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1.
Pain Ther ; 2024 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-39126594

RESUMEN

Postherpetic neuralgia (PHN) manifests as persistent chronic pain that emerges after a herpes zoster outbreak and greatly diminishes quality of life. Unfortunately, its treatment efficacy has remained elusive, with many therapeutic efforts yielding less than satisfactory results. The research to discern risk factors predicting the onset, trajectory, and prognosis of PHN has been extensive. However, these risk factors often present as nonspecific and diverse, indicating the need for more reliable, measurable, and objective detection methods. The exploration of potential biological markers, including hematological indices, pathological insights, and supportive tests, is increasing. This review highlights potential biomarkers that are instrumental for the diagnosis, management, and prognosis of PHN while also delving deeper into its genesis. Drawing from prior research, aspects such as immune responsiveness, neuronal injury, genetic makeup, cellular metabolism, and pain signal modulation have emerged as prospective biomarkers. The immune spectrum spans various cell subtypes, with an emphasis on T cells, interferons, interleukins, and other related cytokines. Studies on nerve injury are directed toward pain-related proteins and the density and health of epidermal nerve fibers. On the genetic and metabolic fronts, the focus lies in the detection of predisposition genes, atypical protein manifestations, and energy-processing dynamics, with a keen interest in vitamin metabolism. Tools such as functional magnetic resonance imaging, electromyography, and infrared imaging have come to the forefront in the pain signaling domain. This review compiles the evidence, potential clinical implications, and challenges associated with these promising biomarkers, paving the way for innovative strategies for predicting, diagnosing, and addressing PHN.

2.
J Environ Manage ; 368: 122219, 2024 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-39153322

RESUMEN

This study, aimed at exploring low-maintenance, high-diversity, and sustainable greening strategies for residential areas, conducted a comprehensive survey and analysis of spontaneous plants in residential green spaces in Fuzhou City, documenting 361 species. Employing methods such as variance partitioning, Canonical Correspondence Analysis (CCA), and ecological niche analysis, we investigated the environmental factors influencing the distribution and composition of these plants, as well as their interrelationships. The study found that the composition of spontaneous plants in residential green spaces differs from other urban environments, with a high proportion of alien species (43.77%) due to influences such as resident activities, including a large number of ornamental and edible plants. Maintenance level, urbanization gradient, and green space ratio are common factors affecting the composition and distribution of spontaneous plants in urban environments, while unique residential socio-economic factors like building age, housing prices, and population density significantly affect the spontaneous plants in residential green spaces. The overall dominant plant community shows a significant positive association, indicating a relatively stable stage of succession. Although competition among most species is not significant and interspecific connectivity is weak, the presence of seven dominant invasive species intensifies competition. Based on these findings, the study proposes several specific sustainable management measures: adopting the concept of New Naturalistic Ecological Planting Design, selecting native spontaneous plants with strong adaptability, and constructing plant communities that are ecologically stable and have ornamental value by mimicking natural ecosystems. Additionally, specific methods for managing specific invasive species in residential green spaces using competitive replacement control methods are proposed. These measures aim to promote the health and sustainable development of urban residential green spaces.

3.
Cardiovasc Diabetol ; 23(1): 215, 2024 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-38907337

RESUMEN

BACKGROUND: Circulating atherogenic index of plasma (AIP) levels has been proposed as a novel biomarker for dyslipidemia and as a predictor of insulin resistance (IR) risk. However, the association between AIP and the incidence of new-onset stroke, particularly in individuals with varying glucose metabolism status, remains ambiguous. METHODS: A total of 8727 participants aged 45 years or older without a history of stroke from the China Health and Retirement Longitudinal Study (CHARLS) were included in this study. The AIP was calculated using the formula log [Triglyceride (mg/dL) / High-density lipoprotein cholesterol (mg/dL)]. Participants were divided into four groups based on their baseline AIP levels: Q1 (AIP ≤ 0.122), Q2 (0.122 < AIP ≤ 0.329), Q3 (0.329 < AIP ≤ 0.562), and Q4 (AIP > 0.562). The primary endpoint was the occurrence of new-onset stroke events. The Kaplan-Meier curves, multivariate Cox proportional hazard models, and Restricted cubic spline analysis were applied to explore the association between baseline AIP levels and the risk of developing a stroke among individuals with varying glycemic metabolic states. RESULTS: During an average follow-up of 8.72 years, 734 participants (8.4%) had a first stroke event. The risk for stroke increased with each increasing quartile of baseline AIP levels. Kaplan-Meier curve analysis revealed a significant difference in stroke occurrence among the AIP groups in all participants, as well as in those with prediabetes mellitus (Pre-DM) and diabetes mellitus (DM) (all P values < 0.05). After adjusting for potential confounders, the risk of stroke was significantly higher in the Q2, Q3, and Q4 groups than in the Q1 group in all participants. The respective hazard ratios (95% confidence interval) for stroke in the Q2, Q3, and Q4 groups were 1.34 (1.05-1.71), 1.52 (1.19-1.93), and 1.84 (1.45-2.34). Furthermore, high levels of AIP were found to be linked to an increased risk of stroke in both pre-diabetic and diabetic participants across all three Cox models. However, this association was not observed in participants with normal glucose regulation (NGR) (p > 0.05). Restricted cubic spline analysis also demonstrated that higher baseline AIP levels were associated with higher hazard ratios for stroke in all participants and those with glucose metabolism disorders. CONCLUSIONS: An increase in baseline AIP levels was significantly associated with the risk of stroke in middle-aged and elderly individuals, and exhibited distinct characteristics depending on the individual's glucose metabolism status.


