RESUMEN

Ferroptosis is an important pathological mechanism of chronic heart failure (CHF). This study aimed to investigate the protective mechanism of Astragaloside IV (AS-IV) on CHF rats by integrating bioinformatics and ferroptosis. CHF-related targets and ferroptosis-related targets were collected. After the intersection, the common targets were obtained. The PPI network of the common targets was constructed, and topological analysis of the network was carried out. The target with the highest topological parameter values was selected as the key target. The key target p53 was obtained through bioinformatics analysis, and its molecular docking model with AS-IV was obtained, as well as molecular dynamics simulation analysis. The rat models of CHF after myocardial infarction were established by ligation of left coronary artery and treated with AS-IV for 4 weeks. AS-IV treatment significantly improved cardiac function in CHF rats, improved cardiomyocyte morphology and myocardial fibrosis, reduced mitochondrial damage, decreased myocardial MDA and Fe2+ content, increased GSH content, inhibited the expression of p53 and p-p53, and up-regulated the expression of SLC7A11 and GPX4. In conclusion, AS-IV improved cardiac function in CHF rats, presumably by regulating p53/SLC7A11/GPX4 signaling pathway and inhibiting myocardial ferroptosis.

Asunto(s)

Biología Computacional , Ferroptosis , Insuficiencia Cardíaca , Saponinas , Triterpenos , Animales , Ferroptosis/efectos de los fármacos , Triterpenos/farmacología , Saponinas/farmacología , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Ratas , Biología Computacional/métodos , Masculino , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Simulación del Acoplamiento Molecular , Enfermedad Crónica , Modelos Animales de Enfermedad , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Simulación de Dinámica Molecular , Miocardio/metabolismo , Miocardio/patología

RESUMEN

Bisphosphonates are potent bone resorption inhibitors, among which alendronate sodium (ALN) is commonly prescribed for most osteoporosis patients, but long-term application of ALN can cause bisphosphonate-related osteonecrosis of jaw (BRONJ), the pathogenesis of which remains unclear. Previous studies have suggested that bisphosphonates cause jaw ischemia by affecting the biological behavior of vascular endothelial cells, leading to BRONJ. However, the impacts of ALN on vascular endothelial cells and its mechanism remain unclear. The purpose of this work is to assess the influence of ALN on human umbilical vein endothelial cells (HUVECs) and clarify the molecular pathways involved. We found that high concentration of ALN induced G1 phase arrest in HUVECs, demonstrated by downregulation of Cyclin D1 and Cyclin D3. Moreover, high concentration of ALN treatment showed pro-apoptotic effect on HUVECs, demonstrated by increased levels of the cleaved caspase-3, the cleaved PARP and Bax, along with decreased levels of anti-apoptotic protein Bcl-2. Further experiments showed that ERK1/2 phosphorylation was decreased. Additionally, ALN provoked the build-up of reactive oxygen species (ROS) in HUVECs, leading to ERK1/2 pathway suppression. N-acetyl-L-cysteine (NAC), a ROS scavenger, efficiently promoted the ERK1/2 phosphorylation and mitigated the G1 phase arrest and apoptosis triggered by ALN in HUVECs. PD0325901, an inhibitor of ERK1/2 that diminishes the ERK1/2 phosphorylation enhanced the ALN-induced G1 phase arrest and apoptosis in HUVECs. These findings show that ALN induces G1 phase arrest and apoptosis through ROS-mediated ERK1/2 pathway inhibition in HUVECs, providing novel insights into the pathogenic process, prevention and treatment of BRONJ in individuals receiving extended use of ALN.

Asunto(s)

Alendronato , Apoptosis , Puntos de Control de la Fase G1 del Ciclo Celular , Células Endoteliales de la Vena Umbilical Humana , Sistema de Señalización de MAP Quinasas , Especies Reactivas de Oxígeno , Humanos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Apoptosis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Alendronato/farmacología , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Conservadores de la Densidad Ósea/farmacología , Células Cultivadas , Proteína Quinasa 3 Activada por Mitógenos

