RESUMEN

Intervertebral disc (IVD) degeneration damaging the extracellular matrix (ECM) of IVDs is the main cause of spine-associated disorders. Degenerative disc disease (DDD) is a multifaceted disorder, where environmental factors, inflammatory cytokines and catabolic enzymes act together. DDD starts typically due to imbalance between ECM biosynthesis and degradation within IVDs, especially through unbalanced degradation of aggrecan and collagen II in nucleus pulposus (NP). Current treatment approaches are primarily based on conservative or surgical therapies, which are insufficient for biological regeneration. The disintegrins and metalloproteinases with thrombospondin motifs (ADAMTSs) and matrix metalloproteinases (MMPs) are the key proteolytic enzymes for degradation of aggrecan and collagens. Previously, high expression levels of ADAMTS4, ADAMTS5, MMP3 and MMP13, which are accompanied with low levels of aggrecan and collagen II, were demonstrated in degenerative human NP cells. Moreover, self-complementary adeno-associated virus type 6 (scAAV6) mediated inhibitions of ADAMTS4 and ADAMTS5 by RNA-interference (RNAi) could specifically enhance aggrecan level. Thus, MMPs are apparently the main degrading enzymes of collagen II in NP. Furthermore, scAAV6-mediated inhibitions of MMP3 and MMP13 have not yet been investigated. Therefore, we attempted to enhance the level of collagen II in degenerative NP cells by scAAV6-RNAi-mediated inhibitions of MMP3 and MMP13. MRI was used to determine preoperative grading of IVD degeneration in patients. After isolation and culturing of NP cells, cells were transduced with scAAV6-shRNAs targeting MMP3 or MMP13; and analysed by fluorescence microscopy, FACS, MTT assay, RT-qPCR, ELISA and western blotting. scAAV6-shRNRs have no impact on cell viability and proliferation, despite high transduction efficiencies (98.6%) and transduction units (1383 TU/Cell). Combined knockdown of MMP3 (92.8%) and MMP13 (90.9%) resulted in highest enhancement of collagen II (143.2%), whereby treatment effects were significant over 56 days (p < 0.001). Conclusively, scAAV6-RNAi-mediated inhibitions of MMP3 and MMP13 help to progress less immunogenic and enduring biological treatments in DDD.

Asunto(s)

Proteína ADAMTS4 , Degeneración del Disco Intervertebral , Metaloproteinasa 13 de la Matriz , Metaloproteinasa 3 de la Matriz , Núcleo Pulposo , Metaloproteinasa 3 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/genética , Humanos , Metaloproteinasa 13 de la Matriz/metabolismo , Degeneración del Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/terapia , Degeneración del Disco Intervertebral/patología , Degeneración del Disco Intervertebral/genética , Núcleo Pulposo/metabolismo , Núcleo Pulposo/patología , Proteína ADAMTS4/metabolismo , Proteína ADAMTS4/genética , Colágeno Tipo II/metabolismo , Dependovirus/genética , Dependovirus/metabolismo , Proteína ADAMTS5/metabolismo , Proteína ADAMTS5/genética , Interferencia de ARN , Células Cultivadas , Agrecanos/metabolismo

RESUMEN

Sensory experiences and learning induce long-lasting changes in both excitatory and inhibitory synapses, thereby providing a crucial substrate for memory. However, the co-tuning of excitatory long-term potentiation (eLTP) or depression (eLTD) with the simultaneous changes at inhibitory synapses (iLTP/iLTD) remains unclear. Herein, we investigated the co-expression of NMDA-induced synaptic plasticity at excitatory and inhibitory synapses in hippocampal CA1 pyramidal cells (PCs) using a combination of electrophysiological, optogenetic, and pharmacological approaches. We found that inhibitory inputs from somatostatin (SST) and parvalbumin (PV)-positive interneurons onto CA1 PCs display input-specific long-term plastic changes following transient NMDA receptor activation. Notably, synapses from SST-positive interneurons consistently exhibited iLTP, irrespective of the direction of excitatory plasticity, whereas synapses from PV-positive interneurons predominantly showed iLTP concurrent with eLTP, rather than eLTD. As neuroplasticity is known to depend on the extracellular matrix, we tested the impact of metalloproteinases (MMP) inhibition. MMP3 blockade interfered with GABAergic plasticity for all inhibitory inputs, whereas MMP9 inhibition selectively blocked eLTP and iLTP in SST-CA1PC synapses co-occurring with eLTP but not eLTD. These findings demonstrate the dissociation of excitatory and inhibitory plasticity co-expression. We propose that these mechanisms of plasticity co-expression may be involved in maintaining excitation-inhibition balance and modulating neuronal integration modes.

Asunto(s)

Interneuronas , Plasticidad Neuronal , Células Piramidales , Animales , Plasticidad Neuronal/fisiología , Interneuronas/metabolismo , Células Piramidales/metabolismo , Células Piramidales/fisiología , N-Metilaspartato/metabolismo , N-Metilaspartato/farmacología , Hipocampo/metabolismo , Hipocampo/fisiología , Parvalbúminas/metabolismo , Masculino , Ratones , Somatostatina/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis/metabolismo , Sinapsis/fisiología , Potenciación a Largo Plazo , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/efectos de los fármacos , Región CA1 Hipocampal/metabolismo , Región CA1 Hipocampal/fisiología , Metaloproteinasa 9 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/genética

