistance, hyperlipidemia, and obesity, through Mendelian randomization (MR) analysis. METHODS: Single nucleotide polymorphisms associated with vitamin levels were selected from genome-wide association studies. The primary analysis was performed using the random-effects inverse-variance-weighted approach. Complementary analyses were conducted using the weighted median, MR-Egger, MR-robust adjusted profile score, and MR-PRESSO approaches. RESULTS: The results provided suggestive evidence of a decreased risk of PCOS with genetically predicted higher levels of vitamin E (odds ratio [OR] = 0.118; 95% confidence interval [CI]: 0.071-0.226; P < 0.001) and vitamin B12 (OR = 0.753, 95%CI: 0.568-0.998, P = 0.048). An association was observed between vitamin E levels and insulin resistance (OR = 0.977, 95%CI: 0.976-0.978, P < 0.001). Additionally, genetically predicted higher concentrations of vitamins E, D, and A were suggested to be associated with a decreased risk of hyperlipidemia. Increased vitamins K and B12 levels were linked to a lower obesity risk (OR = 0.917, 95%CI: 0.848-0.992, P = 0.031). CONCLUSION: The findings of this MR study suggest a causal relationship between increased vitamins A, D, E, K, and B12 levels and a reduced risk of PCOS or primary pathways implicated in its development.
RESUMEN
A rapid and sensitive strategy was proposed for the detection of fluoranthene (FL), which is a polycyclic aromatic hydrocarbon (PAH), in water samples. In this work, syringe solid-phase extraction (SPE) combined with solid-phase fluorescence spectrometry was used to determine FL in PAHs polluted environmental samples. The fluorescence signals were directly monitored on the membrane surface after FL was enriched by syringe SPE. Under the optimal conditions, the proposed method showed a linear relationship in the concentration range 2-50 µg/L with a correlation coefficient (R2 ) of 0.998, and the limit of detection was 0.143 µg/L. The recoveries varied from 93.47% to 109.81% in the actual samples, with the relative standard deviations (n = 3) ranging from 2.06% to 6.32%. According to the results, the established method can be applied in the field of rapid detection as it is fast, simple, portable, and highly sensitive, and has strong anti-interference.
Asunto(s)
Hidrocarburos Policíclicos Aromáticos , Contaminantes Químicos del Agua , Jeringas , Contaminantes Químicos del Agua/análisis , Extracción en Fase Sólida/métodos , Fluorenos , Hidrocarburos Policíclicos Aromáticos/análisisRESUMEN
Proper estimation of the cup-to-disc ratio (C/D ratio) plays a significant role in ophthalmic examinations, and it is urgent to improve the efficiency of C/D ratio automatic measurement. Therefore, we propose a new method for measuring the C/D ratio of OCTs in normal subjects. Firstly, the end-to-end deep convolution network is used to segment and detect the inner limiting membrane (ILM) and the two Bruch's membrane opening (BMO) terminations. Then, we introduce an ellipse fitting technique to post-process the edge of the optic disc. Finally, the proposed method is evaluated on 41 normal subjects using the optic-disc-area scanning mode of three machines: BV1000, Topcon 3D OCT-1, and Nidek ARK-1. In addition, pairwise correlation analyses are carried out to compare the C/D ratio measurement method of BV1000 to existing commercial OCT machines as well as other state-of-the-art methods. The correlation coefficient between the C/D ratio calculated by BV1000 and the C/D ratio calculated by manual annotation is 0.84, which indicates that the proposed method has a strong correlation with the results of manual annotation by ophthalmologists. Moreover, in comparison between BV1000, Topcon and Nidek in practical screening among normal subjects, the proportion of the C/D ratio less than 0.6 calculated by BV1000 accounts for 96.34%, which is the closest to the clinical statistics among the three OCT machines. The above experimental results and analysis show that the proposed method performs well in cup and disc detection and C/D ratio measurement, and compared with the existing commercial OCT equipment, the C/D ratio measurement results are relatively close to reality, which has certain clinical application value.