RESUMEN

Objective: To explore the effect of amyloid-ß peptide (Aß) on mandibular condyle to develop a new treatment for postmenopausal women with Temporomandibular joint osteoarthritis. Methods: A murine bone loss model was established by ovariectomy. Microstructure parameters of the condyle were measured by microcomputed tomography before and after intraperitoneal injection with Aß. Flow cytometry, Alizarin red staining, RT-qPCR assays, FITC/PI staining, Oil Red O staining and western blotting were used to evaluate the effect of Aß on the osteogenic differentiation of mouse bone marrow stromal stem cells (mBMSCs). Results: In vivo, condylar microstructure parameters increased. Serum osteoprotegerin and procollagen type 1 N propeptide increased in a dose-dependent manner after the injection of Aß, which were opposite the changes observed in c-terminal telopeptides of type I collagen, tumor necrosis factor-α and the high serum level of leptin. In vitro, Aß promoted calcium nodule formation in the cells. The expression of ALP, Runx2, osteorix and osteocalcin increased significantly. The expression of mRNAs related to the Wnt signaling pathway was significantly upregulated, which could be blocked by DKK1. Conclusion: Aß can reverse bone loss in the mandibular condyle in ovariectomized mice through promoting the osteogenic differentiation of mBMSCs via the Wnt pathway.

RESUMEN

BACKGROUND: Temporomandibular joint osteoarthritis (TMJOA) has a high incidence rate, but its pathogenesis remains unclear. Circadian rhythm is an important oscillation in the human body and influences various biological activities. However, it is still unclear whether circadian rhythm affects the onset and development of TMJOA. METHODS: We disrupted the normal rhythm of rats and examined the expression of core clock genes in the mandibular condylar cartilage of the jaw and histological changes in condyles. After isolating rat mandibular condylar chondrocytes, we upregulated or downregulated the clock gene Per1, examined the expression of cartilage matrix-degrading enzymes, tested the activation of the GSK3ß/ß-CATENIN pathway and verified it using agonists and inhibitors. Finally, after downregulating the expression of Per1 in the mandibular condylar cartilage of rats with jet lag, we examined the expression of cartilage matrix-degrading enzymes and histological changes in condyles. RESULTS: Jet lag led to TMJOA-like lesions in the rat mandibular condyles, and the expression of the clock gene Per1 and cartilage matrix-degrading enzymes increased in the condylar cartilage of rats. When Per1 was downregulated or upregulated in mandibular condylar chondrocytes, the GSK3ß/ß-CATENIN pathway was inhibited or activated, and the expression of cartilage matrix-degrading enzymes decreased or increased, which can be rescued by activator and inhibitor of the GSK3ß/ß-CATENIN pathway. Moreover, after down-regulation of Per1 in mandibular condylar cartilage in vivo, significant alleviation of cartilage degradation, cartilage loss, subchondral bone loss induced by jet lag, and inhibition of the GSK3ß/ß-CATENIN signaling pathway were observed. Circadian rhythm disruption can lead to TMJOA. The clock gene Per1 can promote the occurrence of TMJOA by activating the GSK3ß/ß-CATENIN pathway and promoting the expression of cartilage matrix-degrading enzymes. The clock gene Per1 is a target for the prevention and treatment of TMJOA.

Asunto(s)

Condrocitos , Ritmo Circadiano , Glucógeno Sintasa Quinasa 3 beta , Cóndilo Mandibular , Osteoartritis , Proteínas Circadianas Period , Articulación Temporomandibular , Regulación hacia Arriba , beta Catenina , Animales , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Condrocitos/metabolismo , Condrocitos/patología , beta Catenina/metabolismo , Osteoartritis/patología , Osteoartritis/metabolismo , Proteínas Circadianas Period/metabolismo , Proteínas Circadianas Period/genética , Cóndilo Mandibular/patología , Cóndilo Mandibular/metabolismo , Articulación Temporomandibular/patología , Articulación Temporomandibular/metabolismo , Masculino , Ratas Sprague-Dawley , Transducción de Señal , Ratas