Asunto(s)
Biomarcadores , Glucemia , Accidente Cerebrovascular , Humanos , Masculino , Femenino , Persona de Mediana Edad , Factores de Riesgo , Anciano , Glucemia/metabolismo , Biomarcadores/sangre , China/epidemiología , Medición de Riesgo , Incidencia , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/diagnóstico , Factores de Tiempo , Estudios Longitudinales , Pronóstico , Resistencia a la Insulina , Triglicéridos/sangre , HDL-Colesterol/sangre , Dislipidemias/sangre , Dislipidemias/epidemiología , Dislipidemias/diagnóstico , Aterosclerosis/sangre , Aterosclerosis/epidemiología , Aterosclerosis/diagnóstico , Estudios Prospectivos
4.
Int Immunopharmacol ; 129: 111648, 2024 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-38335656

RESUMEN

AIMS: To study the role of Aucubin (AU) in cerebral ischemia-reperfusion injury and investigate the potential mechanisms. METHODS: For the in vitro experiment, primary microglia were cultured and stimulated by Lipopolysaccharides (LPS) and treated with AU. Male C57/BL6J mice were used and middle cerebral artery occlusion (MCAO) model was performed to induce cerebral ischemia-reperfusion injury. For the short-term effects, mice administrated with AU (40 mg/kg) for 3 days after MCAO were evaluated for the infarct volume and neurological deficits. The neuroinflammatory factors and microglia activation were determined by Real-time PCR, western blot and immunofluorescence staining. For the long-term effects, MCAO mice were injected daily with AU (5 mg/kg or 10 mg/kg) for 28 days. Behavior tests were used to assess the neurological deficits of MCAO mice, and white matter integrity was determined by myelin basic protein (MBP) staining and black-gold staining. RESULTS: AU suppressed LPS-induced activation of microglia and pro-inflammatory cytokines release, and downregulated the NF-κB and MAPK pathways in primary microglia. In addition, AU attenuated ischemic injury and inhibited the neuro-inflammatory response in MCAO mice. Moreover, AU induced prolonged improvements in sensorimotor function and memory function following MCAO, and preserved white matter integrity in the long-term experiments. CONCLUSIONS: AU protected against ischemic injury, which might be correlated with the downregulation of NF-κB and MAPK signaling pathways. Furthermore, AU alleviated cognitive impairment after stroke and restored white matter integrity. Our data indicated that AU might be a potential compound for the treatment of stroke and post-stroke cognitive impairment.


Asunto(s)
Isquemia Encefálica , Glucósidos Iridoides , Fármacos Neuroprotectores , Daño por Reperfusión , Accidente Cerebrovascular , Ratones , Masculino , Animales , FN-kappa B/metabolismo , Fármacos Neuroprotectores/farmacología , Lipopolisacáridos/farmacología , Accidente Cerebrovascular/metabolismo , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/metabolismo , Microglía , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo
5.
Nature ; 626(7998): 411-418, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38297130