RESUMEN

OBJECTIVE: To investigate the therapeutic mechanism of Tujia medicine Toddalia asiatica alcohol extract (TAAE) for synovial pannus formation in rats with college-induced arthritis (CIA). METHODS: Sixty male SD rats were randomized into normal control group, CIA model group, TGT group, 3 TAAE treatment groups at low, medium and high doses (n=10). Except for those in the normal control group, all the rats were subjected to CIA modeling using a secondary immunization method and treatment with saline, TGT or TAAE by gavage once daily for 35 days. The severity of arthritis was assessed using arthritis index (AI) score, and knee joint synovium pathologies were examined with HE staining. Serum levels of TNF-α, IL-6, and IL-1ß were detected with ELISA; the protein expressions of PI3K, Akt, p-PI3K, p-Akt, VEGF, endostatin, HIF-1α, MMP1, MMP3, and MMP9 in knee joint synovial tissues were determined using Western blotting, and the mRNA expressions of TNF­α, IL-6, IL-1ß, VEGF, HIF-1α, PI3K, and Akt were detected with RT-PCR. RESULTS: Treatment of CIA rat models with TAAE and TGT significantly alleviated paw swelling, lowered AI scores, and reduced knee joint pathology, neoangiogenesis, and serum levels of inflammatory factors. TAAE treatment obviously increased endostatin protein expression, downregulated p-PI3K, p-Akt, MMP1, MMP3, MMP9, VEGF, and HIF-1α proteins, and reduced TNF­α, IL-6, IL-1ß, PI3K, Akt, VEGF, and HIF-1α mRNA levels in the synovial tissues, and these changes were comparable between high-dose TAAE group and TGT group. CONCLUSION: TAAE can improve joint symptoms and inhibit synovial pannus formation in CIA rats by regulating the expressions of HIF-1α, VEGF, endostatin, MMP1, MMP3, and MMP9 via the PI3K/Akt signalling pathway.

Asunto(s)

Artritis Experimental , Subunidad alfa del Factor 1 Inducible por Hipoxia , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Ratas Sprague-Dawley , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular , Animales , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/metabolismo , Ratas , Transducción de Señal/efectos de los fármacos , Masculino , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Interleucina-6/metabolismo , Interleucina-1beta/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Metaloproteinasa 1 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Endostatinas , Membrana Sinovial/metabolismo , Medicamentos Herbarios Chinos/uso terapéutico , Medicamentos Herbarios Chinos/farmacología

RESUMEN

Matrix metalloproteinases (MMPs) such as MMP-9, 3, and 2 degrade the cellular matrix and are believed to play a crucial role in ischemic stroke. We examined how the duration of ischemia (up to 4 h) and treatment with recombinant tissue plasminogen activator altered the comparative expression of these MMPs in experimental ischemic stroke with reperfusion. Both prolonged ischemia and r-tPA treatment markedly increased MMP-9 expression in the ischemic hemisphere (all p < 0.0001). The duration of ischemia and r-tPA treatment also significantly increased MMP-2 expression (p < 0.01-0.001) in the ischemic hemisphere (p < 0.01) but to a lesser degree than MMP-9. In contrast, MMP-3 expression significantly decreased in the ischemic hemisphere (p < 0.001) with increasing duration of ischemia and r-tPA treatment (p < 0.05-0001). MMP-9 expression was prominent in the vascular compartment and leukocytes. MMP-2 expression was evident in the vascular compartment and MMP-3 in NeuN+ neurons. Prolonging the duration of ischemia (up to 4 h) before reperfusion increased brain hemorrhage, infarction, swelling, and neurologic disability in both saline-treated (control) and r-tPA-treated mice. MMP-9 and MMP-2 expression were significantly positively correlated with, and MMP-3 was significantly negatively correlated with, infarct volume, swelling, and brain hemorrhage. We conclude that in experimental ischemic stroke with reperfusion, the duration of ischemia and r-tPA treatment significantly altered MMP-9, 3, and 2 expression, ischemic brain injury, and neurological disability. Each MMP showed unique patterns of expression that are strongly correlated with the severity of brain infarction, swelling, and hemorrhage. In summary, in experimental ischemic stroke in male mice with reperfusion, the duration of ischemia, and r-tPA treatment significantly altered the immunofluorescent expression of MMP-9, 3, and 2, ischemic brain injury, and neurological disability. In this model, each MMP showed unique patterns of expression that were strongly correlated with the severity of brain infarction, swelling, and hemorrhage.

Asunto(s)

Isquemia Encefálica , Metaloproteinasa 2 de la Matriz , Metaloproteinasa 3 de la Matriz , Metaloproteinasa 9 de la Matriz , Activador de Tejido Plasminógeno , Animales , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/metabolismo , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/patología , Factores de Tiempo

RESUMEN

Atractylodes lancea which was listed in "Shennong's Materia Medica" and could be used to treat gastrointestinal-associated diseases. However, its roles, core and active ingredients, and mechanisms in treatment of colorectal cancer (CRC) were still unknown. Therefore, network pharmacology and experimental validation were used to clarify the effects, core active ingredients and molecular mechanisms of Atractylodes lancea. We found that Atractylodes lancea has 28 effective active components and 213 potential targets. Seventy-three genes which demonstrate interaction between the Atractylodes lancea and CRC were confirmed. Enrichment analysis showed that 2033 GO biological process items and 144 KEGG pathways. Survival and molecular docking analysis revealed that luteolin as the core component interacted with these genes (Matrix metalloproteinase 3 (MMP3), Matrix metalloproteinase 9 (MMP9), Tissue inhibitor of metalloproteinases 1 (TIMP1), Vascular endothelial growth factor A (VEGFA)) with the lowest binding energy, and these genes were involved in building a prognostic model for CRC. Cellular phenotyping experiments showed that luteolin could inhibit the proliferation and migration of CRC cells and downregulate the expression of MMP3, MMP9, TIMP1, VEGFA probably by Phosphoinositide 3-kinase/ serine/threonine kinase Akt (PI3K/AKT) pathway. To conclude, Atractylodes lancea could inhibit proliferation and migration of CRC cells through its core active ingredient (luteolin) to suppress the expression of MMP3, MMP9, TIMP1, VEGFA probably by PI3K/AKT pathway.