RESUMEN

Autophagy plays a pivotal role in diverse biological processes, including the maintenance and differentiation of neural stem cells (NSCs). Interestingly, while complete deletion of Fip200 severely impairs NSC maintenance and differentiation, inhibiting canonical autophagy via deletion of core genes, such as Atg5, Atg16l1, and Atg7, or blockade of canonical interactions between FIP200 and ATG13 (designated as FIP200-4A mutant or FIP200 KI) does not produce comparable detrimental effects. This highlights the likely critical involvement of the non-canonical functions of FIP200, the mechanisms of which have remained elusive. Here, utilizing genetic mouse models, we demonstrated that FIP200 mediates non-canonical autophagic degradation of p62/sequestome1, primarily via TAX1BP1 in NSCs. Conditional deletion of Tax1bp1 in fip200 hGFAP conditional knock-in (cKI) mice led to NSC deficiency, resembling the fip200 hGFAP conditional knockout (cKO) mouse phenotype. Notably, reintroducing wild-type TAX1BP1 not only restored the maintenance of NSCs derived from tax1bp1-knockout fip200 hGFAP cKI mice but also led to a marked reduction in p62 aggregate accumulation. Conversely, a TAX1BP1 mutant incapable of binding to FIP200 or NBR1/p62 failed to achieve this restoration. Furthermore, conditional deletion of Tax1bp1 in fip200 hGFAP cKO mice exacerbated NSC deficiency and p62 aggregate accumulation compared to fip200 hGFAP cKO mice. Collectively, these findings illustrate the essential role of the FIP200-TAX1BP1 axis in mediating the non-canonical autophagic degradation of p62 aggregates towards NSC maintenance and function, presenting novel therapeutic targets for neurodegenerative diseases.

Asunto(s)

Proteínas Relacionadas con la Autofagia , Autofagia , Células-Madre Neurales , Animales , Células-Madre Neurales/fisiología , Células-Madre Neurales/metabolismo , Ratones , Autofagia/fisiología , Proteínas Relacionadas con la Autofagia/genética , Proteínas Relacionadas con la Autofagia/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones Noqueados , Proteína Sequestosoma-1/metabolismo , Proteína Sequestosoma-1/genética , Regulación de la Expresión Génica , Proteínas de Neoplasias

RESUMEN

Objective: This study aims to explore the mechanism of action of Yixintai in treating chronic ischemic heart failure by combining bioinformatics and experimental validation. Materials and Methods: Five potential drugs for treating heart failure were obtained from Yixintai (YXT) through early mass spectrometry detection. The targets of YXT for treating heart failure were obtained by a search of online databases. Gene ontology (GO) functional enrichment analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses were conducted on the common targets using the DAVID database. A rat heart failure model was established by ligating the anterior descending branch of the left coronary artery. A small animal color Doppler ultrasound imaging system detected cardiac function indicators. Hematoxylin-eosin (HE), Masson's, and electron microscopy were used to observe the pathological morphology of the myocardium in rats with heart failure. The network pharmacology analysis results were validated by ELISA, qPCR, and Western blotting. Results: A total of 107 effective targets were obtained by combining compound targets and eliminating duplicate values. PPI analysis showed that inflammation-related proteins (TNF and IL1B) were key targets for treating heart failure, and KEGG enrichment suggested that NF-κB signaling pathway was a key pathway for YXT treatment of heart failure. Animal model validation results indicated the following: YXT can significantly reduce the content of intestinal microbiota metabolites such as trimethylamine oxide (TMAO) and improve heart failure by improving the EF and FS values of heart ultrasound in rats and reducing the levels of serum NT-proBNP, ANP, and BNP to improve heart failure. Together, YXT can inhibit cardiac muscle hypertrophy and fibrosis in rats and improve myocardial ultrastructure and serum IL-1ß, IL-6, and TNF-α levels. These effects are achieved by inhibiting the expressions of NF-κB and PKC. Conclusion: YXT regulates the TMAO/PKC/NF-κB signaling pathway in heart failure.

Asunto(s)

Medicamentos Herbarios Chinos , Insuficiencia Cardíaca , Farmacología en Red , Transducción de Señal , Animales , Masculino , Ratas , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Metilaminas/farmacología , FN-kappa B/metabolismo , Proteína Quinasa C/metabolismo , Proteína Quinasa C/antagonistas & inhibidores , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos

RESUMEN

PURPOSE: A serum medicinal chemistry analysis was performed to investigate the pharmacological basis of Xintongtai granule and to predict the potential mechanism of anti-atherosclerotic action based on the blood components. METHODS: UPLC-Q-TOF-MS/MS was used to analyze the in vitro chemical composition and in vivo blood components of Xintongtai granule, and to detect the blood drug concentration. The PPI network was constructed by collecting blood components and disease targets through the network pharmacology method, and the key targets were subjected to GO and KEGG functional enrichment analyses, so as to construct the topology network of drug-component-target-disease, and to validate the network by molecular docking. RESULTS: The UPLC-Q-TOF-MS/MS analysis identified 69 chemical components in Xintongtai granule, including 19 prototype circulating components and 9 metabolites in the bloodstream. Network pharmacology analysis revealed 115 intersecting targets for the circulating components, from which 10 core targets were selected. GO and KEGG analyses unveiled associated signaling pathways and biological processes. The construction of a topology network and preliminary molecular docking provided insights into its mechanism of action. CONCLUSION: The mechanism underlying the anti- atherosclerosis effect of Xintongtai granule may be associated with the intervention of active components such as Cryptotanshinone, Kaempferitrin, and Puerarin in pathways targeting CXCL8, STAT3, TNF, and other related targets.