RESUMEN

Ferroptosis, a form of regulated cell death that is driven by iron-dependent phospholipid peroxidation, has been implicated in multiple diseases, including cancer1-3, degenerative disorders4 and organ ischaemia-reperfusion injury (IRI)5,6. Here, using genome-wide CRISPR-Cas9 screening, we identified that the enzymes involved in distal cholesterol biosynthesis have pivotal yet opposing roles in regulating ferroptosis through dictating the level of 7-dehydrocholesterol (7-DHC)-an intermediate metabolite of distal cholesterol biosynthesis that is synthesized by sterol C5-desaturase (SC5D) and metabolized by 7-DHC reductase (DHCR7) for cholesterol synthesis. We found that the pathway components, including MSMO1, CYP51A1, EBP and SC5D, function as potential suppressors of ferroptosis, whereas DHCR7 functions as a pro-ferroptotic gene. Mechanistically, 7-DHC dictates ferroptosis surveillance by using the conjugated diene to exert its anti-phospholipid autoxidation function and shields plasma and mitochondria membranes from phospholipid autoxidation. Importantly, blocking the biosynthesis of endogenous 7-DHC by pharmacological targeting of EBP induces ferroptosis and inhibits tumour growth, whereas increasing the 7-DHC level by inhibiting DHCR7 effectively promotes cancer metastasis and attenuates the progression of kidney IRI, supporting a critical function of this axis in vivo. In conclusion, our data reveal a role of 7-DHC as a natural anti-ferroptotic metabolite and suggest that pharmacological manipulation of 7-DHC levels is a promising therapeutic strategy for cancer and IRI.


Asunto(s)
Deshidrocolesteroles , Ferroptosis , Humanos , Membrana Celular/metabolismo , Colesterol/biosíntesis , Colesterol/metabolismo , Sistemas CRISPR-Cas/genética , Deshidrocolesteroles/metabolismo , Genoma Humano , Enfermedades Renales/metabolismo , Membranas Mitocondriales/metabolismo , Metástasis de la Neoplasia , Neoplasias/metabolismo , Neoplasias/patología , Fosfolípidos/metabolismo , Daño por Reperfusión/metabolismo
6.
Adv Sci (Weinh) ; 11(12): e2301164, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38229144

RESUMEN

Mechanistic target of rapamycin complex 1 (mTORC1) is a conserved serine/threonine kinase that integrates various environmental signals to regulate cell growth and metabolism. mTORC1 activation requires tethering to lysosomes by the Ragulator-Rag complex. However, the dynamic regulation of the interaction between Ragulator and Rag guanosine triphosphatase (GTPase) remains unclear. In this study, that LAMTOR1, an essential component of Ragulator, is dynamically ubiquitinated depending on amino acid abundance is reported. It is found that the E3 ligase TRAF4 directly interacts with LAMTOR1 and catalyzes the K63-linked polyubiquitination of LAMTOR1 at K151. Ubiquitination of LAMTOR1 by TRAF4 promoted its binding to Rag GTPases and enhanced mTORC1 activation, K151R knock-in or TRAF4 knock-out blocks amino acid-induced mTORC1 activation and accelerates the development of inflammation-induced colon cancer. This study revealed that TRAF4-mediated LAMTOR1 ubiquitination is a regulatory mechanism for mTORC1 activation and provides a therapeutic target for diseases involving mTORC1 dysregulation.


Asunto(s)
Neoplasias Colorrectales , Proteínas de Unión al GTP Monoméricas , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Proteínas de Unión al GTP Monoméricas/genética , Proteínas de Unión al GTP Monoméricas/metabolismo , Factor 4 Asociado a Receptor de TNF/metabolismo , Ubiquitinación , Aminoácidos/metabolismo
7.
Genes (Basel) ; 14(11)2023 Nov 09.
Artículo en Inglés | MEDLINE | ID: mdl-38003000

RESUMEN

Sturgeon is known as a primitive fish with the ZZ/ZW sex determination system and is highly prized for its valuable caviar. Exploring the molecular mechanisms underlying gonadal differentiation would contribute to broadening our knowledge on the genetic regulation of sex differentiation of fish, enabling improved artificial breeding and management of sturgeons. However, the mechanisms are still poorly understood in sturgeons. This study aimed to profile expression patterns between female and male gonads at morphologically undifferentiated and early differentiated stages and identify vital genes involved in gonadal sex differentiation of sturgeons. The sexes of Yangtze sturgeon (Acipenser dabryanus) juveniles were identified via the sex-specific DNA marker and histological observation. Transcriptome analyses were carried out on female and male gonads at 30, 80 and 180 days post-hatching. The results showed that there was a total of 17 overlapped DEGs in the comparison groups of between female and male gonads at the three developmental stages, in which there were three DEGs related to ovarian steroidogenesis, including hsd17b1, foxl2 and cyp19a1. The three DEGs were highly expressed in the female gonads, of which the expression levels were gradually increased with the number of days after hatching. No well-known testis-related genes were found in the overlapped DEGs. Additionally, the expression levels of hsd17b1 and cyp19a1 mRNA were decreased with the knockdown of foxl2 mRNA via siRNA. The results further suggested that foxl2 should play a crucial role in the ovarian differentiation of sturgeons. In conclusion, this study showed that more genes involved in ovarian development than testis development emerged with sexually dimorphic expression during early gonadal sex differentiation, and it provided a preliminary understanding of the molecular regulation on gonadal differentiation of sturgeons.