Asunto(s)
Disco Óptico , Tomografía de Coherencia Óptica , Humanos , Tomografía de Coherencia Óptica/métodos , Lámina Basal de la CoroidesRESUMEN
Background: A major contributor to older disability is osteoarthritis. Radix Angelicae Biseratae (known as Duhuo in China, DH, the dried rhizome of Angelica pubescens) and Dipsaci Radix (known as Xuduan in China, XD, the dried rhizome of Dipsacus asper Wall) herb pair (DXHP) is widely used to treat osteoarthritis, but the underlying molecular mechanisms still have not been revealed. This research aimed to illustrate the therapeutic mechanism of DXHP against osteoarthritis through the techniques of network pharmacology and molecular docking. Methods: Gene targets for osteoarthritis and active ingredients for DXHP were screened based on the pharmacology public database and the gene-disease target database. The software program Cytoscape was used to visualize the active chemical target-disease gene network. The STRING biological information website was used to investigate protein interactions. On the Metascape bioinformatics website, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were carried out. The molecular docking of the important chemicals and primary targets identified by the aforementioned screening was performed using Autodock software. Results: Twenty-six active substances from the DXHP that had strong connections to 138 osteoarthritis-related targets were screened out. According to network analysis, TNF, GAPDH, IL-6, AKT-1, IL-1B, and VEGFA are prospective therapeutic targets, while osthole, cauloside A, ammidin, angelicone, beta-sitosterol, and asperosaponin VI may be significant active components. 1705 biological processes (BP), 155 molecular functions (MF), and 89 cellular components (CC) were identified by GO analysis. KEGG analysis indicated that IL-17, NF-kappa B, HIF-1, MAPK, and AGE-RAGE signaling pathways are potentially involved. Molecular docking showed that cauloside A, osthole, and ß-sitosterol have excellent binding activity with main targets. Conclusions: This study comprehensively illuminated the active ingredients, potential targets, primary pharmacological effects, and relevant mechanisms of the DXHP in the treatment of OA. These findings provide fresh thoughts into the therapeutic mechanisms of the main active ingredients of DXHP and provide a reference for further exploration and clinical applications of DXHP.
RESUMEN
Objective: To observe the clinical efficacy and safety of Yiqi Yangxue formula (YQYXF) on knee osteoarthritis (KOA), and to explore the underlying therapeutic mechanism of YQYXF through endogenous differential metabolites and their related metabolic pathways. Methods: A total of 61 KOA patients were recruited and divided into the treatment group (YQYXF, 30 cases) and the control group (celecoxib, Cxb, 31 cases). Effects of these two drugs on joint pain, swelling, erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP) were observed, and their safety and adverse reactions were investigated. In animal experiments, 63 SD rats were randomly divided into normal control (NC) group, sham operation (sham) group, model (KOA) group, Cxb group, as well as low-dose (YL), medium-dose (YM), and high-dose groups of YQYXF (YH). The KOA rat model was established using a modified Hulth method. Ultra-high-performance liquid chromatography/Q Exactive HF-X Hybrid Quadrupole-Orbitrap Mass (UHPLC-QE-MS)-based metabolomics technology was used to analyze the changes of metabolites in plasma samples of rats. Comprehensive (VIP) >1 and t-test p < 0.05 conditions were used to screen the disease biomarkers of KOA, and the underlying mechanisms of YQYXF were explored through metabolic pathway enrichment analysis. The related markers of YQYXF were further verified by ELISA (enzyme-linked immunosorbent assay). Results: YQYXF can improve joint pain, swelling, range of motion, joint function, Michel Lequesen index of severity for osteoarthritis (ISOA) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, ESR, and CRP. No apparent adverse reactions were reported. In addition, YQYXF can improve cartilage damage in KOA rats, reverse the abnormal changes of 16 different metabolites, and exert an anti-KOA effect mainly through five metabolic pathways. The levels of reactive oxygen species (ROS) and glutathione (GSH) were significantly decreased after the treatment of YQYXF. Conclusion: YQYXF can significantly improve the clinical symptoms of KOA patients without obvious adverse reactions. It mainly improved KOA through modulating lipid metabolism-related biomarkers, reducing lipid peroxidation and oxidative stress.