Asunto(s)

Aterosclerosis , Medicamentos Herbarios Chinos , Simulación del Acoplamiento Molecular , Espectrometría de Masas en Tándem , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/sangre , Espectrometría de Masas en Tándem/métodos , Animales , Cromatografía Líquida de Alta Presión/métodos , Mapas de Interacción de Proteínas/efectos de los fármacos , Masculino , Farmacología en Red , Humanos , Ratones

RESUMEN

Introduction: Orthodontic tooth movement (OTM) involves complex interactions between mechanical forces and periodontal tissue adaptation, mainly mediated by periodontal ligament cells, including periodontal ligament stem cells (PDLSCs), osteoblasts, and osteoclasts. Dopamine (DA), a neurotransmitter known for its critical role in bone metabolism, is investigated in this study for its potential to enhance osteogenic differentiation in PDLSCs, which are pivotal in OTM. This study examined the potential of DA to facilitate OTM by binding to DA receptors (D1R and D2R) and activating the ERK1/2 signaling pathway. We propose that DA's interaction with these receptors on PDLSCs could enhance osteogenic differentiation, thereby accelerating bone remodeling and reducing the duration of orthodontic treatments, which offering a novel approach to improve clinical outcomes in orthodontic care. Methods: This study utilized a rat OTM model, micro-CT, histological analyses, and in vitro assays to investigate dopamine's effect on osteogenesis. PDLSCs were cultured and treated with DA, and cytotoxicity, osteogenic differentiation, gene and protein expression assessed. Results: Dopamine administration significantly increased trabecular bone density and osteogenic marker expression in an OTM rat model. In vitro, DA at 10 nM optimally promoted human PDLSCs osteogenesis without affecting proliferation. Blocking DA receptors or inhibiting the ERK1/2 pathway attenuated these effects, underscoring the importance of dopaminergic signaling in tension-induced osteogenesis during OTM. Conclusion: Taken together, our study reveals that local dopamine administration at a concentration of 10 nM not only enhances tension-induced osteogenesis in vivo but also significantly promotes osteogenic differentiation of PDLSCs in vitro through D1 and D2 receptor-mediated ERK1/2 signaling pathway activation.

RESUMEN

Chimeric antigen receptor (CAR) T-cell therapies are increasingly adopted as a commercially available treatment for hematologic and solid tumor cancers. As CAR-T therapies reach more patients globally, the cryopreservation and banking of patients' leukapheresis materials is becoming imperative to accommodate intra/inter-national shipping logistical delays and provide greater manufacturing flexibility. This study aims to determine the optimal temperature range for transferring cryopreserved leukapheresis materials from two distinct types of controlled rate freezing systems, Liquid Nitrogen (LN2)-based and LN2-free Conduction Cooling-based, to the ultracold LN2 storage freezer (≤-135 °C), and its impact on CAR T-cell production and functionality. Presented findings demonstrate that there is no significant influence on CAR T-cell expansion, differentiation, or downstream in-vitro function when employing a transfer temperature range spanning from -30 °C to -80 °C for the LN2-based controlled rate freezers as well as for conduction cooling controlled rate freezers. Notably, CAR T-cells generated from cryopreserved leukapheresis materials using the conduction cooling controlled rate freezer exhibited suboptimal performance in certain donors at transfer temperatures lower than -60 °C, possibly due to the reduced cooling rate of lower than 1 °C/min and extended dwelling time needed to reach the final temperatures within these systems. This cohort of data suggests that there is a low risk to transfer cryopreserved leukapheresis materials at higher temperatures (between -30 °C and -60 °C) with good functional recovery using either controlled cooling system, and the cryopreserved materials are suitable to use as the starting material for autologous CAR T-cell therapies.