Asunto(s)
Peces , Gónadas , Animales , Femenino , Masculino , Gónadas/metabolismo , Peces/fisiología , Testículo/metabolismo , Perfilación de la Expresión Génica , ARN Mensajero/metabolismo
8.
Clin Implant Dent Relat Res ; 25(3): 481-489, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37186153

RESUMEN

OBJECTIVE: To evaluate the performance of the indirect technique in peri-implant soft tissue contour duplication after the delivery procedure in the anterior maxilla. MATERIALS AND METHODS: Patients with single implant-supported fixed restorations in the anterior maxilla were recruited. For the impression procedure, an intraoral scan was acquired by both the direct and the indirect techniques. For the delivery procedure, implants were randomly allocated into one of the two groups according to the approaches of digital impression preceding definite crown fabrication (A-direct technique; B-indirect technique) and were scanned again after the definite crown delivery. The stereolithography files were superimposed to analyze changes in peri-implant soft tissue contour after the delivery procedure. The main outcomes were dimensional deviations of peri-implant mucosa, and the secondary outcome was differences in the pink esthetic score (PES). RESULTS: A total of 20 implants that underwent the complete workflow were included. After the delivery procedure, significant deviations in palatal tissue thickness between the provisional and definite crowns were observed in Group A but these were absent in Group B. Additionally, deviations in labial thickness (0.27 ± 0.12 mm vs. 0.08 ± 0.09 mm) and palatal thickness (0.17 ± 0.15 mm vs. 0.03 ± 0.08 mm), and labial volume of soft tissue (1.87 ± 0.94 mm3 vs. 0.75 ± 0.74 mm3 ) in Group A were significantly higher than those in Group B. No significant differences in PES were found. CONCLUSION: The indirect technique of scanning the provisional crown can more accurately duplicate the peri-implant soft tissue contour than the direct technique, resulting in a smaller deviation of the soft tissue in the delivery procedure.


Asunto(s)
Implantes Dentales de Diente Único , Maxilar , Humanos , Maxilar/diagnóstico por imagen , Maxilar/cirugía , Proyectos Piloto , Estética Dental , Implantación Dental Endoósea/métodos , Coronas , Resultado del Tratamiento
9.
Curr Eye Res ; 47(11): 1538-1546, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36066502

RESUMEN

PURPOSE: To evaluate the relationship between ocular magnification correction and macular choroidal thickness (ChT) measurements in children, and to demonstrate when ocular magnification correction is necessary. METHODS: Chinese children aged 6-9 years with various refractive statuses were included. Swept-source optical coherence tomography was used to measure macular ChT. A self-designed program was adopted to simulate ChT changes in each sector of the ETDRS grid in the macula under various simulated axial lengths (ALs). RESULTS: ChT measurements were not affected for all simulated ALs in over 95% of the individuals in the central fovea. In the inferior, superior, and temporal parafoveal sectors, the extent of AL that may include 95% of the individuals narrowed from approximately 22.0 mm to 27.2 mm. In the nasal parafoveal sector and inferior, superior, and temporal perifoveal sectors, the extent of AL that may include 95% of the individuals became even narrower, from approximately 22.8 mm to 26.0 mm. The narrowest extent was observed in the perifoveal nasal sector, ranging from 23.3 mm to 25.5 mm. The effect of ocular magnification was more significant in hyperopes than in myopes in the inferior parafoveal sector and temporal, superior, and nasal perifoveal sectors. CONCLUSION: During macular ChT measurements, ocular magnification correction is not necessary in the central fovea. However, ocular magnification should be corrected normally in the nasal perifoveal region and in individuals with ALs shorter than 22.8 mm or longer than 26.0 mm in the remaining macular regions.


Asunto(s)
Mácula Lútea , Miopía , Niño , Coroides , Estudios Transversales , Humanos , Tomografía de Coherencia Óptica/métodos
10.
J Transl Int Med ; 10(3): 197-206, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-36776238

RESUMEN

To maintain energy supply to the brain, a direct energy source called adenosine triphosphate (ATP) is produced by oxidative phosphorylation and aerobic glycolysis of glucose in the mitochondria and cytoplasm. Brain glucose metabolism is reduced in many neurodegenerative diseases, including Alzheimer's disease (AD), where it appears presymptomatically in a progressive and region-specific manner. Following dysregulation of energy metabolism in AD, many cellular repair/regenerative processes are activated to conserve the energy required for cell viability. Glucose metabolism plays an important role in the pathology of AD and is closely associated with the tricarboxylic acid cycle, type 2 diabetes mellitus, and insulin resistance. The glucose intake in neurons is from endothelial cells, astrocytes, and microglia. Damage to neurocentric glucose also damages the energy transport systems in AD. Gut microbiota is necessary to modulate bidirectional communication between the gastrointestinal tract and brain. Gut microbiota may influence the process of AD by regulating the immune system and maintaining the integrity of the intestinal barrier. Furthermore, some therapeutic strategies have shown promising therapeutic effects in the treatment of AD at different stages, including the use of antidiabetic drugs, rescuing mitochondrial dysfunction, and epigenetic and dietary intervention. This review discusses the underlying mechanisms of alterations in energy metabolism in AD and provides potential therapeutic strategies in the treatment of AD.