Asunto(s)

Atractylodes , Neoplasias Colorrectales , Luteolina , Simulación del Acoplamiento Molecular , Farmacología en Red , Atractylodes/química , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/genética , Humanos , Luteolina/farmacología , Proliferación Celular/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Movimiento Celular/efectos de los fármacos , Metaloproteinasa 9 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Transducción de Señal/efectos de los fármacos , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Inhibidor Tisular de Metaloproteinasa-1/genética , Línea Celular Tumoral , Medicamentos Herbarios Chinos/farmacología , Metaloproteinasa 3 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Antineoplásicos Fitogénicos/farmacología

RESUMEN

Ischemic stroke followed by reperfusion (IR) leads to extensive cerebrovascular injury characterized by neuroinflammation and brain cell death. Inhibition of matrix metalloproteinase-3 (MMP-3) emerges as a promising therapeutic approach to mitigate IR-induced stroke injury. We employed middle cerebral artery occlusion with subsequent reperfusion (MCAO/R) to model ischemic stroke in adult mice. Specifically, we investigated the impact of MMP-3 knockout (KO) on stroke pathophysiology using RNA sequencing (RNA-seq) of stroke brains harvested 48 h post-MCAO. MMP-3 KO significantly reduced brain infarct size following stroke. Notably, RNA-seq analysis showed that MMP-3 KO altered expression of 333 genes (252 downregulated) in male stroke brains and 3768 genes (889 downregulated) in female stroke brains. Functional pathway analysis revealed that inflammation, integrin cell surface signaling, endothelial- and epithelial-mesenchymal transition (EndMT/EMT), and apoptosis gene signatures were decreased in MMP-3 KO stroke brains. Intriguingly, MMP-3 KO downregulated gene signatures more profoundly in females than in males, as indicated by greater negative enrichment scores. Our study underscores MMP-3 inhibition as a promising therapeutic strategy, impacting multiple cellular pathways following stroke.

Asunto(s)

Infarto Cerebral , Modelos Animales de Enfermedad , Accidente Cerebrovascular Isquémico , Metaloproteinasa 3 de la Matriz , Ratones Noqueados , Animales , Metaloproteinasa 3 de la Matriz/genética , Metaloproteinasa 3 de la Matriz/metabolismo , Masculino , Femenino , Ratones , Accidente Cerebrovascular Isquémico/genética , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/patología , Infarto Cerebral/genética , Infarto Cerebral/patología , Infarto Cerebral/metabolismo , Infarto de la Arteria Cerebral Media/genética , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/patología , Ratones Endogámicos C57BL , Transcriptoma , Regulación de la Expresión Génica , Encéfalo/metabolismo , Encéfalo/patología

RESUMEN

BACKGROUND: The increasing production and usage of copper oxide nanoparticles (Nano-CuO) raise human health concerns. Previous studies have demonstrated that exposure to Nano-CuO could induce lung inflammation, injury, and fibrosis. However, the potential underlying mechanisms are still unclear. Here, we proposed that matrix metalloproteinase-3 (MMP-3) might play an important role in Nano-CuO-induced lung inflammation, injury, and fibrosis. RESULTS: Exposure of mice to Nano-CuO caused acute lung inflammation and injury in a dose-dependent manner, which was reflected by increased total cell number, neutrophil count, macrophage count, lactate dehydrogenase (LDH) activity, and CXCL1/KC level in bronchoalveolar lavage fluid (BALF) obtained on day 3 post-exposure. The time-response study showed that Nano-CuO-induced acute lung inflammation and injury appeared as early as day 1 after exposure, peaked on day 3, and ameliorated over time. However, even on day 42 post-exposure, the LDH activity and macrophage count were still higher than those in the control group, suggesting that Nano-CuO caused chronic lung inflammation. The Nano-CuO-induced pulmonary inflammation was further confirmed by H&E staining of lung sections. Trichrome staining showed that Nano-CuO exposure caused pulmonary fibrosis from day 14 to day 42 post-exposure with an increasing tendency over time. Increased hydroxyproline content and expression levels of fibrosis-associated proteins in mouse lungs were also observed. In addition, Nano-CuO exposure induced MMP-3 overexpression and increased MMP-3 secretion in mouse lungs. Knocking down MMP-3 in mouse lungs significantly attenuated Nano-CuO-induced acute and chronic lung inflammation and fibrosis. Moreover, Nano-CuO exposure caused sustained production of cleaved osteopontin (OPN) in mouse lungs, which was also significantly decreased by knocking down MMP-3. CONCLUSIONS: Our results demonstrated that short-term Nano-CuO exposure caused acute lung inflammation and injury, while long-term exposure induced chronic pulmonary inflammation and fibrosis. Knocking down MMP-3 significantly ameliorated Nano-CuO-induced pulmonary inflammation, injury, and fibrosis, and also attenuated Nano-CuO-induced cleaved OPN level. Our study suggests that MMP-3 may play important roles in Nano-CuO-induced pulmonary inflammation and fibrosis via cleavage of OPN and may provide a further understanding of the mechanisms underlying Nano-CuO-induced pulmonary toxicity.

Asunto(s)

Líquido del Lavado Bronquioalveolar , Cobre , Metaloproteinasa 3 de la Matriz , Neumonía , Fibrosis Pulmonar , Animales , Cobre/toxicidad , Metaloproteinasa 3 de la Matriz/metabolismo , Ratones , Neumonía/inducido químicamente , Neumonía/patología , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/patología , Líquido del Lavado Bronquioalveolar/química , Ratones Endogámicos C57BL , Pulmón/patología , Pulmón/efectos de los fármacos , Masculino , Nanopartículas del Metal/toxicidad , Nanopartículas del Metal/química