Asunto(s)

Criopreservación , Inmunoterapia Adoptiva , Leucaféresis , Linfocitos T , Criopreservación/métodos , Leucaféresis/métodos , Humanos , Linfocitos T/citología , Linfocitos T/inmunología , Inmunoterapia Adoptiva/métodos , Receptores Quiméricos de Antígenos , Temperatura , Congelación , Técnicas de Cultivo de Célula/métodos

RESUMEN

BACKGROUND: The evolutionarily conserved protein FBXO9 acts as a substrate receptor for the SKP1-cullin-1-RBX1 ubiquitin ligase and is implicated in cancer, exhibiting either tumor-suppressive or oncogenic effects depending on the specific tumor type. However, their role in lung cancer metastasis remains unclear. METHODS: Lentiviral vectors carrying miRNA-based shRNA sequences for gene-specific knockdown were generated, and Lenti-CRISPR-Cas9 vectors containing gene-specific sgRNA sequences were designed. Gene overexpression was achieved using doxycycline-inducible lentiviral constructs, while gene knockdown or knockout cells were generated using shRNA and CRISPR-Cas9, respectively. Functional assays included migration, clonogenic survival assays, tumor sphere assays, and protein interaction studies using mass spectrometry, immunoprecipitation, and immunoblot analysis. RESULTS: This study identified FBXO9 as a crucial regulator that suppresses lung cancer cell migration, tumor sphere growth and restricts metastasis. We showed that FBXO9 facilitates the ubiquitination of the catalytic subunit A (ATP6V1A) of the Vacuolar-type H+-ATPase (V-ATPase), resulting in its interaction with the cytoplasmic chaperone HSPA8 and subsequent sequestration within the cytoplasm. This process hinders the assembly of functional V-ATPase, resulting in reduced vesicular acidification. In contrast, depletion of FBXO9 reduced ATP6V1A ubiquitination, resulting in increased V-ATPase assembly and vesicular acidification, thus promoting pro-metastatic Wnt signaling and metastasis of lung cancer cells. Furthermore, we demonstrated the effectiveness of inhibitors targeting V-ATPase in inhibiting lung cancer metastasis in a mouse model. Finally, we established a correlation between lower FBXO9 levels and poorer survival outcomes in patients with lung cancer. CONCLUSION: These findings collectively elucidate the critical role of FBXO9 in regulating V-ATPase assembly and provide a molecular basis for FBXO9's function in inhibiting lung cancer metastasis. This highlights the potential therapeutic opportunities of FBXO9 supplementation.

RESUMEN

BACKGROUND: Rheumatoid arthritis (RA) is a prevalent autoimmune disease marked by chronic synovitis as well as cartilage and bone destruction. Halofuginone hydrobromide (HF), a bioactive compound derived from the Chinese herbal plant Dichroa febrifuga Lour., has demonstrated substantial anti-arthritic effects in RA. Nevertheless, the molecular mechanisms responsible for the anti-RA effects of HF remain unclear. METHODS: This study employed a combination of network pharmacology, molecular docking, and experimental validation to investigate potential targets of HF in RA. RESULTS: Network pharmacology analyses identified 109 differentially expressed genes (DEGs) resulting from HF treatment in RA. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses unveiled a robust association between these DEGs and the IL-17 signaling pathway. Subsequently, a protein-protein interaction (PPI) network analysis revealed 10 core DEGs, that is, EGFR, MMP9, TLR4, ESR1, MMP2, PPARG, MAPK1, JAK2, STAT1, and MAPK8. Among them, MMP9 displayed the greatest binding energy for HF. In an in vitro assay, HF significantly inhibited the activity of inflammatory macrophages, and regulated the IL-17 signaling pathway by decreasing the levels of IL-17 C, p-NF-κB, and MMP9. CONCLUSION: In summary, these findings suggest that HF has the potential to inhibit the activation of inflammatory macrophages through its regulation of the IL-17 signaling pathway, underscoring its potential in the suppression of immune-mediated inflammation in RA.