11.
Environ Res ; 203: 111795, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34343556

RESUMEN

BACKGROUND: During the COVID-19 epidemic period, people showed a stronger connection to the environment within their communities. Although tree canopy in residential areas has been shown to positively affect psychological distress, it is not clear whether the COVID-19 epidemic played a role in this process. Elucidation of the relationship between tree canopy and the impact on psychological distress during the COVID-19 epidemic could provide valuable information as to the best methods to help individuals cope with urban mental stress events. METHODS: A total of 15 randomly selected residential areas of Beijing were enrolled in this repeated cross-sectional study. A total of 900 residents were included in the two-waves of the investigation (450 residents per wave) before and during the COVID-19 epidemic (i.e., May 2019 and May 2020). Psychological distress was estimated using the 12-question General Health Questionnaire (GHQ-12). Tree canopy coverage (TCC) was measured through visual interpretation based on the 2013 data sources (World View 2 satellite imagery of Beijing urban areas with a resolution of 0.5 m). The demographic characteristics, distance to the nearest surrounding green or blue space, residential area house price, household density, and construction year were also collected in this study. A multivariate logistic regression, relative risk due to interaction (RERI), and synergy index (SI) were used to explore the relationships among tree canopy, COVID-19, and psychological distress. RESULTS: The negative impact of the COVID-19 epidemic on mental health was significant, with the prevalence of psychological distress increased 7.84 times (aOR = 7.84, 95% CI = 4.67-13.95) during the COVID-19 epidemic period. Tree canopy coverage in the group without psychological distress was significantly higher than that of the psychologically distressed group (31.07 ± 11.38% vs. 27.87 ± 12.97%, P = 0.005). An increase in 1% of TCC, was related to a 5% decrease in the prevalence of psychological distress (aOR = 0.95, 95% CI = 0.93-0.98). An antagonism joint action between tree canopy and the COVID-19 epidemic existed (RERI = 1.09, 95% CI = 0.72-1.47; SI = 0.16, 95% CI = 0.05-0.52), and persisted enhancing only in medium (26.45%-33.21%) and above TCC level. Correlation of GHQ items and TCC significantly differed between the COVID-19 non-epidemic and epidemic periods, with the effects of tree canopy on GHQ-12 items covering topics, such as social function and depression, presumably absent because of epidemic limitations. CONCLUSIONS: This study indicates that the COVID-19 epidemic harmed mental health and verified the positive effects of residential tree canopy on psychological distress in Beijing. We suggest paying more attention to residents in areas of low TCC and dealing with psychological distress caused by public health stress events based on tree canopy strategies.


Asunto(s)
COVID-19 , Epidemias , Distrés Psicológico , Estudios Transversales , Humanos , SARS-CoV-2 , Estrés Psicológico/epidemiología , Árboles
12.
Cancer Res ; 81(20): 5217-5229, 2021 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-34385181

RESUMEN

Ferroptosis is a lipid peroxidation-dependent cell death caused by metabolic dysfunction. Ferroptosis-associated enzymes are promising therapeutic targets for cancer treatment. However, such therapeutic strategies show limited efficacy due to drug resistance and other largely unknown underlying mechanisms. Here we report that cystine transporter SLC7A11 is upregulated in lung cancer stem-like cells (CSLC) and can be activated by stem cell transcriptional factor SOX2. Mutation of SOX2 binding site in SLC7A11 promoter reduced SLC7A11 expression and increased sensitivity to ferroptosis in cancer cells. Oxidation at Cys265 of SOX2 inhibited its activity and decreased the self-renewal capacity of CSLCs. Moreover, tumors with high SOX2 expression were more resistant to ferroptosis, and SLC7A11 expression was positively correlated with SOX2 in both mouse and human lung cancer tissue. Together, our study provides a mechanism by which cancer cells evade ferroptosis and suggests that oxidation of SOX2 can be a potential therapeutic target for cancer treatment. SIGNIFICANCE: This study uncovers a SOX2-SLC7A11 regulatory axis that confers resistance to ferroptosis in lung cancer stem-like cells.