RESUMEN
As natural functional bioactive ingredients found in foods and plants, polyphenols play various antioxidant and anti-inflammatory roles to prevent the development of disease and restore human health. The multi-target modulation of polyphenols provides a novel practical therapeutic strategy for neurodegenerative diseases that are difficult to treat with traditional drugs like glutathione and cholinesterase inhibitors. This review mainly focuses on the efficacy of polyphenols on ischemic stroke, Parkinson's disease and Alzheimer's disease, including in vivo and in vitro experimental studies. It is further emphasized that polyphenols exert neuroprotective effects primarily through inhibiting production of oxidative stress and inflammatory cytokines, which may be the underlying mechanism. However, polyphenols are still rarely used as medicines to treat neurodegenerative diseases. Due to the lack of clinical trials, the mechanism of polyphenols is still in the stage of insufficient exploration. Future large-scale multi-center randomized controlled trials and in-depth mechanism studies are still needed to fully assess the safety, efficacy and side effects of polyphenols.
RESUMEN
BACKGROUND: Choroid neovascularization (CNV) has no obvious symptoms in the early stage, but with its gradual expansion, leakage, rupture, and bleeding, it can cause vision loss and central scotoma. In some severe cases, it will lead to permanent visual impairment. PURPOSE: Accurate prediction of disease progression can greatly help ophthalmologists to formulate appropriate treatment plans and prevent further deterioration of the disease. Therefore, we aim to predict the growth trend of CNV to help the attending physician judge the effectiveness of treatment. METHODS: In this paper, we develop a CNN-based method for CNV growth prediction. To achieve this, we first design a registration network to rigidly register the spectral domain optical coherence tomography (SD-OCT) B-scans of each subject at different time points to eliminate retinal displacements of longitudinal data. Then, considering the correlation of longitudinal data, we propose a co-segmentation network with a correlation attention guidance (CAG) module to cooperatively segment CNV lesions of a group of follow-up images and use them as input for growth prediction. Finally, based on the above registration and segmentation networks, an encoder-recurrent-decoder framework is developed for CNV growth prediction, in which an attention-based gated recurrent unit (AGRU) is embedded as the recurrent neural network to recurrently learn robust representations. RESULTS: The registration network rigidly registers the follow-up images of patients to the reference images with a root mean square error (RMSE) of 6.754 pixels. And compared with other state-of-the-art segmentation methods, the proposed segmentation network achieves high performance with the Dice similarity coefficients (Dsc) of 85.27%. Based on the above experiments, the proposed growth prediction network can play a role in predicting the future CNV morphology, and the predicted CNV has a Dsc of 83.69% with the ground truth, which is significantly consistent with the actual follow-up visit. CONCLUSION: The proposed registration and segmentation networks provide the possibility for growth prediction. In addition, accurately predicting the growth of CNV enables us to know the efficacy of the drug against individuals in advance, creating opportunities for formulating appropriate treatment plans.