RESUMEN

The intron retention (IR) is a phenomenon utilized by cells to allow diverse fates at the same mRNA, leading to a different pattern of synthesis of the same protein. In this study, we analyzed the modulation of phosphoinositide-specific phospholipase C (PI-PLC) enzymes by Harpagophytum procumbens extract (HPE) in synoviocytes from joins of osteoarthritis (OA) patients. In some samples, the PI-PLC γ1 isoform mature mRNA showed the IR and, in these synoviocytes, the HPE treatment increased the phenomenon. Moreover, we highlighted that as a consequence of IR, a lower amount of PI-PLC γ1 was produced. The decrease of PI-PLC γ1 was associated with the decrease of metalloprotease-3 (MMP-3), and MMP-13, and ADAMTS-5 after HPE treatment. The altered expression of MMPs is a hallmark of the onset and progression of OA, thus substances able to decrease their expression are very desirable. The interesting outcomes of this study are that 35% of analyzed synovial tissues showed the IR phenomenon in the PI-PLC γ1 mRNA and that the HPE treatment increased this phenomenon. For the first time, we found that the decrease of PI-PLC γ1 protein in synoviocytes interferes with MMP production, thus affecting the pathways involved in the MMP expression. This finding was validated by the silencing of PI-PLC γ1 in synoviocytes where the IR phenomenon was not present. Our results shed new light on the biochemical mechanisms involved in the degrading enzyme production in the joint of OA patients, suggesting a new therapeutic target and highlighting the importance of personalized medicine.

Asunto(s)

Fibroblastos , Intrones , Fosfolipasa C gamma , ARN Mensajero , Humanos , ARN Mensajero/metabolismo , ARN Mensajero/genética , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Fosfolipasa C gamma/metabolismo , Fosfolipasa C gamma/genética , Células Cultivadas , Osteoartritis/metabolismo , Osteoartritis/patología , Membrana Sinovial/metabolismo , Membrana Sinovial/citología , Membrana Sinovial/efectos de los fármacos , Metaloproteinasa 3 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/genética , Proteína ADAMTS5/metabolismo , Proteína ADAMTS5/genética , Sinoviocitos/metabolismo , Sinoviocitos/efectos de los fármacos , Metaloproteinasa 13 de la Matriz/metabolismo , Metaloproteinasa 13 de la Matriz/genética

RESUMEN

Rheumatoid arthritis is a chronic inflammatory disease that shows characteristic diurnal variation in symptom severity, where joint resident fibroblast-like synoviocytes (FLS) act as important mediators of arthritis pathology. We investigate the role of FLS circadian clock function in directing rhythmic joint inflammation in a murine model of inflammatory arthritis. We demonstrate FLS time-of-day-dependent gene expression is attenuated in arthritic joints, except for a subset of disease-modifying genes. The deletion of essential clock gene Bmal1 in FLS reduced susceptibility to collagen-induced arthritis but did not impact symptomatic severity in affected mice. Notably, FLS Bmal1 deletion resulted in loss of diurnal expression of disease-modulating genes across the joint, and elevated production of MMP3, a prognostic marker of joint damage in inflammatory arthritis. This work identifies the FLS circadian clock as an influential driver of daily oscillations in joint inflammation, and a potential regulator of destructive pathology in chronic inflammatory arthritis.

Asunto(s)

Factores de Transcripción ARNTL , Artritis Experimental , Ritmo Circadiano , Fibroblastos , Sinoviocitos , Animales , Sinoviocitos/metabolismo , Sinoviocitos/patología , Ratones , Factores de Transcripción ARNTL/genética , Factores de Transcripción ARNTL/metabolismo , Artritis Experimental/patología , Artritis Experimental/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patología , Relojes Circadianos/genética , Metaloproteinasa 3 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/genética , Inflamación/metabolismo , Inflamación/patología , Inflamación/genética , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Ratones Noqueados , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Masculino

RESUMEN

BACKGROUND: Imbalanced intestinal microbiota and damage to the intestinal barrier contribute to the development of necrotizing enterocolitis (NEC). Autoinducer-2 (AI-2) plays a crucial role in repairing intestinal damage and reducing inflammation. OBJECTIVE: This study aimed to investigate the impact of AI-2 on the expression of intestinal zonula occludens-1 (ZO-1) and occludin proteins in NEC. We evaluated its effects in vivo using NEC mice and in vitro using lipopolysaccharide (LPS)-stimulated intestinal cells. METHODS: Pathological changes in the intestines of neonatal mice were assessed using histological staining and scoring. Cell proliferation was measured using the cell counting kit-8 (CCK-8) assay to determine the optimal conditions for LPS and AI-2 interventions. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to analyze the mRNA levels of matrix metalloproteinase-3 (MMP3), protease activated receptor-2 (PAR2), interleukin-1ß (IL-1ß), and IL-6. Protein levels of MMP3, PAR2, ZO-1, and occludin were evaluated using western blot, immunohistochemistry, or immunofluorescence. RESULTS: AI-2 alleviated NEC-induced intestinal damage (P < 0.05) and enhanced the proliferation of damaged IEC-6 cells (P < 0.05). AI-2 intervention reduced the mRNA and protein expressions of MMP3 and PAR2 in intestinal tissue and cells (P < 0.05). Additionally, it increased the protein levels of ZO-1 and occludin (P < 0.05), while reducing IL-1ß and IL-6 mRNA expression (P < 0.05). CONCLUSION: AI-2 intervention enhances the expression of tight junction proteins (ZO-1 and occludin), mitigates intestinal damage in NEC neonatal mice and IEC-6 cells, potentially by modulating PAR2 and MMP3 signaling. AI-2 holds promise as a protective intervention for NEC. AI-2 plays a crucial role in repairing intestinal damage and reducing inflammation.