Asunto(s)
Sistema de Transporte de Aminoácidos y+/metabolismo , Biomarcadores de Tumor/metabolismo , Ferroptosis , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/patología , Células Madre Neoplásicas/patología , Factores de Transcripción SOXB1/metabolismo , Sistema de Transporte de Aminoácidos y+/genética , Animales , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Humanos , Peroxidación de Lípido , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Ratones , Mutación , Células Madre Neoplásicas/metabolismo , Pronóstico , Factores de Transcripción SOXB1/genética , Tasa de Supervivencia , Activación Transcripcional , Células Tumorales Cultivadas
13.
Neuro Oncol ; 23(10): 1709-1722, 2021 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-34214167

RESUMEN

BACKGROUND: Chordoma is a rare mesenchymal malignancy, with a high recurrence rate and unclear tumorigenic mechanism. Genetic alterations, epigenetic regulators, and chromatin spatial organization play crucial roles in the initiation and progression of chordoma. In the current study, we aim to uncover the novel therapeutical targets for chordoma via using integrated multi-omics analysis. METHODS: The RNA-sequencing (RNA-seq), assay for transposable accessible chromatin by high-throughput sequencing (ATAC-seq), and Hi-C were performed between chordoma and human nucleus pulposus (HNP), along with imageological examination and clinical information. The expressions of identified targets were validated by clinical samples and their functions were further evaluated by cell and animal experiments via gene knockdown and inhibitors. RESULTS: The integrated multi-omics analysis revealed the important roles of bone microenvironment in chordoma tumorigenesis. By comparing the hierarchical structures, CA2 (carbonic anhydrase II) and THNSL2 (threonine synthase-like 2) were identified in the switched compartments, cell-specific boundaries, and loops. Additionally, CA2 was highly expressed in chordoma but barely found in HNP. The cell growth and migration of chordoma cells were dramatically suppressed via inhibition of CA2 either with genetic deletion or pharmaceutical treatment with Dorzolamide HCl. Furthermore, Dorzolamide HCl also regulated the bone microenvironment by blocking the osteoclast differentiation of bone marrow monocytes. CONCLUSION: This study uncovers the roles of bone microenvironment in the chordoma tumorigenesis and identifies CA2 as a novel therapeutic target for chordoma. Besides, our findings suggest Dorzolamide HCl as a promising therapeutic option for chordoma.


Asunto(s)
Cordoma , Animales , Carcinogénesis , Ciclo Celular , Proliferación Celular , Transformación Celular Neoplásica , Cordoma/tratamiento farmacológico , Cordoma/genética , Humanos , Microambiente Tumoral
14.
BMJ Open ; 11(7): e044668, 2021 07 02.
Artículo en Inglés | MEDLINE | ID: mdl-34215599

RESUMEN

AIMS: Inflammation plays a key role in the pathophysiology of cardiogenic shock (CS). Low-density lipoprotein cholesterol (LDL-C) is a biomarker of inflammation and is used to predict prognostic outcomes of several diseases. The primary purpose of this study was to evaluate if LDL-C can be used as a biomarker to predict the mortality of CS. METHODS AND RESULTS: Records of critically ill patients with CS were identified from the Medical Information Mart for Intensive Care III database. A multivariate Cox regression model was employed to adjust for imbalances by incorporating parameters and potential confounders.A total of 551 critically ill patients with CS were enrolled for this analysis, including 207 with LDL-C <1.8 mmol/L and 344 with LDL-C ≥1.8 mmol/L. Results of multivariate Cox regression models found that higher concentration of LDL-C (LDL-C ≥1.8mmol/L) was associated with a reduced risk of in-hospital mortality (HR 0.66, 95% CI 0.50 to 0.87; p=0.003) and 28-day mortality (HR 0.61, 95% CI 0.46 to 0.80; p=0.002) LDL-C in patients with CS. Patients with LDL-C ≥1.8 mmol/L were independently associated with improved in-hospital survival (HR 0.32, 95% CI 0.20 to 0.52, p<0.001) and 28-day survival (HR 0.51, 95% CI 0.33 to 0.73, p=0.002) compared with patients with LDL-C <1.8 mmol/L. The impact of LDL-C on in-hospital mortality and 28-day mortality persisted in patients with acute coronary syndrome (ACS) and was not statistically significant in the non-ACS subgroup. CONCLUSIONS: Our study observed that increased LDL-C level was related with improved survival in patients with CS, but not with improved outcomes in patients with uncomplicated ACS. The results need to be verified in randomised controlled trials.