Asunto(s)
Coroides , Neovascularización Coroidal , Humanos , Coroides/patología , Tomografía de Coherencia Óptica/métodos , Neovascularización Coroidal/diagnóstico por imagen , Neovascularización Coroidal/tratamiento farmacológico , Retina/patología , Progresión de la EnfermedadRESUMEN
Carbon chain microplastics, polyethylene (PE), and polypropylene (PP) are the main types of refractory organics. Compared to heterochain microplastics, PE/PP degrading bacterial community and their distribution characteristics in natural rivers are unclear. In this study, the field in situ experiment and indoor enrichment experiment with PE/PP resin as only carbon sources were conducted for a total period of 1150 days. The microbial degradation of pure PE/PP resin was determined by SEM, FTIR, CLSM, GC-MS, and GPC. The Chao 1 index and Invsimpson index of the bacterial community significantly reduced after a series of incubation, demonstrating that the bacterial community was selectively enriched. Empirical core PE/PP degrading bacteria (C-bacteria) and resuscitated PE/PP degrading bacteria (R-bacteria) were screened based on the variation of the abundance of OTUs, and co-occurrence analysis displayed that C-bacteria presented higher betweenness centrality than R-bacteria. The higher abundance and diversity of R-bacteria in biofilms suggest the presence of many rare or low abundance bacteria in natural rivers that may be potential PE/PP degrading bacteria or PE/PP degrading bacteria to be activated, while the lower abundance and diversity of C-bacteria support the slow degradation rate of PE and PP in waters. Compared to the isolated and indicatory PE/PP degrading bacterial genera, the C-bacteria OTUs or genera enriched in this study displayed higher richness and abundance. Enriched PE/PP degrading bacteria occurred in all sampled sites of the Qinhuai River with higher abundance and standard betweenness centrality in sediments (averaging 0.01354 and 0.44421, respectively) than those in overlying water (averaging 0.00536 and 0.17571, respectively), while the highest abundance of degrading bacteria presented in the eutrophic sediments. Inorganic nitrogen was determined to be significantly correlated with the distribution of PE/PP degrading bacteria in sediments via redundancy analysis. This study provides a new perspective on the natural degradation potential of carbon chain microplastics by microbial communities in rivers.
Asunto(s)
Microplásticos , Contaminantes Químicos del Agua , Polipropilenos , Plásticos , Polietileno , Ríos , Sedimentos Geológicos/microbiología , Contaminantes Químicos del Agua/análisis , Bacterias , Monitoreo del AmbienteRESUMEN
KRAS is widely mutated in human cancers, resulting in unchecked tumor proliferation and metastasis, which makes identifying KRAS-targeting therapies a priority. Herein, we observe that mutant KRAS specifically promotes the formation of the ERK2-p53 complex in stomach/colorectal tumor cells. Disruption of this complex by applying MEK1/2 and ERK2 inhibitors elicits strong apoptotic responses in a p53-dependent manner, validated by genome-wide knockout screening. Mechanistically, p53 physically associates with phosphorylated ERK2 through a hydrophobic interaction in the presence of mutant KRAS, which suppresses p53 activation by preventing the recruitment of p300/CBP; trametinib disrupts the ERK2-p53 complex by reducing ERK2 phosphorylation, allowing the acetylation of p53 protein by recruiting p300/CBP; acetylated p53 activates PUMA transcription and thereby kills KRAS-mutant tumors. Our study shows an important role for the ERK2-p53 complex and provides a potential therapeutic strategy for treating KRAS-mutant cancer.
Asunto(s)
Neoplasias Colorrectales , Proteínas Proto-Oncogénicas p21(ras) , Humanos , Fosforilación , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , EstómagoRESUMEN
Autophagy is an intracellular degradation system that maintains the stable state of cell energy metabolism. Some recent findings have indicated that autophagy dysfunction is an important driving factor for the occurrence and development of osteoarthritis (OA). The decrease of autophagy leads to the accumulation of damaged organelles and macromolecules in chondrocytes, which affects the survival of chondrocytes and ultimately leads to OA. An appropriate level of autophagic activation may be a new method to prevent articular cartilage degeneration in OA. This minireview discussed the mechanism of autophagy and OA, key autophagy targets regulating OA progression, and evaluated therapeutic applications of drugs targeting autophagy in preclinical and clinical research. Some critical issues worth paying attention to were also raised to guide future research efforts.