Asunto(s)

Enterocolitis Necrotizante , Metaloproteinasa 3 de la Matriz , Receptor PAR-2 , Transducción de Señal , Animales , Humanos , Ratones , Animales Recién Nacidos , Línea Celular , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Enterocolitis Necrotizante/patología , Enterocolitis Necrotizante/tratamiento farmacológico , Enterocolitis Necrotizante/metabolismo , Homoserina/análogos & derivados , Homoserina/farmacología , Mucosa Intestinal/patología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/inmunología , Intestinos/patología , Intestinos/efectos de los fármacos , Lactonas/farmacología , Lipopolisacáridos , Metaloproteinasa 3 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/genética , Ratones Endogámicos C57BL , Ocludina/metabolismo , Ocludina/genética , Receptor PAR-2/metabolismo , Receptor PAR-2/genética , Transducción de Señal/efectos de los fármacos , Proteína de la Zonula Occludens-1/metabolismo , Proteína de la Zonula Occludens-1/genética

RESUMEN

Haemophilic arthropathy (HA), a common comorbidity in haemophilic patients leads to joint pain, deformity and reduced quality of life. We have recently demonstrated that a long non-coding RNA, Neat1 as a primary regulator of matrix metalloproteinase (MMP) 3 and MMP13 activity, and its induction in the target joint has a deteriorating effect on articular cartilage. In the present study, we administered an Adeno-associated virus (AAV) 5 vector carrying an short hairpin (sh)RNA to Neat1 via intra-articular injection alone or in conjunction with systemic administration of a capsid-modified AAV8 (K31Q) vector carrying F8 gene (F8-BDD-V3) to study its impact on HA. AAV8K31Q-F8 vector administration at low dose, led to an increase in FVIII activity (16%-28%) in treated mice. We further observed a significant knockdown of Neat1 (~40 fold vs. untreated injured joint, p = 0.005) in joint tissue of treated mice and a downregulation of chondrodegenerative enzymes, MMP3, MMP13 and the inflammatory mediator- cPLA2, in mice receiving combination therapy. These data demonstrate that AAV mediated Neat1 knockdown in combination with F8 gene augmentation can potentially impact mediators of haemophilic joint disease.

Asunto(s)

Dependovirus , Factor VIII , Vectores Genéticos , Hemofilia A , Metaloproteinasa 13 de la Matriz , Metaloproteinasa 3 de la Matriz , ARN Largo no Codificante , Animales , Hemofilia A/genética , Hemofilia A/terapia , Hemofilia A/complicaciones , Dependovirus/genética , ARN Largo no Codificante/genética , Metaloproteinasa 13 de la Matriz/metabolismo , Metaloproteinasa 13 de la Matriz/genética , Ratones , Metaloproteinasa 3 de la Matriz/genética , Metaloproteinasa 3 de la Matriz/metabolismo , Vectores Genéticos/genética , Vectores Genéticos/administración & dosificación , Factor VIII/genética , Factor VIII/metabolismo , Artropatías/terapia , Artropatías/genética , Artropatías/etiología , Humanos , Terapia Genética/métodos , Ratones Endogámicos C57BL , Cartílago Articular/metabolismo , Cartílago Articular/patología , Modelos Animales de Enfermedad , Masculino

RESUMEN

Keloids, marked by abnormal cellular proliferation and excessive extracellular matrix (ECM) accumulation, pose significant therapeutic challenges. Ethyl pyruvate (EP), an inhibitor of the high-mobility group box 1 (HMGB1) and TGF-ß1 pathways, has emerged as a potential anti-fibrotic agent. Our research evaluated EP's effects on keloid fibroblast (KF) proliferation and ECM production, employing both in vitro cell cultures and ex vivo patient-derived keloid spheroids. We also analyzed the expression levels of ECM components in keloid tissue spheroids treated with EP through immunohistochemistry. Findings revealed that EP treatment impedes the nuclear translocation of HMGB1 and diminishes KF proliferation. Additionally, EP significantly lowered mRNA and protein levels of collagen I and III by attenuating TGF-ß1 and pSmad2/3 complex expression in both human dermal fibroblasts and KFs. Moreover, metalloproteinase I (MMP-1) and MMP-3 mRNA levels saw a notable increase following EP administration. In keloid spheroids, EP induced a dose-dependent reduction in ECM component expression. Immunohistochemical and western blot analyses confirmed significant declines in collagen I, collagen III, fibronectin, elastin, TGF-ß, AKT, and ERK 1/2 expression levels. These outcomes underscore EP's antifibrotic potential, suggesting its viability as a therapeutic approach for keloids.

Asunto(s)

Fibroblastos , Queloide , Piruvatos , Esferoides Celulares , Humanos , Queloide/metabolismo , Queloide/patología , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Piruvatos/farmacología , Esferoides Celulares/efectos de los fármacos , Esferoides Celulares/metabolismo , Metaloproteinasa 1 de la Matriz/metabolismo , Metaloproteinasa 1 de la Matriz/genética , Factor de Crecimiento Transformador beta1/metabolismo , Proteína HMGB1/metabolismo , Proteína HMGB1/genética , Colágeno/metabolismo , Colágeno/biosíntesis , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Metaloproteinasa 3 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/genética , Matriz Extracelular/metabolismo , Matriz Extracelular/efectos de los fármacos , Colágeno Tipo I/metabolismo , Colágeno Tipo I/genética , Proteína Smad2/metabolismo , Proteína Smad2/genética , Proteína smad3/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Masculino

RESUMEN

KMT2C and KMT2D, encoding histone H3 lysine 4 methyltransferases, are among the most commonly mutated genes in triple-negative breast cancer (TNBC). However, how these mutations may shape epigenomic and transcriptomic landscapes to promote tumorigenesis is largely unknown. Here we describe that deletion of Kmt2c or Kmt2d in non-metastatic murine models of TNBC drives metastasis, especially to the brain. Global chromatin profiling and chromatin immunoprecipitation followed by sequencing revealed altered H3K4me1, H3K27ac and H3K27me3 chromatin marks in knockout cells and demonstrated enhanced binding of the H3K27me3 lysine demethylase KDM6A, which significantly correlated with gene expression. We identified Mmp3 as being commonly upregulated via epigenetic mechanisms in both knockout models. Consistent with these findings, samples from patients with KMT2C-mutant TNBC have higher MMP3 levels. Downregulation or pharmacological inhibition of KDM6A diminished Mmp3 upregulation induced by the loss of histone-lysine N-methyltransferase 2 (KMT2) and prevented brain metastasis similar to direct downregulation of Mmp3. Taken together, we identified the KDM6A-matrix metalloproteinase 3 axis as a key mediator of KMT2C/D loss-driven metastasis in TNBC.