Asunto(s)
Síndrome Coronario Agudo , Choque Cardiogénico , LDL-Colesterol , Humanos , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo
15.
Oncol Lett ; 22(2): 580, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34122631

RESUMEN

MicroRNA (miR)-497 has been reported as a tumor suppressor in various cancer types. Nonetheless, the regulation of triple-negative breast cancer (TNBC) by miR-497 remains poorly understood. The present study aimed to investigate the potential function and mechanism of miR-497 in TNBC. A total of 36 TNBC and matched non-cancerous tissue samples were collected for analysis. Reverse transcription-quantitative PCR was performed to detect the miR-497 levels in TNBC tissue. The association between miR-497 expression, clinical characteristics and survival was then analyzed. To investigate the role of miR-497 in TNBC, MTT, colony formation, Transwell invasion, cell cycle and cell apoptosis assays were conducted following transfection of miR-497 mimics into the MDA-MB-231 and MDA-MB-468 cell lines. Luciferase reporter assays and western blot analysis were used to confirm the regulation of a putative target of miR-497. The results indicated that the expression of miR-497 was downregulated in the TNBC specimens. Further analysis demonstrated that the expression of miR-497 was downregulated in patients with advanced TNBC stages and that low miR-497 was associated with poor prognosis in patients with TNBC. Transfection of miR-497 mimics inhibited TNBC cell proliferation and increased cell apoptosis in MDA-MB-231 and MDA-MB-468 cells. Moreover, cell migration was inhibited following overexpression of miR-497, which also led to the arrest of the breast cancer cells in the G0/G1 phase of the cell cycle. Yes-associated protein 1 (YAP1), a critical molecule in the Hippo pathway, was identified as a target of miR-497. Notably, the protein and mRNA expression levels of YAP1 in MDA-MB-231 and MDA-MB-468 cells were downregulated following overexpression of miR-497. Overall, the findings of the present study indicated that miR-497 inhibited TNBC cell proliferation and migration and induced cell apoptosis by negatively regulating YAP1 expression. Thus, targeting miR-497 may represent a potential strategy for the treatment of TNBC.

16.
Exp Mol Pathol ; 121: 104645, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33989616

RESUMEN

We have focused on the underlying role of miR-1224 in cardiomyocyte injury stimulated by hypoxia/reoxygenation (H/R). In the current study, the rat cardiomyocyte cell line H9C2 was used to construct a H/R cell model to validate the cardioprotective effects of miR-1224. Data from the dual-luciferase assay revealed that the glutathione peroxidase 4 (GPX4) was a direct target of miR-1224. Expression of miR-1224, determined using qRT-PCR, was remarkably increased while that of GPX4 protein, evaluated via western blotting, was significantly decreased in cardiomyocytes in response to H/R exposure. ROS generation, superoxide dismutase (SOD) activity, concentrations of malondialdehyde (MDA) and 4-hydroxy aldehydes (4-HNE), and H9C2 cell apoptosis were further evaluated following overexpression of miR-1224 or silencing of GPX4 in H9C2 cells. H9C2 cells under H/R conditions displayed increased synthesis of ROS, along with overexpression of miR-1224 and downregulation of GPX4. SOD activity was significantly decreased while concentrations of MDA and 4-HNE were markedly increased under H/R injury conditions. In addition, miR-1224 mimic or GPX4 siRNA plasmids dramatically enhanced H/R-mediated apoptosis, Bax expression and caspase-3 activity, with a concomitant reduction in Bcl-2 expression. Conversely, inhibition of miR-1224 exerted suppressive effects on oxidative stress and apoptosis in H9C2 cells under H/R conditions. Interestingly, silencing of GPX4 attenuated the negative effects of miR-1224 inhibition. Our results suggested that inhibition of miR-1224 caused resistance to H/R and diminished oxidative stress in vitro through targeting of GPX4.


Asunto(s)
Apoptosis , Hipoxia/fisiopatología , MicroARNs/antagonistas & inhibidores , Daño por Reperfusión Miocárdica/prevención & control , Miocitos Cardíacos/patología , Estrés Oxidativo , Oxígeno/toxicidad , Fosfolípido Hidroperóxido Glutatión Peroxidasa/antagonistas & inhibidores , Animales , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Miocitos Cardíacos/metabolismo , Ratas
17.
Neurochem Int ; 147: 105019, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33905763

RESUMEN

Ischemic stroke is a leading cause of disability and mortality worldwide due to the narrow therapeutic time window of the only two approved therapies, intravenous thrombolysis and thrombectomy. The pathophysiological processes of ischemic stroke are driven by multiple complex molecular and cellular interactions that ultimately induce brain damage and neurobehavioral impairment. Long non-coding RNAs (LncRNAs) are significantly altered in the blood and brains of ischemic stroke patients and play a critical role in the pathogenesis of stroke, which serve as potential targets for stroke interventions. In this review, we provide an overview of the roles of lncRNAs in the pathophysiology of ischemic stroke and discuss the opportunities and challenges for the clinical application of lncRNAs in the diagnosis and treatment of ischemic stroke.