Asunto(s)

Artritis Reumatoide , Metaloproteinasa 9 de la Matriz , Piperidinas , Quinazolinonas , Humanos , Simulación del Acoplamiento Molecular , Interleucina-17 , Farmacología en Red , Transducción de Señal , Artritis Reumatoide/tratamiento farmacológico

RESUMEN

PURPOSE: Temporomandibular joint osteoarthritis (TMJOA) is a common disease that negatively affects the life quality of human beings. Circadian rhythm acts an important role in life activities. However, whether the clock genes are rhythmic expressed in mandibular condylar chondrocytes, or the clock genes have an effect on the progression of TMJOA remains unknown. In this study, we aim to explore expression of clock genes and regulatory mechanism of TMJOA in rat mandibular condylar chondrocytes. METHODS: After synchronized by dexamethasone, the expression of core clock genes Per1, Per2, Clock, Cry1, Cry2 and Bmal1 and cartilage matrix degrading factor gene Mmp13 were analyzed in mandibular condylar chondrocytes every 4 h with RT-qPCR. The mandibular condylar chondrocytes were stimulated with IL-1ß, and expression of Per1, Mmp13, P65 and p-P65 was assessed by RT-qPCR and Western blot. Sh-Per1 lentivirus was used to assess the effect of clock gene Per1 in IL-1ß-induced chondrocytes, and expression of Mmp13, P65 and p-P65 was measured. After establishing a rat TMJOA model using unilateral anterior crossbite (UAC), micro-CT, H & E, Alcian Blue & Nuclear Fast Red and Safranin O & Fast Green, cartilage thickness was utilized to assess the damage of cartilage and subchondral bone. Immunohistochemistry of PER1, MMP13 and P65 was performed in condylar sections. RESULTS: All core clock genes and Mmp13 were rhythmically expressed. And Mmp13 expression curve was closed in phase and amplitude with Per1. After stimulation with IL-1ß, the expression of MMP13, PER1 and P65 and ratio of p-P65/P65 increased in condylar chondrocytes. After Per1 was down-regulated in condylar chondrocytes, the expression of MMP13 and P65 and ratio of p-P65/P65 decreased. Compared with the condyles of Sham group, the bony parameters of UAC group were significantly worse. The thickness of cartilage in UAC group significantly reduced. The modified Mankin scores and the expression of PER1, MMP13 and P65 in cartilage of UAC group significantly increased compared with Sham group. CONCLUSION: Core clock genes and Mmp13 are rhythmic expressed in rat mandibular condylar chondrocytes. PER1 can regulate the expression of MMP13 through NF-κB pathway in IL-1ß-induced mandibular condylar chondrocytes.

Asunto(s)

FN-kappa B , Osteoartritis , Animales , Ratas , Condrocitos/metabolismo , Cóndilo Mandibular/metabolismo , Metaloproteinasa 13 de la Matriz/genética , Metaloproteinasa 13 de la Matriz/metabolismo , FN-kappa B/metabolismo , Osteoartritis/genética , Osteoartritis/metabolismo , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Articulación Temporomandibular/metabolismo

RESUMEN

Heart failure (HF) is the terminal manifestation of various cardiovascular diseases. Recently, accumulating evidence has demonstrated that gut microbiota are involved in the development of various cardiovascular diseases. Gut microbiota and their metabolites might play a pivotal role in the development of HF. However, previous studies have rarely described the complex role of gut microbiota and their metabolites in HF. In this review, we mainly discussed bile acids (BAs), the metabolites of gut microbiota. We explained the mechanisms by which BAs are involved in the pathogenesis of HF. We also discussed the use of gut microbiota and BAs for treating HF in Chinese medicine, highlighting the advantages of Chinese medicine in treating HF.

Asunto(s)

Enfermedades Cardiovasculares , Microbioma Gastrointestinal , Insuficiencia Cardíaca , Humanos , Ácidos y Sales Biliares

RESUMEN

This study investigates the influence of chronotype on the prevalence of temporomandibular joint disorders (TMD) and the morphology of temporomandibular joint (TMJ). According to the Morningness-Eveningness Questionnaire-Self-Assessment, the participants were divided into morning group (n = 30), intermediate group (n = 83), and evening group (n = 30). Thirty participants were randomly selected from the intermediate group for subsequent examination and measurements. The morphology of TMJs was investigated using questionnaire and clinical examination form in Diagnostic Criteria for Temporomandibular Disorder. Meanwhile, the morphological results of TMJs were measured from cone-beam computed tomography images. The prevalence rate of TMD in the morning group (23%) was significantly lower than that in the intermediate group (56.7%), while there was no difference between the evening (53.4%) and intermediate groups. As to morphological measurements, there was no significant difference among three groups in mediolateral width of condylar process, anteroposterior width of condylar process, radius of condyle, medial joint space, lateral joint space, condylar stress angle, horizontal condylar inclination, width of glenoid fossa, depth of glenoid fossa, and posterior joint space, while there was a significant difference in horizontal condylar angle (p = 0.00490), articular eminence inclination (p < .0001), anterior joint space (p = 0.0163), and superior joint space (p = 0.0004). The morphology of TMJ in the morning group was better than that in the evening and intermediate groups. An association was found between TMD prevalence, temporomandibular morphology, and chronotype.