Asunto(s)

Neoplasias Encefálicas , Regulación Neoplásica de la Expresión Génica , Histona Demetilasas , Metaloproteinasa 3 de la Matriz , Neoplasias de la Mama Triple Negativas , Regulación hacia Arriba , Animales , Humanos , Metaloproteinasa 3 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/genética , Histona Demetilasas/metabolismo , Histona Demetilasas/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Femenino , Línea Celular Tumoral , Ratones , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Ratones Noqueados , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Epigénesis Genética , Proteína de la Leucemia Mieloide-Linfoide

RESUMEN

Fibrosis is a ubiquitous pathology, and prior studies have indicated that various artemisinin (ART) derivatives (including artesunate (AS), artemether (AM), and dihydroartemisinin (DHA)) can reduce fibrosis in vitro and in vivo. The medicinal plant Artemisia annua L. is the natural source of ART and is widely used, especially in underdeveloped countries, to treat a variety of diseases including malaria. A. afra contains no ART but is also antimalarial. Using human dermal fibroblasts (CRL-2097), we compared the effects of A. annua and A. afra tea infusions, ART, AS, AM, DHA, and a liver metabolite of ART, deoxyART (dART), on fibroblast viability and expression of key fibrotic marker genes after 1 and 4 days of treatment. AS, DHA, and Artemisia teas reduced fibroblast viability 4 d post-treatment in up to 80% of their respective controls. After 4 d of treatment, AS DHA and Artemisia teas downregulated ACTA2 up to 10 fold while ART had no significant effect, and AM increased viability by 10%. MMP1 and MMP3 were upregulated by AS, 17.5 and 32.6 fold, respectively, and by DHA, 8 and 51.8 fold, respectively. ART had no effect, but A. annua and A. afra teas increased MMP3 5 and 16-fold, respectively. Although A. afra tea increased COL3A1 5 fold, MMP1 decreased >7 fold with no change in either transcript by A. annua tea. Although A. annua contains ART, it had a significantly greater anti-fibrotic effect than ART alone but was less effective than A. afra. Immunofluorescent staining for smooth-muscle α-actin (α-SMA) correlated well with the transcriptional responses of drug-treated fibroblasts. Together, proliferation, qPCR, and immunofluorescence results show that treatment with ART, AS, DHA, and the two Artemisia teas yield differing responses, including those related to fibrosis, in human dermal fibroblasts, with evidence also of remodeling of fibrotic ECM.

Asunto(s)

Artemisia , Artemisininas , Fibroblastos , Fibrosis , Humanos , Artemisininas/farmacología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Artemisia/química , Extractos Vegetales/farmacología , Extractos Vegetales/química , Supervivencia Celular/efectos de los fármacos , Metaloproteinasa 1 de la Matriz/metabolismo , Metaloproteinasa 1 de la Matriz/genética , Metaloproteinasa 3 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/genética , Actinas/metabolismo , Actinas/genética , Artesunato/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Arteméter/farmacología , Piel/efectos de los fármacos , Piel/metabolismo , Piel/patología

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) is a heterogeneous condition that encompasses a wide range of liver diseases that progresses from simple hepatic steatosis to the life-threatening state of cirrhosis. However, due to the heterogeneity of this disease, comprehensive analysis of several physicochemical and biological factors that drive its progression is necessary. Therefore, an in vitro platform is required that would enable real-time monitoring of these changes to better understand the progression of these diseases. The earliest stage of NAFLD, i.e. hepatic steatosis, is characterised by triglyceride accumulation in the form of lipid vacuoles in the cytosol of hepatocytes. This fatty acid accumulation is usually accompanied by hepatic inflammation, leading to tissue acidification and dysregulated expression of certain proteases such as matrix metalloproteinases (MMPs). Taking cues from the biological parameters of the disease, we report here a 3D in vitro GelMA/alginate microscaffold platform encapsulating a triple-marker (pH, MMP-3 and MMP-9) sensitive fluorescent nanoprobe for monitoring, and hence, distinguishing the fatty liver disease (hepatic steatosis) from healthy livers on the basis of pH change and MMP expression. The nanoprobe consists of a carbon nanoparticle (CNP) core, which exhibits intrinsic pH-dependent fluorescence properties, decorated either with an MMP-3 (NpMMP3) or MMP-9 (NpMMP9) sensitive peptide substrate. These peptide substrates are flanked with a fluorophore-quencher pair that separates on enzymatic cleavage, resulting in fluorescence emission. The cocktail of these nanoprobes generated multiple fluorescence signals corresponding to slightly acidic pH (blue) and overexpression of MMP-3 (green) and MMP-9 (red) enzymes in a 3D in vitro fatty liver model, whereas no/negligible fluorescence signals were observed in a healthy liver model. Moreover, this platform enabled us to mimic fatty liver disease in a more realistic manner. Therefore, this 3D in vitro platform encapsulating triple-marker sensitive fluorescent nanoprobes would facilitate the monitoring of the changes in pH and MMP expression, thereby enabling us to distinguish a healthy liver from a diseased liver and to study liver disease stages on the basis of these markers.