Asunto(s)
Isquemia Encefálica/genética , Accidente Cerebrovascular Isquémico/genética , ARN Largo no Codificante/metabolismo , Accidente Cerebrovascular/genética , Animales , Biomarcadores/análisis , Encéfalo/metabolismo , Encéfalo/patología , Isquemia Encefálica/patología , Humanos , Accidente Cerebrovascular/patología
18.
Mol Ther ; 29(9): 2873-2885, 2021 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-33895326

RESUMEN

Dysregulated long non-coding RNAs (lncRNAs) have been shown to contribute to the pathogenesis of ischemic stroke. However, the potential role of lncRNAs in post-stroke microglial activation remains largely unknown. Here, we uncovered that lncRNA-U90926 was significantly increased in microglia exposed to ischemia/reperfusion both in vivo and in vitro. In addition, adenovirus-associated virus (AAV)-mediated microglial U90926 silencing alleviated neurological deficits and reduced infarct volume in experimental stroke mice. Microglial U90926 knockdown could reduce the infiltration of neutrophils into ischemic lesion site, which might be attributed to the downregulation of C-X-C motif ligand 2 (CXCL2). Mechanistically, U90926 directly bound to malate dehydrogenase 2 (MDH2) and competitively inhibited the binding of MDH2 to the CXCL2 3' untranslated region (UTR), thus protecting against MDH2-mediated decay of CXCL2 mRNA. Taken together, our study demonstrated that microglial U90926 aggravated ischemic brain injury via facilitating neutrophil infiltration, suggesting that U90926 might be a potential biomarker and therapeutic target for ischemic stroke.


Asunto(s)
Quimiocina CXCL2/genética , Accidente Cerebrovascular Isquémico/inmunología , Malato Deshidrogenasa/genética , Microglía/química , ARN Largo no Codificante/genética , Regulación hacia Arriba , Regiones no Traducidas 5' , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Células HEK293 , Humanos , Accidente Cerebrovascular Isquémico/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Infiltración Neutrófila , Cultivo Primario de Células
19.
Theranostics ; 11(8): 3839-3852, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33664865

RESUMEN

Background: Lactate greatly contributes to the regulation of intracellular communication within the tumor microenvironment (TME). However, the role of lactate in pituitary adenoma (PA) invasion is unclear. In this study, we aimed to clarify the effects of lactate on the TME and the effects of TME on PA invasion. Methods: To explore the correlation between TME acidosis and tumor invasion, LDHA and LAMP2 expression levels were quantified in invasive (n = 32) and noninvasive (n = 32) PA samples. The correlation between immune cell infiltration and tumor invasion was evaluated in 64 PAs. Critical chemokine and key signaling pathway components were detected by qPCR, Western blotting, siRNA knockdown, and specific inhibitors. The functional consequences of CCR4 signaling inhibition were evaluated in vitro and in vivo. Results: Lactate was positively associated with PA invasion. Of the 64 PA tissues, invasive PAs were related to high infiltration of M2-like tumor-associated macrophages (TAMs) (P < 0.05). Moreover, lactate secreted from PA cells facilitated M2 polarization via the mTORC2 and ERK signaling pathways, while activated TAMs secreted CCL17 to promote PA invasion via the CCL17/CCR4/mTORC1 axis. According to univariate analysis of clinical data, high CCL17 expression was associated with larger tumor size (P = 0.0438), greater invasion (P = 0.0334), and higher susceptibility to postoperative recurrence (P = 0.0195) in human PAs. Conclusion: This study illustrates the dynamics between PA cells and immune TME in promoting PA invasion via M2 polarization. CCL17 levels in the TME are related to the PA invasiveness and clinical prognosis, and the CCL17/CCR4/mTOCR1 axis may serve as potential therapeutic targets for Pas.


Asunto(s)
Adenoma/patología , Adenoma/fisiopatología , Quimiocina CCL17/metabolismo , Ácido Láctico/metabolismo , Neoplasias Hipofisarias/patología , Neoplasias Hipofisarias/fisiopatología , Macrófagos Asociados a Tumores/fisiología , Adulto , Femenino , Humanos , Ácido Láctico/farmacología , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Persona de Mediana Edad , Modelos Biológicos , Invasividad Neoplásica , Recurrencia Local de Neoplasia/metabolismo , Medicina de Precisión , Receptores CCR4/metabolismo , Transducción de Señal , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/fisiología , Macrófagos Asociados a Tumores/clasificación , Macrófagos Asociados a Tumores/efectos de los fármacos
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