Asunto(s)

Cóndilo Mandibular , Trastornos de la Articulación Temporomandibular , Humanos , Cronotipo , Prevalencia , Ritmo Circadiano , Trastornos de la Articulación Temporomandibular/diagnóstico por imagen , Trastornos de la Articulación Temporomandibular/epidemiología

RESUMEN

According to previous theories of aggression, positive outcome expectancy for aggression can predict aggression, while moral disengagement and negative outcome expectancy for aggression may, respectively, serve as mediators and moderators in this prediction process. To test the hypothesis, Study 1 first developed the Aggression Outcome Expectancy Questionnaire and examined its two-factor structure, which consists of positive and negative outcome expectancy for aggression. Next, 677 college students were recruited to participate in Study 2 and were asked to complete the Aggression Outcome Expectancy Questionnaire, Civic Moral Disengagement Questionnaire, and Buss-Perry Aggression Questionnaire. The findings indicated the following: (1) The Aggression Outcome Expectancy Questionnaire for college students demonstrated acceptable reliability and construct validity, confirming the two-factor structure of aggression outcome expectancy. (2) After controlling for sex and age, moral disengagement partially mediated the relationship between positive outcome expectancy and aggression. (3) Negative outcome expectancy for aggression moderated the effect of positive outcome expectancy on aggression, as well as moral disengagement. Specifically, negative outcome expectancy for aggression attenuated the positive predictive effect of positive outcome expectancy on aggression and moral disengagement. In conclusion, the present study extends our understanding of the motivational mechanism of aggression, offering a theoretical reference for preventing and intervening in aggressive behavior among college students.

RESUMEN

BACKGROUND: Xin-tong-tai Granule (XTTG), a traditional Chinese medicine, has been used to treat atherosclerosis (AS), but its mechanism is poorly understood. Intriguingly, oxidative stress has been recognized as vital factors in the treatment of atherosclerosis. PURPOSE: This study aims to explore the potential mechanism of XTTG for treating AS. METHODS: An in-vivo model of AS was established by feeding ApoE-/- mice with a high-fat diet (HFD), and the Human Aortic Vascular Smooth Muscle Cells (HAVSMCs) were induced by oxidized low-density lipoprotein (ox-LDL) in vitro. After treatment, the blood lipid levels and pathological aortic changes of each group were observed, and the cell proliferation and lipid droplet aggregation in each group were evaluated. The oxidative stress indicators such as malondialdehyde (MDA) and superoxide dismutase (SOD) levels and related NOX/ROS/NF-κB signaling pathway indicators were observed. RESULTS: XTTG improved blood lipid levels and pathological aortic changes of ApoE-/- mice with HFD feeding, inhibited HAVSMCs proliferation and lipid droplet aggregation induced by ox-LDL, reduced MDA content, increased SOD content, inhibited NOX4 and p22phox protein expression, downregulated ROS content, inhibited IKK-α, IKK-ß, NF-κB protein and mRNA expression and the phosphorylation of NF-κB. CONCLUSION: XTTG can inhibit NOX/ROS/NF-κB signaling pathway, reduce damages caused by oxidative stress, and exert anti-AS effects.

Asunto(s)

Aterosclerosis , Medicamentos Herbarios Chinos , Estrés Oxidativo , Transducción de Señal , Animales , Humanos , Ratones , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/prevención & control , Aterosclerosis/genética , Lipoproteínas LDL/farmacología , FN-kappa B/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/metabolismo , Medicamentos Herbarios Chinos/farmacología

RESUMEN

The techniques that harvest mechanical energy from low-frequency, multidirectional environmental vibrations have been considered a promising strategy to implement a sustainable power source for wireless sensor networks and the Internet of Things. However, the obvious inconsistency in the output voltage and operating frequency among different directions may bring a hindrance to energy management. To address this issue, this paper reports a cam-rotor-based approach for a multidirectional piezoelectric vibration energy harvester. The cam rotor can transform vertical excitation into a reciprocating circular motion, producing a dynamic centrifugal acceleration to excite the piezoelectric beam. The same beam group is utilized when harvesting vertical and horizontal vibrations. Therefore, the proposed harvester reveals similar characterization in its resonant frequency and output voltage at different working directions. The structure design and modeling, device prototyping and experimental validation are conducted. The results show that the proposed harvester can produce a peak voltage of up to 42.4 V under a 0.2 g acceleration with a favorable power of 0.52 mW, and the resonant frequency for each operating direction is stable at around 3.7 Hz. Practical applications in lighting up LEDs and powering a WSN system demonstrate the promising potential of the proposed approach in capturing energy from ambient vibrations to construct self-powered engineering systems for structural health monitoring, environmental measuring, etc.