Asunto(s)

Metaloproteinasa 3 de la Matriz , Metaloproteinasa 9 de la Matriz , Enfermedad del Hígado Graso no Alcohólico , Metaloproteinasa 9 de la Matriz/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Humanos , Concentración de Iones de Hidrógeno , Metaloproteinasa 3 de la Matriz/metabolismo , Nanopartículas/química , Colorantes Fluorescentes/química , Alginatos/química , Células Hep G2 , Andamios del Tejido/química , Hepatocitos/metabolismo

RESUMEN

BACKGROUND AND AIM: Huangqin decoction (HQD) is a Chinese medicine used to treat colitis and colorectal cancer (CRC). However, the specific compounds and mechanisms of HQD remain unclear despite its good curative clinical results. Through bioinformatics, network pharmacology, and experiments, this study aims to explore the progressive mechanisms of colitis-associated colorectal cancer (CAC) from ulcerative colitis (UC) while examining the protective effects of HQD and its compounds against this. METHODS: Bioinformatics was utilized to identify the hub genes between UC and CRC, and their clinical predictive significance, function, and expression were validated. Employing network pharmacology in combination with hub genes, key targets of HQD for preventing the development of UC into CAC were identified. Molecular docking and molecular dynamics (MD) were utilized to procure compounds that effectively bind to these targets and their transcription factors (TFs). Finally, the expression and mechanism of key targets were demonstrated in mice with UC or CAC. RESULTS: (1) Joint analysis of UC and CRC gene sets resulted in 14 hub genes, mainly related to extracellular matrix receptor binding, biological processes in the extracellular matrix, focal adhesion and neutrophil migration; (2) Network pharmacology results show HQD has 133 core targets for treating UC and CRC, acting on extracellular matrix, inflammatory bowel disease, chemical carcinogen receptor activation and other pathways; (3) The intersection of hub genes and core targets yielded two key targets, MMP1 and MMP3; (4) STAT3 is a shared TF of MMP1 and MMP3. (5) Molecular docking and MD verified that the dockings between Glabridin and STAT3/MMP1/MMP3 are stable and reliable; (6) In murine vivo experiments verified that Glabridin reduces inflammation, extracellular matrix degradation, and the occurrence of epithelial-mesenchymal transition to prevent UC transforming into CAC by inhibiting the phosphorylation of STAT3 and regulating the activity of MMP1/3.

Asunto(s)

Colitis Ulcerosa , Medicamentos Herbarios Chinos , Isoflavonas , Metaloproteinasa 1 de la Matriz , Metaloproteinasa 3 de la Matriz , Simulación del Acoplamiento Molecular , Fenoles , Factor de Transcripción STAT3 , Animales , Isoflavonas/farmacología , Isoflavonas/uso terapéutico , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inducido químicamente , Metaloproteinasa 1 de la Matriz/genética , Metaloproteinasa 1 de la Matriz/metabolismo , Humanos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Metaloproteinasa 3 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/genética , Fenoles/uso terapéutico , Fenoles/farmacología , Ratones , Masculino , Factor de Transcripción STAT3/metabolismo , Neoplasias Asociadas a Colitis/tratamiento farmacológico , Neoplasias Asociadas a Colitis/prevención & control , Ratones Endogámicos C57BL , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/prevención & control , Modelos Animales de Enfermedad , Sulfato de Dextran

RESUMEN

Objective: To explore the early effectiveness and influence on cartilage of local injection of multimodal drug cocktail (MDC) during anterior cruciate ligament reconstruction (ACLR). Methods: Between February 2022 and August 2023, patients undergone arthroscopic ACLR using autologous hamstring tendons were selected as the study subjects. Among them, 90 patients met the selection criteria and were randomly divided into 3 groups ( n=30) according to the different injection drugs after ligament reconstruction. There was no significant difference in baseline data such as gender, age, body mass index, surgical side, disease duration, preoperative thigh circumference, and preoperative levels of tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), IL-1, matrix metalloproteinase 3 (MMP-3), MMP-13, and aggrecan (ACAN) in synovial fluid between groups ( P>0.05). After the ligament reconstruction during operation, corresponding MDC (consisting of ropivacaine, tranexamic acid, and betamethasone in group A, and ropivacaine, betamethasone, and saline in group B) or saline (group C) were injected into the joint and tendon site, respectively. The length of hospital stay, postoperative tramadol injection volume, incidence of complications, degree of knee joint swelling and range of motion, visual analogue scale (VAS) score, International Knee Documentation Committee (IKDC) score, Lyshlom score, and Hospital for Special Surgery (HSS) score were recorded and compared between groups. The T2 * values in different cartilage regions were detected by MRI examination and the levels of TNF-α, IL-6, IL-1, MMP-3, MMP-13, and ACAN in synovial fluid were detected by ELISA method. Results: The patients in group A, B, and C were followed up (12.53±3.24), (13.14±2.87), and (12.82±3.32) months, respectively. All incisions healed by first intention. Compared with group C, group A and group B had shorter length of hospital stay, less tramadol injection volume, and lower incidence of complications, showing significant differences ( P<0.05); there was no significant difference between group A and group B ( P>0.05). The degree of knee swelling in group A was significantly less than that in group B and group C ( P<0.05), but there was no significant difference between group B and group C ( P>0.05). At 3, 6, 12, 24, and 48 hours after operation, VAS scores of group A and group B were significantly lower than those of group C ( P<0.05); at 72 hours after operation, there was no significant difference among the three groups ( P>0.05). At 3 days, 14 days, and 1 month after operation, the range of motion of knee joint in group A were significantly better than those in group C ( P<0.05), and there was no significant difference between the other groups ( P>0.05). At 1 month after operation, the IKDC score of group A and group B was significantly higher than that of group C ( P<0.05); there was no significant difference among the three groups at other time points ( P>0.05). There was no significant difference in Lyshlom score and HSS score among the three groups at each time point ( P>0.05). At 14 days after operation, the levels of IL-1 and IL-6 in the synovial fluid in groups A and B were significantly lower than those in group C ( P<0.05). There was no significant difference in the levels of TNF-α, MMP-3, MMP-13, and ACAN between groups A and B ( P>0.05). At 1 month after operation, there was no significant difference in the above indicators among the three groups ( P>0.05). At 3, 6, and 12 months after operation, there was no significant difference in the T2 * values of different cartilage regions among the three groups ( P>0.05). Conclusion: Injecting MDC (ropivacaine, tranexamic acid, betamethasone) into the joint and tendon site during ACLR can achieve good early effectiveness without significant impact on cartilage.

Asunto(s)

Reconstrucción del Ligamento Cruzado Anterior , Betametasona , Ropivacaína , Humanos , Reconstrucción del Ligamento Cruzado Anterior/métodos , Ropivacaína/administración & dosificación , Masculino , Betametasona/administración & dosificación , Femenino , Adulto , Metaloproteinasa 3 de la Matriz/metabolismo , Anestésicos Locales/administración & dosificación , Artroscopía , Lesiones del Ligamento Cruzado Anterior/cirugía , Agrecanos/metabolismo , Metaloproteinasa 13 de la Matriz/metabolismo , Ligamento Cruzado Anterior/cirugía , Resultado del Tratamiento , Tendones/trasplante , Cartílago/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo

RESUMEN

BACKGROUND: The objectives of this research were to establish an animal model of adjacent segment degeneration (ASD) bordering lumbar fusion and to investigate the expression of autophagy factors in nucleus pulposus cells of adjacent intervertebral disks. MATERIALS AND METHODS: Twenty-four adult New Zealand white rabbits were enrolled and divided into two groups: group A (n=12) and group B (n=12). Posterolateral fusion and fixation were performed after intervertebral disk degeneration occurred in group A, and the rabbits were monitored for 6 months. Group B was the control group and did not undergo fusion surgery. These rabbits were monitored for 6 months. Real-time quantitative polymerase chain reaction and immunohistochemistry were performed to detect the mRNA and protein expressions of PTEN-induced kinase 1 (PINK1), Parkin, ADAMTS-4, and MMP-3. An external database, the GEO database, was used to examine the expression of these genes and analyze them for differential expression. RESULTS: After lumbar fusion in rabbits, the animal model of ASD exhibited gradual degeneration of adjacent intervertebral disks over time. Group A displayed significantly higher mRNA and protein expressions of PINK1 and MMP-3 but lower expression of ADAMTS-4 compared with group B (P<.05). The results analyzed in the GEO database showed that the expression of PINK1 was higher in group A than in group B, while the expression of ADAMTS-4 was lower in group A than in group B. CONCLUSION: After posterolateral lumbar fusion in rabbits, the animal ASD model showed gradual deterioration of adjacent intervertebral disks with prolonged follow-up. The findings indicate the important role of autophagy in the apoptosis of nucleus pulposus cells in adjacent intervertebral disks. [Orthopedics. 2024;47(4):e167-e173.].

Asunto(s)

Autofagia , Modelos Animales de Enfermedad , Degeneración del Disco Intervertebral , Vértebras Lumbares , Núcleo Pulposo , Fusión Vertebral , Animales , Conejos , Núcleo Pulposo/metabolismo , Núcleo Pulposo/patología , Degeneración del Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/patología , Degeneración del Disco Intervertebral/genética , Autofagia/fisiología , Vértebras Lumbares/cirugía , Vértebras Lumbares/patología , Proteína ADAMTS4/metabolismo , Proteína ADAMTS4/genética , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas Quinasas/metabolismo , Proteínas Quinasas/genética , Metaloproteinasa 3 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/genética , Masculino

RESUMEN

Osteoarthritis is the most prevalent type of degenerative arthritis. It is characterized by persistent pain, joint dysfunction, and physical disability. Pain relief and inflammation control are prioritised during osteoarthritis treatment Mume Fructus (Omae), a fumigated product of the Prunus mume fruit, is used as a traditional medicine in several Asian countries. However, its therapeutic mechanism of action and effects on osteoarthritis and articular chondrocytes remain unknown. In this study, we analyzed the anti-osteoarthritis and articular regenerative effects of Mume Fructus extract on rat chondrocytes. Mume Fructus treatment reduced the interleukin-1ß-induced expression of matrix metalloproteinase 3, matrix metalloproteinase 13, and a disintegrin and metalloproteinase with thrombospondin type 1 motifs 5. Additionally, it enhanced collagen type II alpha 1 chain and aggrecan accumulation in rat chondrocytes. Furthermore, Mume Fructus treatment regulated the inflammatory cytokine levels, mitogen-activated protein kinase phosphorylation, and nuclear factor-kappa B activation. Overall, our results demonstrated that Mume Fructus inhibits osteoarthritis progression by inhibiting the nuclear factor-kappa B and mitogen-activated protein kinase pathways to reduce the levels of inflammatory cytokines and prevent cartilage degeneration. Therefore, Mume Fructus may be a potential therapeutic option for osteoarthritis.

Asunto(s)

Cartílago Articular , Condrocitos , Interleucina-1beta , Osteoartritis , Extractos Vegetales , Prunus , Animales , Masculino , Ratas , Proteína ADAMTS5/metabolismo , Proteína ADAMTS5/genética , Agrecanos/metabolismo , Cartílago Articular/efectos de los fármacos , Cartílago Articular/metabolismo , Células Cultivadas , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Colágeno Tipo II/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Frutas/química , Interleucina-1beta/efectos de los fármacos , Interleucina-1beta/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Metaloproteinasa 13 de la Matriz/metabolismo , Metaloproteinasa 13 de la Matriz/genética , Metaloproteinasa 3 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/genética , Proteínas Quinasas Activadas por Mitógenos/metabolismo , FN-kappa B/efectos de los fármacos , FN-kappa B/metabolismo , Osteoartritis/tratamiento farmacológico , Osteoartritis/metabolismo , Osteoartritis/patología , Extractos Vegetales/farmacología , Prunus/química , Ratas Sprague-Dawley

Asunto(s)

Metaloproteinasa 3 de la Matriz , Calcificación Vascular , Humanos , Calcificación Vascular/enzimología , Calcificación Vascular/patología , Calcificación Vascular/metabolismo , Calcificación Vascular/genética , Animales , Metaloproteinasa 3 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/genética , Transducción de Señal , Inhibidores de la Metaloproteinasa de la Matriz/uso terapéutico , Inhibidores de la Metaloproteinasa de la Matriz/farmacología