RESUMEN

Periodontal ligament stem cells (PDLSCs) are considered ideal cell sources for the regeneration of periodontal and alveolar bone tissue. Cytoskeleton Regulator RNA (CYTOR), a newly discovered long noncoding RNA, has been reported to function as competing endogenous RNA (ceRNA) and to be involved in many biological processes. However, its roles in PDLSC osteogenic differentiation remain unclear. Here, we firstly found CYTOR was mainly sublocalized in the cytoplasm of PDLSCs and CYTOR expression was increased during osteogenic differentiation of PDLSCs. By employing gain- and loss-of-function approaches, we then identified CYTOR overexpression promoted osteogenic differentiation of PDLSCs while CYTOR knockdown inhibited this process. Furthermore, bioinformatics analysis was utilized to show that both CYTOR and SOX11 mRNA contained the same seed sites for miR-6512-3p, which was further confirmed by dual luciferase reporter assay and RNA-binding protein immunoprecipitation. Notably, CYTOR conferred its functions by directly binding to miR-6512-3p and an inverse correlation between CYTOR and miR-6512-3p on the level on SOX11 and osteogenic differentiation of PDLSCs was obtained. Additionally, miR-6512-3p could bind to SOX11 mRNA 3' UTR and repressed SOX11 expression. Moreover, level of SOX11 was significantly increased during osteogenic differentiation of PDLSCs. Knockdown of SOX11 attenuated the increasing effect of CYTOR overexpression on osteogenic differentiation of PDLSCs. Collectively, these data supported that CYTOR positively modulated the expression of SOX11 through competitively binding to miR-6512-3p, thus promoting osteogenic differentiation of PDLSCs. The CYTOR/miR-6512-3p/SOX11 axis could be a novel therapeutic target for periodontal regeneration medicine.

RESUMEN

In order to collect mechanical energy from human motions on pavement without an obvious disturbance, a piezoelectric harvester for small displacement is proposed. A seesaw mechanism is utilized to transmit the pressure displacement to piezoelectric beams. Benefitting from the superiority of used axially deformed beams, the designed scheme can produce a higher voltage than the ones based on the conventional bending cantilever. Favorable electrical energy is achieved by the manufactured prototype under a displacement lower than 1 mm. Two practical applications, including charging a capacitor and powering an environmental sensing node, demonstrate the feasibility of this energy harvester in supplying power for engineering devices. The proposed device shows a favorable capacity to capture energy from humans walking on pavements. Also, this category of axially deformed beam could provide ideas for developing piezoelectric harvesters under small displacements.

RESUMEN

Positive outcome expectancy is a crucial cognitive factor influencing aggression, yet its neural basis remains unclear. Therefore, the present study combined voxel-based morphometry (VBM) with a resting-state functional connectivity (RSFC) analysis to investigate the brain correlates of positive outcome expectancy in aggression in young people. In the VBM analysis, multiple linear regression was conducted to explore the relationship between individual differences in aggressive positive outcome expectancy and regional gray matter volume (GMV) among 325 undergraduate students. For the RSFC analysis, seed regions were selected based on the results of the VBM analysis. Subsequently, multiple linear regression was employed to examine whether a significant correlation existed between individual differences in aggressive positive outcome expectancy and the RSFC of seed regions with other brain regions in 304 undergraduate students. The findings indicated that aggressive positive outcome expectancy was positively correlated with GMV in the posterior cingulate cortex (PCC), right temporoparietal junction (TPJ), and medial prefrontal cortex (MPFC). Moreover, it was also positively associated with RSFC between the PCC and the left dorsolateral prefrontal cortex (DLPFC). The prediction analysis indicated robust relationships between aggressive positive outcome expectancy and the GMV in the PCC, right TPJ, as well as the RSFC between the PCC and the left DLPFC. Our research provides the initial evidence for the neural basis of positive outcome expectancy in aggression, suggesting the potential role of the PCC as a hub in its neural network.